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1.
Genes Dev ; 25(13): 1399-411, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21724832

RESUMO

Blood vessel networks are typically formed by angiogenesis, a process in which new vessels form by sprouting of endothelial cells from pre-existing vessels. This process is initiated by vascular endothelial growth factor (VEGF)-mediated tip cell selection and subsequent angiogenic sprouting. Surprisingly, we found that VEGF directly controls the expression of Plexin-D1, the receptor for the traditional repulsive axon guidance cue, semaphorin 3E (Sema3E). Sema3E-Plexin-D1 signaling then negatively regulates the activity of the VEGF-induced Delta-like 4 (Dll4)-Notch signaling pathway, which controls the cell fate decision between tip and stalk cells. Using the mouse retina as a model system, we show that Plexin-D1 is selectively expressed in endothelial cells at the front of actively sprouting blood vessels and its expression is tightly controlled by VEGF secreted by surrounding tissues. Therefore, although the Sema3E secreted by retinal neurons is evenly distributed throughout the retina, Sema3E-Plexin-D1 signaling is spatially controlled by VEGF through its regulation of Plexin-D1. Moreover, we show that gain and loss of function of Sema3E and Plexin-D1 disrupts normal Dll4 expression, Notch activity, and tip/stalk cell distribution in the retinal vasculature. Finally, the retinal vasculature of mice lacking sema3E or plexin-D1 has an uneven growing front, a less-branched vascular network, and abnormal distribution of dll4-positive cells. Lowering Notch activity in the mutant mice can reverse this defect, solidifying the observation that Dll4-Notch signaling is regulated by Sema3E-Plexin-D1 and is required for its function in vivo. Together, these data reveal a novel role of Sema3E-Plexin-D1 function in modulating angiogenesis via a VEGF-induced feedback mechanism.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Retroalimentação Fisiológica/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Neovascularização Fisiológica/fisiologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Moléculas de Adesão Celular Neuronais/genética , Linhagem Celular , Células Endoteliais/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Neovascularização Fisiológica/genética , Proteínas do Tecido Nervoso , Fenótipo , Receptores Notch/metabolismo , Retina/citologia , Retina/embriologia , Células Ganglionares da Retina/metabolismo , Semaforinas/genética , Semaforinas/metabolismo
2.
Glia ; 65(9): 1471-1490, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28581123

RESUMO

Lipocalin-2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post-tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2-deficient mice, compared with wild-type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood-brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1-neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF-1α-LCN2-VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.


Assuntos
Astrócitos/metabolismo , Disfunção Cognitiva/metabolismo , Demência Vascular/metabolismo , Hipocampo/metabolismo , Lipocalina-2/metabolismo , Animais , Astrócitos/patologia , Biomarcadores/sangue , Células Cultivadas , Cognição/fisiologia , Disfunção Cognitiva/patologia , Demência Vascular/patologia , Modelos Animais de Doenças , Hipocampo/irrigação sanguínea , Hipocampo/patologia , Humanos , Lipocalina-2/administração & dosagem , Lipocalina-2/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Microvasos/metabolismo , Microvasos/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
J Cosmet Laser Ther ; 18(7): 405-408, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27223252

RESUMO

BACKGROUND: Forehead wrinkles are the result of contracture of the frontalis muscle and the skin aging process. Currently, hyaluronic acid filler and botulinum toxin are the main materials used for correction of these wrinkles. In addition, polydioxanone (PDO) thread has also been applied for this treatment. OBJECTIVE: In order to evaluate the efficacy and safety of multi-PDO scaffold in animal and human skin, we tested PDO insertion in rat and mini-pig models and human volunteers with forehead wrinkles. METHODS: A stent-shaped multi-PDO scaffold was inserted under the panniculus carnosus of rat dorsal skin and the subcutaneous layer of mini-pig dorsal skin and forehead wrinkles in three human volunteers. RESULTS: Histological analysis at 12 weeks revealed evidence of de novo collagen synthesis, which was consistent with clinical results on photo evaluation. CONCLUSION: Stent-shaped multi-PDO scaffolds may be another effective and safe treatment modality for reduction of forehead wrinkles.


Assuntos
Testa/cirurgia , Regeneração Tecidual Guiada/métodos , Polidioxanona/administração & dosagem , Animais , Materiais Biocompatíveis , Feminino , Humanos , Projetos Piloto , Suínos
4.
Semin Cell Dev Biol ; 24(3): 156-62, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23270617

RESUMO

Class 3 secreted semaphorins (Sema3A-3G) participate in many aspects of axon guidance through holoreceptor complexes that include Neuropilin-1 (Npn-1) or Neuropilin-2 and one of the four class A plexin proteins. However, unlike other Sema3 family proteins, Sema3E directly binds to Plexin-D1 without neuropilins. Its biological function was first explored in intersomitic vessel formation and since its initial discovery, Sema3E-Plexin-D1 signaling has been found to participate in the many biological systems in addition to vascular development, via seemingly different mode of actions. For example, temporal and spatial control of ligand vs. receptor results in two different mechanisms governing vascular patterning. Interactions with other transmembrane proteins such as neuropilin and VEGFR2 result in different axonal behaviors. Ligand receptor localization on pre- vs. post-synaptic neurons is used to control different types of synapse formation. Perhaps different downstream effectors will also result in different functional outcomes. Given the limited number of ligands and receptors in the genome and their multifunctional nature, we expect that more modes of action will be discovered in the future. In this review, we highlight current advances on the mechanisms of how Sema3E-Plexin-D1 interaction shapes the networks of multiple biological systems, in particular the vascular and nervous systems.


Assuntos
Moléculas de Adesão Celular/metabolismo , Sistema Nervoso Central/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Semaforinas/metabolismo , Animais , Sistema Nervoso Central/irrigação sanguínea , Humanos , Neovascularização Patológica , Neovascularização Fisiológica , Semaforinas/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Elife ; 132024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38526535

RESUMO

Axon guidance molecules are critical for neuronal pathfinding because they regulate directionality and growth pace during nervous system development. However, the molecular mechanisms coordinating proper axonal extension and turning are poorly understood. Here, metastasis suppressor 1 (Mtss1), a membrane protrusion protein, ensured axonal extension while sensitizing axons to the Semaphorin 3E (Sema3E)-Plexin-D1 repulsive cue. Sema3E-Plexin-D1 signaling enhanced Mtss1 expression in projecting striatonigral neurons. Mtss1 localized to the neurite axonal side and regulated neurite outgrowth in cultured neurons. Mtss1 also aided Plexin-D1 trafficking to the growth cone, where it signaled a repulsive cue to Sema3E. Mtss1 ablation reduced neurite extension and growth cone collapse in cultured neurons. Mtss1-knockout mice exhibited fewer striatonigral projections and irregular axonal routes, and these defects were recapitulated in Plxnd1- or Sema3e-knockout mice. These findings demonstrate that repulsive axon guidance activates an exquisite autoregulatory program coordinating both axonal extension and steering during neuronal pathfinding.


Assuntos
Moléculas de Adesão Celular , Glicoproteínas de Membrana , Proteínas do Tecido Nervoso , Semaforinas , Animais , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Knockout , Semaforinas/genética , Semaforinas/metabolismo
6.
Sci Rep ; 13(1): 22613, 2023 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-38114623

RESUMO

Misfolding of α-synuclein (α-Syn) in the brain causes cellular dysfunction, leading to cell death in a group of neurons, and consequently causes the progression of Parkinson's disease (PD). Although many studies have demonstrated the pathological connections between vascular dysfunction and neurodegenerative diseases, it remains unclear how neuronal accumulation of α-Syn affects the structural and functional aspects of the cerebrovasculature to accelerate early disease progression. Here, we demonstrated the effect of aberrant α-Syn expression on the brain vasculature using a PD mouse model expressing a familial mutant form of human α-Syn selectively in neuronal cells. We showed that young PD mice have an underdeveloped cerebrovasculature without significant α-Syn accumulation in the vasculature. During the early phase of PD, toxic α-Syn was selectively increased in neuronal cells, while endothelial cell proliferation was decreased in the absence of vascular cell death or neuroinflammation. Instead, we observed altered neuronal activation and minor changes in the activity-dependent gene expression in brain endothelial cells (ECs) in young PD mice. These findings demonstrated that neuronal expression of mutant α-Syn in the early stage of PD induces abnormal neuronal activity and contributes to vascular patterning defects, which could be associated with a reduced angiogenic potential of ECs.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Camundongos , Animais , Humanos , Doença de Parkinson/metabolismo , Células Endoteliais/metabolismo , alfa-Sinucleína/metabolismo , Neurônios/metabolismo , Doenças Neurodegenerativas/metabolismo , Células Cultivadas
7.
J Korean Med Sci ; 27(7): 803-10, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22787379

RESUMO

The balance between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolysis. PAI-1 expression increases in atherosclerotic arteries and vascular smooth muscle cells (VSMCs) are one of major constituents of atheroma. We investigated the impact of lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoprotein, on the plasminogen activator system of the rat VSMCs. The lysoPC stimulated the protein and gene expressions of PAI-1 but did not affect the protein expression of t-PA. Fibrin overlay zymography revealed that lysoPC increased the activity of PAI-1 in the conditioned media, while concurrently decreasing that of free t-PA. Vitamin E inhibited the lysoPC-induced PAI-1 expression. Further, lysoPC increased the intracellular reactive oxygen species (ROS) formation. Caffeic acid phenethyl ester, an inhibitor of NF-κB, blocked this lysoPC effect. Indeed, lysoPC induced the NF-κB-mediated transcriptional activity as measured by luciferase reporter assay. In addition, genistein, an inhibitor of protein-tyrosine kinase (PTK), diminished the lysoPC effect, while 7,12-dimethylbenz[a]anthracene, a stimulator of PTK, stimulated PAI-1 production. In conclusion, lysoPC does not affect t-PA expression but induces PAI-1 expression in the VSMC by mediating NF-κB and the genistein-sensitive PTK signaling pathways via oxidative stress. Importantly, lysoPC stimulates the enzyme activity of PAI-1 and suppresses that of t-PA.


Assuntos
Lisofosfatidilcolinas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Animais , Benzo(a)Antracenos/farmacologia , Ácidos Cafeicos/farmacologia , Células Cultivadas , Genisteína/farmacologia , Lipoproteínas LDL/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Inibidor 1 de Ativador de Plasminogênio/agonistas , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Vitamina E/farmacologia
8.
PLoS One ; 17(9): e0275036, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36170290

RESUMO

Brain endothelial cells (BECs) are important conduits that deliver oxygen and nutrients, protect parenchyma cells from toxins, and drain wastes to maintain brain homeostasis. Impairment of BECs has been implicated in diverse neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Therefore, molecular analysis of BECs is important for understanding the molecular pathogenesis of these neurological diseases. Even though many transcriptome analyses for BECs have been developed, mRNA levels do not necessarily correlate with the levels of actively translated proteins. Translatome analysis using RiboTag mice, in which Rpl22, a ribosomal component, is tagged by the hemagglutinin epitope under Cre recombinase activation, could serve as an excellent tool that overcomes these caveats. However, implementation of this technique is limited by high noise-to-signal ratios as well as the low yield of mRNAs from BECs, which limits bulk gene expression analysis. In this study, we established a protocol to isolate highly pure mRNAs from BECs in the cortex of eight- to twelve-week-old male Tie2-Cre; Rpl22HA/HA mice by using a cell strainer to trap blood vessels prior to immunoprecipitation. According to the results of RT-PCR, the specificity of the mRNA pools isolated by our protocol was much higher than that of the pools isolated by the standard protocol. We were also able to generate a high-quality cDNA library for RNA-seq with the small amount of mRNA isolated with our protocol. Thus, this optimized method will be useful for future studies of BECs at the molecular level.


Assuntos
Células Endoteliais , Hemaglutininas , Animais , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Epitopos/metabolismo , Hemaglutininas/metabolismo , Masculino , Camundongos , Oxigênio/metabolismo , RNA Mensageiro/metabolismo
9.
Transl Stroke Res ; 13(1): 142-159, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33978913

RESUMO

Post-stroke vascular remodeling, including angiogenesis, facilitates functional recovery. Proper vascular repair is important for efficient post-stroke recovery; however, the underlying mechanisms coordinating the diverse signaling pathways involved in vascular remodeling remain largely unknown. Recently, axon guidance molecules were revealed as key players in injured vessel remodeling. One such molecule, Semaphorin 3E (Sema3E), and its receptor, Plexin-D1, control vascular development by regulating vascular endothelial growth factor (VEGF) signaling. In this study, using a mouse model of transient brain infarction, we aimed to investigate whether Sema3E-Plexin-D1 signaling was involved in cerebrovascular remodeling after ischemic injury. We found that ischemic damage rapidly induced Sema3e expression in the neurons of peri-infarct regions, followed by Plexin-D1 upregulation in remodeling vessels. Interestingly, Plexin-D1 reemergence was concurrent with brain vessels entering an active angiogenic process. In line with this, Plxnd1 ablation worsened neurological deficits, infarct volume, neuronal survival rate, and blood flow recovery. Furthermore, reduced and abnormal vascular morphogenesis was caused by aberrantly increased VEGF signaling. In Plxnd1 knockout mice, we observed significant extravasation of intravenously administered tracers in the brain parenchyma, junctional protein downregulation, and mislocalization in regenerating vessels. This suggested that the absence of Sema3E-Plexin-D1 signaling is associated with blood-brain barrier (BBB) impairment. Finally, the abnormal behavioral performance, aberrant vascular phenotype, and BBB breakdown defects in Plxnd1 knockout mice were restored following the inhibition of VEGF signaling during vascular remodeling. These findings demonstrate that Sema3E-Plexin-D1 signaling can promote functional recovery by downregulating VEGF signaling in the injured adult brain.


Assuntos
Semaforinas , Acidente Vascular Cerebral , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Regulação para Baixo , Infarto , Peptídeos e Proteínas de Sinalização Intracelular/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Semaforinas/genética , Semaforinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Vascular
11.
Exp Neurobiol ; 29(5): 334-343, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33154196

RESUMO

Guanine nucleotide exchange factors (GEFs) play multiple functional roles in neurons. In a previous study, we reported that Arhgef4 (Rho guanine nucleotide exchange factor 4) functioned as a negative regulator of the excitatory synaptic function by sequestering postsynaptic density protein 95 (PSD-95). However, the role of Arhgef4 in behavior has not been examined. We performed comprehensive behavioral tests in knockout (KO) mice to investigate of the effects of Arhgef4 deficiency. We found that the expressed PSD-95 particle size was significantly increased in hippocampal neuronal cultures from Arhgef4 KO mice, which is consistent with the previous in vitro findings. Arhgef4 KO mice exhibited general motor activity and anxiety-like behavior comparable to those of the wild type littermates. However, spatial memory and object recognition memory were significantly enhanced in the Arhgef4 KO mice. Taken together, these data confirm the role of Arhgef4 as a negative synaptic regulator at the behavioral level.

12.
Exp Ther Med ; 19(5): 3282-3288, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32266024

RESUMO

Penetration of any compound into the body from the outside is prevented primarily by the corneal layer of the epidermis. The only way to circumvent the properties of the corneal layer is to disrupt it. Currently, transdermal systems can currently only deliver drugs that are of low molecular weight. The purpose of the present study was to assess the improvement of the slimming cream's efficacy using a novel fabric, with the aim of developing an improved method for transdermal drug delivery. The current study was conducted on four groups of guinea pigs. The control group was untreated, whereas the test groups were treated with either slimming cream and no fabric, slimming cream with 100% cotton fabric or slimming cream with the novel fabric. Ultrasound and microscopic histological analysis were used to assess animals. The results demonstrated that compared with the other groups, the novel fabric group demonstrated the greatest reductions in fat layer thickness, adipocyte size and number and proliferator-activated receptor-γ levels in adipose tissue. Furthermore, the novel fabric also enhanced the transdermal delivery of rhodamine B base and caffeine penetration compared with the control fabric (3.18-fold). In conclusion, the results of the present study demonstrated that the novel fabric can potentially be used to enhance transdermal drug delivery.

13.
J Menopausal Med ; 26(1): 1-8, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32307944

RESUMO

OBJECTIVES: Coronary heart disease (CHD) risk increases in women after menopause, but menopausal hormone therapy (MHT) helps prevent CHD if started early after menopause. To explore the mechanism underlying the direct vascular actions of estrogen, the effects of 17ß-estradiol (E2) on apoptosis of vascular smooth muscle cells (VSMCs) induced with lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoprotein, were investigated in the present study. METHODS: VSMCs were isolated from rat aortas. Apoptosis and protein expression of caspases were assessed using propidium iodide staining and Western blot analysis, respectively. Intracellular formation of reactive oxygen species (ROS) was examined using dichlorofluorescein diacetate, a cell-permeable oxidation-sensitive probe, and quantitated with flow cytometry. Nuclear factor-κB (NF-κB) activation was determined after transfection with a reporter plasmid containing the luciferase reporter gene. RESULTS: After pre-treatment for 24 hours, 17ß-E2 suppressed lysoPC-induced (15 µM) apoptotic cell death in a dose-dependent manner with statistical significance at near physiological concentration. 17ß-E2 (10⁻6 M) also increased protein levels of caspase-9 and -8 precursors and decreased the active form of caspase-3. Western blot analysis using subcellular fractions showed that 17ß-E2 decreased mitochondrial Bax levels and concomitantly increased cytosolic Bax expression. Furthermore, intracellular production of ROS and NF-κB-mediated transcriptional activity were reduced with 17ß-E2. In addition, estrogen effects on apoptosis were partially blocked by ICI 182,780, a specific estrogen receptor antagonist. CONCLUSIONS: In cultured VSMCs treated with lysoPC, 17ß-E2 reduced apoptotic cell death by down-regulating both extrinsic and intrinsic apoptosis pathways, contributing to the preventive action of MHT against CHD.

14.
J Menopausal Med ; 26(1): 9-17, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32307945

RESUMO

OBJECTIVES: When administered soon after menopause, hormone therapy can prevent coronary heart diseases in women. To explore the mechanism underlying the cardioprotective actions of estrogen, we investigated the effects of 17ß-estradiol (17ß-E2) on the plasminogen activator system using cultured vascular smooth muscle cells (VSMCs). METHODS: VSMCs were isolated from rat aortas. Protein expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated using Western blotting and enzyme-linked immunosorbent assay, respectively. The enzyme activity of PAI-1 in a conditioned medium was assessed via reverse fibrin overlay zymography and that of t-PA was assessed via fibrin overlay zymography. Gene expression was quantified using real-time reverse transcription-polymerase chain reaction. RESULTS: Following pre-treatment for 24 hours, 17ß-E2 suppressed both protein expression and enzyme activity of PAI-1 stimulated by lysophosphatidylcholine (lysoPC) in a significant and dose-dependent manner at a near physiological concentration. Moreover, 17ß-E2 (10⁻7 M) inhibited PAI-1 gene expression, and ICI 182,780-a specific estrogen receptor antagonist-blocked the effects of 17ß-E2 on the PAI-1 protein. 17ß-E2 did not affect t-PA secretion but significantly enhanced free t-PA activity through reduced binding to PAI-1. Furthermore, 17ß-E2 suppressed intracellular reactive oxygen species production and nuclear factor-κB-mediated transcription. CONCLUSIONS: In VSMCs stimulated with lysoPC, 17ß-E2 reduced PAI-1 expression through a non-receptor-mediated mechanism via antioxidant activity as well as a receptor-mediated mechanism; however, it did not alter t-PA secretion. Of note, 17ß-E2 suppressed PAI-1 activity and concurrently enhanced t-PA activity, suggesting a beneficial influence on fibrinolysis.

15.
PLoS One ; 13(4): e0195339, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29608598

RESUMO

α-Synuclein (α-syn) is a major component of Lewy bodies found in synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Under the pathological conditions, α-syn tends to generate a diverse form of aggregates showing toxicity to neuronal cells and able to transmit across cells. However, mechanisms by which α-syn aggregates affect cytotoxicity in neurons have not been fully elucidated. Here we report that α-syn aggregates preferentially sequester specific synaptic proteins such as vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 (SNAP25) through direct binding which is resistant to SDS. The sequestration effect of α-syn aggregates was shown in a cell-free system, cultured primary neurons, and PD mouse model. Furthermore, we identified a specific blocking peptide derived from VAMP2 which partially inhibited the sequestration by α-syn aggregates and contributed to reduced neurotoxicity. These results provide a mechanism of neurotoxicity mediated by α-syn aggregates and suggest that the blocking peptide interfering with the pathological role of α-syn aggregates could be useful for designing a potential therapeutic drug for the treatment of PD.


Assuntos
Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Agregação Patológica de Proteínas/tratamento farmacológico , Proteína 2 Associada à Membrana da Vesícula/metabolismo , alfa-Sinucleína/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Escherichia coli , Humanos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo
17.
J Dermatolog Treat ; 27(6): 510-514, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27121901

RESUMO

BACKGROUND: A previous 6-month study using a more highly concentrated novel hyaluronic acid (HA) filler, PP-501-B, found nasolabial fold (NLF) improvements with increased tolerability. OBJECTIVE: We investigated the long-term efficacy, durability and safety of PP-501-B in the correction of NLFs. METHODS: Subjects completing the initial six-month study were enrolled in this 24-month, randomized, multicenter, double-blind, split-face, extension study. The injection areas and treatment procedures were identical to those of the initial study: each subject was injected with PP-501-B in one NLF and with Restylane Perlane (Q-med) in the contralateral NLF. We reassessed wrinkle improvement using the five-point Wrinkle Severity Rating Scale (WSRS) and changes in the Global Aesthetic Improvement Scale at 12, 18 and 24 months after the initial treatment. RESULTS: Of the 81 patients enrolled, 72 completed the study. The WSRS score significantly decreased from baseline throughout the follow-up period after retreatment with both fillers. There was no significant difference in the WSRS scores between the two fillers at 24 months. Both fillers were well tolerated with no severe complications or adverse reactions. CONCLUSION: The new HA filler PP-501-B is safe and effective in the long term for the correction of moderate-to-severe NLFs, even after a second treatment.


Assuntos
Técnicas Cosméticas , Ácido Hialurônico/administração & dosagem , Sulco Nasogeniano , Adulto , Técnicas Cosméticas/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Ácido Hialurônico/uso terapêutico , Injeções , Masculino , Pessoa de Meia-Idade , Retratamento
18.
Gene ; 351: 39-49, 2005 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-15826867

RESUMO

The vesicular inhibitory amino acid transporter, VIAAT (also known as vesicular GABA transporter VGAT) transports GABA or glycine into synaptic vesicles. To initiate an analysis of the expression and regulation of VIAAT during neurogenesis we have cloned and characterized the mouse Viaat gene. We find that the mouse Viaat coding sequence is encoded by two exons spanning 5.3 kb. A survey of expression by whole mount in situ hybridization of mouse embryos indicates that Viaat is activated early in neuron differentiation and is expressed widely within the developing CNS; however, we did not detect expression in the superficial non-neural structures that express the GABA synthase Gad1. Analysis of the Viaat promoter indicates that a minimal promoter region containing a CG rich sequence is sufficient for efficient expression in neural stem and precursor cells. Our analysis of the Viaat sequence and splicing does not support the existence of two Viaat isoforms as previously proposed [Ebihara et al., Brain Res. Mol Brain Res. 110 (2003), 126-139]. Instead, the alternative isoform Viaat-a appears to be due to PCR artifacts that have occurred independently in multiple labs.


Assuntos
Sistemas de Transporte de Aminoácidos/genética , Regulação da Expressão Gênica no Desenvolvimento , Regiões Promotoras Genéticas/genética , Processamento Alternativo , Animais , Sequência de Bases , Linhagem Celular , Linhagem Celular Tumoral , Ilhas de CpG/genética , Hibridização In Situ , Luciferases/genética , Luciferases/metabolismo , Camundongos , Dados de Sequência Molecular , Sistema Nervoso/embriologia , Sistema Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Isoformas de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Homologia de Sequência do Ácido Nucleico , Células-Tronco/metabolismo , Transfecção , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores
19.
Biomed Res Int ; 2015: 596161, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26558274

RESUMO

BACKGROUND: Photodynamic therapy (PDT) has been used for acne, with various combinations of photosensitizers and light sources. OBJECTIVE: We evaluated the effectiveness and safety of indocyanine green (ICG) and intense pulsed light (IPL) in the treatment of acne. MATERIALS AND METHODS: A total of 1,213 patients with facial acne were retrospectively reviewed. Patients received three or five treatments of ICG and IPL at two-week intervals. Clinical response to treatment was assessed by comparing pre- and posttreatment clinical photographs and patient satisfaction scores. RESULTS: Marked to excellent improvement was noted in 483 of 1,213 (39.8%) patients, while minimal to moderate improvement was achieved in the remaining 730 (60.2%) patients. Patient satisfaction scores revealed that 197 (16.3%) of 1,213 patients were highly satisfied, 887 (73.1%) were somewhat satisfied, and 129 (10.6%) were unsatisfied. There were no significant side effects. CONCLUSION: These results suggest that PDT with ICG and IPL can be effectively and safely used in the treatment of acne.


Assuntos
Acne Vulgar/tratamento farmacológico , Verde de Indocianina/uso terapêutico , Pele/efeitos dos fármacos , Adolescente , Adulto , Povo Asiático , Face , Feminino , Humanos , Verde de Indocianina/efeitos adversos , Luz , Masculino , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/efeitos adversos , Fármacos Fotossensibilizantes/uso terapêutico , Estudos Retrospectivos , Adulto Jovem
20.
Elife ; 3: e01936, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24843012

RESUMO

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.DOI: http://dx.doi.org/10.7554/eLife.01936.001.


Assuntos
Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Mesencéfalo/metabolismo , Inibição Neural , Sinapses/metabolismo , Transmissão Sináptica , Ácido gama-Aminobutírico/metabolismo , Animais , Transporte Biológico , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , GABAérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Potenciais Pós-Sinápticos Inibidores , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Fatores de Tempo
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