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1.
Mol Psychiatry ; 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39215186

RESUMEN

Epigenetics plays a crucial role in regulating gene expression during adolescent brain maturation. In adolescents with depression, microglia-mediated chronic neuroinflammation may contribute to the activation of cellular signaling cascades and cause central synapse loss. However, the exact mechanisms underlying the epigenetic regulation of neuroinflammation leading to adolescent depression remain unclear. In this study, we found that the expression of polycomb group 1 (PCGF1), an important epigenetic regulator, was decreased both in the plasma of adolescent major depressive disorder (MDD) patients and in the microglia of adolescent mice in a mouse model of depression. We demonstrated that PCGF1 alleviates neuroinflammation mediated by microglia in vivo and in vitro, reducing neuronal damage and improving depression-like behavior in adolescent mice. Mechanistically, PCGF1 inhibits the transcription of MMP10 by upregulating RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, specifically inhibiting microglia-mediated neuroinflammation. These results provide valuable insights into the pathogenesis of adolescent depression, highlighting potential links between histone modifications, neuroinflammation and nerve damage. Potential mechanisms of microglial PCGF1 regulates depression-like behavior in adolescent mice. Microglial PCGF1 inhibits NF-κB/MAPK pathway activation through regulation of RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, which attenuates neuroinflammation and ameliorates depression-like behaviors in adolescent mice.

2.
Ecotoxicol Environ Saf ; 280: 116559, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38865937

RESUMEN

2-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential adverse effects. EHDPP exhibits cytotoxicity, genotoxicity, developmental toxicity, and endocrine disruption. However, the toxicity of EHDPP in mammalian oocytes and the underlying mechanisms remain poorly understood. Melatonin is a natural free radical scavenger that has demonstrated cytoprotective properties. In this study, we investigated the effect of EHDPP on mouse oocytes in vitro culture system and evaluated the rescue effect of melatonin on oocytes exposed to EHDPP. Our results indicated that EHDPP disrupted oocyte maturation, resulting in the majority of oocytes arrested at the metaphase I (MI) stage, accompanied by cytoskeletal damage and elevated levels of reactive oxygen species (ROS). Nevertheless, melatonin supplementation partially rescued EHDPP-induced mouse oocyte maturation impairment. Results of single-cell RNA sequencing (scRNA-seq) analysis elucidated potential mechanisms underlying these protective effects. According to the results of scRNA-seq, we conducted further tests and found that EHDPP primarily disrupts mitochondrial distribution and function, kinetochore-microtubule (K-MT) attachment, DNA damage, apoptosis, and histone modification, which were rescued upon the supplementation of melatonin. This study reveals the mechanisms of EHDPP on female reproduction and indicates the efficacy of melatonin as a therapeutic intervention for EHDPP-induced defects in mouse oocytes.


Asunto(s)
Retardadores de Llama , Melatonina , Mitocondrias , Oocitos , Animales , Melatonina/farmacología , Ratones , Oocitos/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Femenino , Retardadores de Llama/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Organofosfatos/toxicidad , Daño del ADN/efectos de los fármacos , Apoptosis/efectos de los fármacos , Compuestos Organofosforados/toxicidad
3.
Ecotoxicol Environ Saf ; 275: 116264, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38564869

RESUMEN

Triocresyl phosphate (TOCP) was commonly used as flame retardant, plasticizer, lubricant, and jet fuel additive. Studies have shown adverse effects of TOCP on the reproductive system. However, the potential harm brought by TOCP, especially to mammalian female reproductive cells, remains a mystery. In this study, we employed an in vitro model for the first time to investigate the effects of TOCP on the maturation process of mouse oocytes. TOCP exposure hampered the meiotic division process, as evidenced by a reduction in the extrusion of the first polar body from oocytes. Subsequent research revealed the disruption of the oocyte cell cytoskeleton induced by TOCP, resulting in abnormalities in spindle organization, chromosome alignment, and actin filament distribution. This disturbance further extended to the rearrangement of organelles within oocytes, particularly affecting the mitochondria. Importantly, after TOCP treatment, mitochondrial function in oocytes was impaired, leading to oxidative stress, DNA damage, cell apoptosis, and subsequent changes of epigenetic modifications. Supplementation with nicotinamide mononucleotide (NMN) alleviated the harmful effects of TOCP. NMN exerted its mitigating effects through two fundamental mechanisms. On one hand, NMN conferred stability to the cell cytoskeleton, thereby supporting nuclear maturation. On the other hand, NMN enhanced mitochondrial function within oocytes, reducing the excess reactive oxygen species (ROS), restoring meiotic division abnormalities caused by TOCP, preventing oocyte DNA damage, and suppressing epigenetic changes. These findings not only enhance our understanding of the molecular basis of TOCP induced oocyte damage but also offer a promising avenue for the potential application of NMN in optimizing reproductive treatment strategies.


Asunto(s)
Mononucleótido de Nicotinamida , Fosfatos , Tritolilfosfatos , Femenino , Ratones , Animales , Mononucleótido de Nicotinamida/metabolismo , Mononucleótido de Nicotinamida/farmacología , Fosfatos/metabolismo , Oocitos , Citoesqueleto , Mitocondrias , Especies Reactivas de Oxígeno/metabolismo , Mamíferos
4.
Angew Chem Int Ed Engl ; 63(9): e202312755, 2024 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-38195886

RESUMEN

Controlling the nanoparticle-cell membrane interaction to achieve easy and fast membrane anchoring and cellular internalization is of great importance in a variety of biomedical applications. Here we report a simple and versatile strategy to maneuver the nanoparticle-cell membrane interaction by creating a tunable hydrophobic protrusion on Janus particles through swelling-induced symmetry breaking. When the Janus particle contacts cell membrane, the protrusion will induce membrane wrapping, leading the particles to docking to the membrane, followed by drawing the whole particles into the cell. The efficiencies of both membrane anchoring and cellular internalization can be promoted by optimizing the size of the protrusion. In vitro, the Janus particles can quickly anchor to the cell membrane in 1 h and be internalized within 24 h, regardless of the types of cells involved. In vivo, the Janus particles can effectively anchor to the brain and skin tissues to provide a high retention in these tissues after intracerebroventricular, intrahippocampal, or subcutaneous injection. This strategy involving the creation of a hydrophobic protrusion on Janus particles to tune the cell-membrane interaction holds great potential in nanoparticle-based biomedical applications.


Asunto(s)
Nanopartículas Multifuncionales , Nanopartículas , Nanopartículas/química , Membrana Celular/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas
5.
Wound Repair Regen ; 30(3): 365-375, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35384152

RESUMEN

Maximum survival area after perforator flap elevation is mainly achieved through vasodilation and angiogenesis, and endothelial Ca2+ signals play a pivotal role in both of them. Transient receptor potential (TRP) channels modulate many endothelial cell functions via mediating the extracellular Ca2+ entry. This study aims to investigate the correlation of TRPV4, TRPV1, and TRPA1 with vascular change after the inferior gluteal artery perforator flap elevation. A total of 50 adult male SD rats were used in this study. Ten rats were used in the part one to assess the flap viability on postoperative day 7. Twenty rats were used in the part two to evaluate blood flow change after flap elevation. The correlation of vascular change with TRPV1, TRPV4, and TRPA1 protein changes was investigated in 20 rats in the part three. The mean flap survival area percentage was 55 ± 5.7%. Blood flow in the overall flap and Zone II after the flap elevation markedly increased from the postoperative day 3. The most marked change of the vasodilation occurred on Days 3 and 5 after flap elevation. The angiogenesis occurred on Day 5 after flap elevation and the microvessel density peaked also on Day 5. Moreover, TRPA1 expression showed a trend towards continuous reduction over time. The expression of TRPV1 and TRPV4 reached the peak value on Day 3. The endothelial NO synthase expression showed an increasing trend at first, followed by a reduction over time, while VEGF expression reached the peak value on Day 3. The vascular changes after flap elevation might be associated with the changes in TRPV4, TRPV1, and TRPA1.


Asunto(s)
Colgajo Perforante , Canales Catiónicos TRPV , Animales , Arterias/metabolismo , Masculino , Neovascularización Patológica , Colgajo Perforante/irrigación sanguínea , Ratas , Ratas Sprague-Dawley , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/metabolismo , Cicatrización de Heridas
6.
Clin Anat ; 35(2): 211-221, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34851529

RESUMEN

While blended learning has been growing in popularity in recent years, the effectiveness of this procedure remains controversial. In this report, we assess the effectiveness of blended learning of embryology within international medical students. The participants were international medical students taking embryology in the Bachelor of Medicine and Bachelor of Surgery program. The blended learning group (BLG) consisted of students (n = 43) in the 2018-2019 academic year, taught with blended learning model via a customized small private online course (SPOC). The control traditional teaching group (TTG) consisted students (n = 48) in the 2017-2018 academic year, taught with traditional teaching model. Academic performance, including mean scores and passing ratios on the final exam of two groups were compared and analyzed with a t-test. In addition, a questionnaire directed toward evaluating student's perceptions with the blended learning was administered to students in BLG. The majority of students in BLG actively participated in online self-study activities and discussion in face-to-face class sessions. The mean score and passing ratio were significantly greater than those of students in TTG (p < 0.01). Results from the questionnaire revealed that the majority of BLG students felt that this method was beneficial for their learning of human embryology. The blended learning model, that integrates SPOC with face-to-face class lectures proved a more effective means for the teaching of embryology than the traditional lecture-based teaching model. This blended learning method may serve as a feasible model that can be readily applied for use in other medical courses.


Asunto(s)
Rendimiento Académico , Estudiantes de Medicina , Curriculum , Evaluación Educacional , Humanos , Aprendizaje Basado en Problemas , Enseñanza
7.
J Transl Med ; 18(1): 200, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32410622

RESUMEN

BACKGROUND: Glioblastoma stem-like cells (GSCs) are hypothesized to contribute to self-renewal and therapeutic resistance in glioblastoma multiforme (GBM) tumors. Constituting only a small percentage of cancer cells, GSCs possess "stem-like", tumor-initiating properties and display resistance to irradiation and chemotherapy. Thus, novel approaches that can be used to suppress GSCs are urgently needed. A new carbon material-graphene oxide (GO), has been reported to show potential for use in tumor therapy. However, the exact effect of GO on GSCs and the inherent mechanism underlying its action are not clear. In this study, we aimed to investigate the usefulness of GO to inhibit the growth and promote the differentiation of GSCs, so as to suppress the malignancy of GBM. METHODS: In vitro effects of GO on sphere-forming ability, cell proliferation and differentiation were evaluated in U87, U251 GSCs and primary GSCs. The changes in cell cycle and the level of epigenetic modification H3K27me3 were examined. GO was also tested in vivo against U87 GSCs in mouse subcutaneous xenograft models by evaluating tumor growth and histological features. RESULTS: We cultured GSCs to explore the effect of GO and the underlying mechanism of its action. We found, for the first time, that GO triggers the inhibition of cell proliferation and induces apoptotic cell death in GSCs. Moreover, GO could promote the differentiation of GSCs by decreasing the expression of stem cell markers (SOX2 and CD133) and increasing the expression of differentiation-related markers (GFAP and ß-III tubulin). Mechanistically, we found that GO had a striking effect on GSCs by inducing cell cycle arrest and epigenetic regulation. GO decreased H3K27me3 levels, which are regulated by EZH2 and associated with transcriptional silencing, in the promoters of the differentiation-related genes GFAP and ß-III tubulin, thereby enhancing GSC differentiation. In addition, compared with untreated GSCs, GO-treated GSCs that were injected into nude mice exhibited decreased tumor growth in vivo. CONCLUSION: These results suggested that GO could promote differentiation and reduce malignancy in GSCs via an unanticipated epigenetic mechanism, which further demonstrated that GO is a potent anti-GBM agent that could be useful for future clinical applications.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Epigénesis Genética , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Grafito , Ratones , Ratones Desnudos , Células Madre Neoplásicas
8.
Biochem Biophys Res Commun ; 475(2): 194-201, 2016 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-27235108

RESUMEN

Upon fertilization, maternal factors direct development and trigger zygotic genome activation at the maternal-to-zygotic transition (MZT). However, the factors that activate the zygotic program in vertebrates are not well defined. Here, we found that protein palmitoylation played an important role in acquiring transcriptional competency and orchestrating the clearance of the maternal program in zebrafish. After inhibition of protein palmitoylation, zebrafish embryos developed normally before the Mid-Blastula Transition (MBT); however, they did not initiate epiboly. Moreover, our results showed that protein palmitoylation is required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR-430 expression.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Lipoilación , MicroARNs/genética , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Cigoto/metabolismo , Animales , Metilación de ADN , Femenino , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Cigoto/crecimiento & desarrollo
9.
J Neuroinflammation ; 13(1): 77, 2016 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-27075756

RESUMEN

BACKGROUND: Overactivated microglia is involved in various kinds of neurodegenerative diseases. Suppression of microglial overactivation has emerged as a novel strategy for treatment of neuroinflammation-based neurodegeneration. In the current study, anti-inflammatory effects of oxytocin (OT), which is a highly conserved nonapeptide with hormone and neurotransmitter properties, were investigated in vitro and in vivo. METHODS: BV-2 cells and primary microglia were pre-treated with OT (0.1, 1, and 10 µM) for 2 h followed by LPS treatment (500 ng/ml); microglial activation and pro-inflammatory mediators were measured by Western blot, RT-PCR, and immunofluorescence. The MAPK and NF-κB pathway proteins were assessed by Western blot. The intracellular calcium concentration ([Ca(2+)]i) was determined using Fluo2-/AM assay. Intranasal application of OT was pre-treated in BALB/C mice (adult male) followed by injected intraperitoneally with LPS (5 mg/kg). The effect of OT on LPS-induced microglial activation and pro-inflammatory mediators was measured by Western blot, RT-PCR, and immunofluorescence in vivo. RESULTS: Using the BV-2 microglial cell line and primary microglia, we found that OT pre-treatment significantly inhibited LPS-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, OT inhibited phosphorylation of ERK and p38 but not JNK MAPK in LPS-induced microglia. OT remarkably reduced the elevation of [Ca(2+)]i in LPS-stimulated BV-2 cells. Furthermore, a systemic LPS-treated acute inflammation murine brain model was used to study the suppressive effects of OT against neuroinflammation in vivo. We found that pre-treatment with OT showed marked attenuation of microglial activation and pro-inflammatory factor levels. CONCLUSIONS: Taken together, the present study demonstrated that OT possesses anti-neuroinflammatory activity and might serve as a potential therapeutic agent for treating neuroinflammatory diseases.


Asunto(s)
Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Inflamación/inmunología , Microglía/efectos de los fármacos , Oxitocina/farmacología , Animales , Western Blotting , Encéfalo/inmunología , Encéfalo/metabolismo , Técnica del Anticuerpo Fluorescente , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos BALB C , Microglía/inmunología , Microglía/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
10.
J Pineal Res ; 61(2): 208-17, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27121240

RESUMEN

Glioblastoma stem-like cells (GSCs) displaying self-renewing and tumor-propagating capacity play a particularly important role in maintaining tumor growth, therapeutic resistance, and tumor recurrence. Therefore, new therapeutic strategies focusing on impairing GSC maintenance are urgently needed. Here, we used GSCs isolated from surgical specimens from patients with glioblastoma multiforme (GBM) to study the roles and underlying mechanisms associated with melatonin in GSC biology. The results showed that melatonin directly targeted glioma tumor cells by altering GSC biology and inhibiting GSC proliferation. Additionally, melatonin altered profile of transcription factors to inhibit tumor initiation and propagation. Furthermore, EZH2 S21 phosphorylation and EZH2-STAT3 interaction in GSCs were impaired following melatonin treatment. These results suggested that melatonin attenuated multiple key signals involved in GSC self-renewal and survival, and further supported melatonin as a promising GBM therapeutic.


Asunto(s)
Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Glioblastoma/metabolismo , Melatonina/farmacología , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Glioblastoma/patología , Humanos , Células Madre Neoplásicas/patología , Células Tumorales Cultivadas
11.
Mol Cell Neurosci ; 68: 194-202, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26232532

RESUMEN

Correct axonal growth during nervous system development is critical for synaptic transduction and nervous system function. Proper axon outgrowth relies on a suitable growing environment and the expression of a series of endogenous neuronal factors. However, the mechanisms of these neuronal proteins involved in neuronal development remain unknown. ZDHHC17 is a member of the DHHC (Asp-His-His-Cys)-containing family, a family of highly homologous proteins. Here, we show that loss of function of ZDHHC17 in zebrafish leads to motor dysfunction in 3-day post-fertilization (dpf) larvae. We performed immunolabeling analysis to reveal that mobility dysfunction was due to a significant defect in the axonal outgrowth of spinal motor neurons (SMNs) without affecting neuron generation. In addition, we found a similar phenotype in zdhhc17 siRNA-treated neural stem cells (NSCs) and PC12 cells. Inhibition of zdhhc17 limited neurite outgrowth and branching in both NSCs and PC12. Furthermore, we discovered that the level of phosphorylation of extracellular-regulated kinase (ERK) 1/2, a major downstream effector of tyrosine kinase (TrkA), was largely upregulated in ZDHHC17 overexpressing PC12 cells by a mechanism independent on its palmitoyltransferase (PAT) activity. Specifically, ZDHHC17 is necessary for proper TrkA-tubulin module formation in PC12 cells. These results strongly indicate that ZDHHC17 is essential for correct axon outgrowth in vivo and in vitro. Our findings identify ZDHHC17 as an important upstream factor of ERK1/2 to regulate the interaction between TrkA and tubulin during neuronal development.


Asunto(s)
Aciltransferasas/metabolismo , Axones/fisiología , Neuronas Motoras/citología , Receptor trkA/metabolismo , Tubulina (Proteína)/metabolismo , Aciltransferasas/genética , Animales , Axones/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Larva , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos , Morfolinas/farmacología , Neuronas Motoras/efectos de los fármacos , Trastornos del Movimiento/genética , Factor de Crecimiento Nervioso/farmacología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/fisiología , Interferencia de ARN/fisiología , Ratas , Médula Espinal/citología , Factores de Tiempo , Pez Cebra
12.
J Cell Biochem ; 116(12): 2980-91, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26095893

RESUMEN

The aspartate-histidine-histidine-cysteine (DHHC) protein family shares a 50-amino acid cysteine-rich domain with a conserved DHHC signature motif. DHHC proteins play a critical role in several biological processes. Several DHHC family members have been implicated in neuronal differentiation and synaptic plasticity. And disruptions to their function can lead to disease in the nervous system. Here, we investigate the role of Zdhhc15b, a DHHC family member, in neuro development in zebrafish. Whole-mount in situ hybridization (WISH) revealed that zdhhc15b, an ortholog to human ZDHHC15, is abundant in zebrafish (Danio rerio) forebrain, especially in the diencephalon. Downregulation of zdhhc15b resulted in a smaller diencephalon and a reduction in mature dopaminergic neurons (DA neurons). In the meanshile, mutant zdhhc15b zebrafish was associated with poor learning behavior as detected by T-maze testing. The expression of zdhhc15b was upregulated during DA neuronal differentiation whereas knock-down of zdhhc15b diminished DA neuronal differentiation. Tyrosine hydroxylase (TH) immunofluorescence of cultured DA neurons in vitro also showed that DA neurons were immature following zdhhc15b knock-down. Consistent with the decreased number of DA neurons following knock-down of zdhhc15b, the expression of fate determination-related transcription factors such as nurr1, foxA2, and lmx1a were also reduced in morphant zebrafish. Our results reveal that zdhhc15b controls DA neuronal fate decisions by regulating differentiation but not progenitor cell proliferation or DA neuronal survival.


Asunto(s)
Aciltransferasas/genética , Diferenciación Celular/genética , Proteínas de Unión al ADN/genética , Neuronas Dopaminérgicas/metabolismo , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Apoptosis/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Dopamina/metabolismo , Neuronas Dopaminérgicas/citología , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Pez Cebra/crecimiento & desarrollo
13.
Lab Invest ; 95(12): 1439-49, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26524416

RESUMEN

Granulocyte colony-stimulating factor (G-CSF) was investigated for its capacity to induce autophagy and related neuroprotective mechanisms in an acute spinal cord injury model. To accomplish this goal, we established a mouse spinal cord hemisection model to test the effects of recombinant human G-CSF. The results showed that autophagy was activated after spinal cord injury and G-CSF appears to induce a more rapid activation of autophagy within injured spinal cords as compared with that of non-treated animals. Apoptosis as induced in mechanically injured neurons with G-CSF treatment was enhanced after inhibiting autophagy by 3-methyladenine (3-MA), which partially blocked the neuroprotective effect of autophagy as induced by G-CSF. In addition, G-CSF inhibited the activity of the NF-κB signal pathway in neurons after mechanical injury. We conclude that G-CSF promotes autophagy by inhibiting the NF-κB signal pathway and protects neuronal structure after spinal cord injury. We therefore suggest that G-CSF, which rapidly induces autophagy after spinal cord injury to inhibit neuronal apoptosis, may thus provide an effective auxiliary therapeutic intervention for spinal cord injury.


Asunto(s)
Autofagia , Factor Estimulante de Colonias de Granulocitos/metabolismo , Recuperación de la Función , Traumatismos de la Médula Espinal/metabolismo , Adenina/análogos & derivados , Animales , Apoptosis , Células Cultivadas , Femenino , Humanos , Locomoción , Ratones , FN-kappa B/metabolismo , Neuronas/fisiología , Distribución Aleatoria , Proteínas Recombinantes
14.
J Neurooncol ; 125(2): 265-75, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26386687

RESUMEN

Glioblastoma, the most common type of primary malignant brain tumor, is a devastating disease associated with a median survival of approximately 12 months. Here, we have tested E804, the commercially available indirubin derivatives, against U251 and U87 glioblastoma cells. Treatment with E804 significantly inhibits the growth of human glioblastoma cells lines via induction of differentiation and apoptosis. Differentiation induction is coupled with increased expression of glial fibriliary acidic protein, a marker for mature astrocytes. Apoptosis is associated with activation of Caspase 3 and reduction of Bcl-xL and Mcl-1. Furthermore, we demonstrate that E804 reduces signal transducer and activator of transcription-3 (Stat3) signaling to a remarkable extent, suggesting that inactivation of Stat3, at least in part, mediates the effects of this indirubin derivative. Consistently, reduction of Stat3 activity promotes E804-mediated anti-tumor effects, whereas overexpression of Stat3C mutant recues cell apoptosis induced by E804. Taken together, our results indicate that E804 can effectively suppress tumor cell growth, induce tumor cell differentiation and apoptosis mediated partially by Stat3 signaling pathway, suggesting that E804 could be useful for a potential anti-glioblastoma therapeutic approach.


Asunto(s)
Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Indoles/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Anexina A5/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Ciclina D1/metabolismo , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/patología , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Oximas , ARN Interferente Pequeño/farmacología , Ratas , Factor de Transcripción STAT3/genética , Survivin , Factores de Tiempo , Proteína bcl-X/metabolismo
15.
J Pineal Res ; 59(4): 508-17, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26475080

RESUMEN

Melatonin, an endogenous neurohormone secreted by the pineal gland, has a variety of physiological functions and neuroprotective effects. However, its protective role on the neural tube defects (NTDs) was not very clear. The aim of this study was to investigate the effects of melatonin on the incidence of NTDs (including anencephaly, encephalocele, and spina bifida) of offspring from diabetic pregnant mice as well as its underlying mechanisms. Pregnant mice were given 10 mg/kg melatonin by daily i.p. injection from embryonic day (E) 0.5 until being killed on E11.5. Here, we showed that melatonin decreased the NTDs (especially exencephaly) rate of embryos exposed to maternal diabetes. Melatonin stimulated proliferation of neural stem cells (NSCs) under hyperglycemic condition through the extracellular regulated protein kinases (ERK) pathway. Furthermore, as a direct free radical scavenger, melatonin decreased apoptosis of NSCs exposed to hyperglycemia. In the light of these findings, it suggests that melatonin supplementation may play an important role in the prevention of neural malformations in diabetic pregnancy.


Asunto(s)
Melatonina/uso terapéutico , Defectos del Tubo Neural/tratamiento farmacológico , Animales , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Femenino , Hiperglucemia/tratamiento farmacológico , Ratones , Embarazo
16.
J Assist Reprod Genet ; 32(3): 461-70, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25561158

RESUMEN

PURPOSE: To investigate the expression of GRIM-19 (Gene associated with retinoid-interferon-induced mortality 19) in mouse oocytes and preimplantation embryos, and to study the effect of GRIM-19 on the developmental competence of mouse oocytes and embryos. METHODS: GRIM-19 was evaluated at both mRNA and protein levels. The expression of GRIM-19 gene was downregulated in mouse oocytes cultured in vitro by specific small interfering RNA (siRNA) injection, while the activity of GRIM-19 was decreased by microinjection of a GRIM-19 antibody into the cytoplasm of germinal vesicle (GV) oocytes. Oocytes matured in vitro were then fertilized by intracytoplasmic sperm injection (ICSI), followed by observation and evaluation of fertilization rate, cleavage rate, blastocyst formation rate and implantation rate. RESULTS: GRIM-19 is expressed throughout oocyte maturation and preimplantation embryo development stages. GRIM-19 was localized primarily in the cytoplasm of all cells examined. Downregulation of gene expression and activity of GRIM-19 resulted in decreased oocyte viability, potency of oocyte maturation, embryo development and implantation. CONCLUSIONS: GRIM-19 may play important roles in mouse oogenesis and early embryonic development and implantation.


Asunto(s)
Implantación del Embrión/genética , Desarrollo Embrionario/genética , NADH NADPH Oxidorreductasas/biosíntesis , Oocitos/crecimiento & desarrollo , Oogénesis/genética , Animales , Femenino , Fertilización , Fertilización In Vitro , Regulación del Desarrollo de la Expresión Génica , Humanos , Técnicas de Maduración In Vitro de los Oocitos , Masculino , Ratones , NADH NADPH Oxidorreductasas/genética , Oocitos/metabolismo , Embarazo
17.
EMBO J ; 29(17): 2994-3006, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20657550

RESUMEN

p53 mediates DNA damage-induced cell-cycle arrest, apoptosis, or senescence, and it is controlled by Mdm2, which mainly ubiquitinates p53 in the nucleus and promotes p53 nuclear export and degradation. By searching for the kinases responsible for Mdm2 S163 phosphorylation under genotoxic stress, we identified S6K1 as a multifaceted regulator of Mdm2. DNA damage activates mTOR-S6K1 through p38alpha MAPK. The activated S6K1 forms a tighter complex with Mdm2, inhibits Mdm2-mediated p53 ubiquitination, and promotes p53 induction, in addition to phosphorylating Mdm2 on S163. Deactivation of mTOR-S6K1 signalling leads to Mdm2 nuclear translocation, which is facilitated by S163 phosphorylation, a reduction in p53 induction, and an alteration in p53-dependent cell death. These findings thus establish mTOR-S6K1 as a novel regulator of p53 in DNA damage response and likely in tumorigenesis. S6K1-Mdm2 interaction presents a route for cells to incorporate the metabolic/energy cues into DNA damage response and links the aging-controlling Mdm2-p53 and mTOR-S6K pathways.


Asunto(s)
Ciclo Celular , Daño del ADN , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Estrés Fisiológico , Línea Celular , Reparación del ADN , Dimerización , Humanos , Fosforilación , Unión Proteica , Serina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
18.
Biochem Biophys Res Commun ; 446(4): 830-5, 2014 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-24589730

RESUMEN

We introduced a lentiviral vector containing the Sox11 gene into injured spinal cords of mice to evaluate the therapeutic potential of Sox11 in spinal cord injury. Sox11 markedly improved locomotor recovery after spinal cord injury and this recovery was accompanied by an up-regulation of Nestin/Doublecortin expression in the injured spinal cord. Sox11 was mainly located in endogenous neural stem cells lining the central canal and in newly-generated neurons in the spinal cord. In addition, Sox 11 significantly induced expressions of BDNF in the spinal cords of LV-Sox11-treated mice. We concluded that Sox11 induced activation of endogenous neural stem cells into neuronal determination and migration within the injured spinal cord. The resultant increase of BDNF at the injured site might form a distinct neurogenic niche which induces a final neuronal differentiation of these neural stem cells. Enhancing Sox11 expression to induce neurogenic differentiation of endogenous neural stem cells after injury may be a promising strategy in restorative therapy after SCI in mammals.


Asunto(s)
Vectores Genéticos/uso terapéutico , Neurogénesis , Factores de Transcripción SOXC/genética , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/terapia , Médula Espinal/citología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Femenino , Terapia Genética , Vectores Genéticos/genética , Lentivirus/genética , Locomoción , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Factores de Transcripción SOXC/análisis , Médula Espinal/metabolismo , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Regeneración de la Medula Espinal , Regulación hacia Arriba
19.
J Neurosci Res ; 92(5): 574-86, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24446229

RESUMEN

High-lipid diet composed of saturated fatty acids (SFAs) has significant detrimental effects on brain homeostasis, and deleterious effects of SFAs on various cells have been well documented. However, the effects of SFAs on neural stem Cells (NSCs) function have not been fully explored. The aim of this study was to determine whether palmitic acid (PA) affected the proliferation and differentiation of murine-derived NSCs. The results showed that PA dose dependently suppressed viability of NSCs and was cytotoxic at high concentrations. The toxic levels of PA inhibited the proliferation of NSCs as shown by reduced bromodeoxyuridine labeling of NSCs, which is correlated with reactive oxygen species generation. Pretreatment of the cells with the antioxidant N-acetyl-L-cysteine inhibitor significantly attenuated the effects of PA on the proliferation of NSCs. Furthermore, nontoxic levels of PA promoted astrocytogenesis in the differentiated NSCs, associated with Stat3 activation and altered expression of serial of basic helix-loop-helix transcription factor genes. Altogether, our data have demonstrated that PA has a significant impact on proliferation and differentiation of NSCs in vitro and may be useful for elucidating the role of SFAs in regulating NSCs fate in physiological and pathological settings.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Células-Madre Neurales/efectos de los fármacos , Ácido Palmítico/farmacología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Encéfalo/citología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Embrión de Mamíferos , Lipopolisacáridos/farmacología , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo
20.
J Neurosci Res ; 92(6): 751-60, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24829950

RESUMEN

Granulocyte colony-stimulating factor (G-CSF) and its related mechanisms were investigated to assess the potential for this factor to exert neuroprotective effects against spinal cord injury in mice. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was injected into mice spinal cord hemisection models. Locomotor activity was assessed by using the Basso-Bettie-Bresnahan scale. Neurons isolated from spinal cords were cultured in vitro and used in a neuronal mechanical injury model. Three treatment groups were compared with this model, 1) G-CSF, 2) G-CSF + NSC348884 (a nucleophosmin 1-specific inhibitor), and 3) NSC348884. Immunofluorescence staining and Western blotting were performed to analyze the expression of G-CSF and nucleophosmin 1 (Npm1). TUNEL staining was performed to analyze apoptosis after G-CSF treatment. We found that the G-CSF receptor (G-CSFR) and Npm1 were expressed in neurons and that Npm1 expression was induced after G-CSF treatment. G-CSF inhibited neuronal apoptosis. NSC348884 induced p53-dependent cell apoptosis and partially blocked the neuroprotective activity of G-CSF on neurons in vitro. G-CSF promoted locomotor recovery and demonstrated neuroprotective effects in an acute spinal cord injury model. The mechanism of G-CSF's neuroprotection may be related in part to attenuating neuronal apoptosis by NPM1.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/metabolismo , Neuronas/metabolismo , Proteínas Nucleares/biosíntesis , Traumatismos de la Médula Espinal/metabolismo , Animales , Apoptosis/fisiología , Western Blotting , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica/fisiología , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Etiquetado Corte-Fin in Situ , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuronas/patología , Nucleofosmina , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/patología
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