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1.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198710

RESUMO

Microglial activity in the aging neuroimmune system is a central player in aging-related dysfunction. Aging alters microglial function via shifts in protein signaling cascades. These shifts can propagate neurodegenerative pathology. Therapeutics require a multifaceted approach to understand and address the stochastic nature of this process. Polyphenols offer one such means of rectifying age-related decline. Our group used mass spectrometry (MS) analysis to explicate the complex nature of these aging microglial pathways. In our first experiment, we compared primary microglia isolated from young and aged rats and identified 197 significantly differentially expressed proteins between these groups. Then, we performed bioinformatic analysis to explore differences in canonical signaling cascades related to microglial homeostasis and function with age. In a second experiment, we investigated changes to these pathways in aged animals after 30-day dietary supplementation with NT-020, which is a blend of polyphenols. We identified 144 differentially expressed proteins between the NT-020 group and the control diet group via MS analysis. Bioinformatic analysis predicted an NT-020 driven reversal in the upregulation of age-related canonical pathways that control inflammation, cellular metabolism, and proteostasis. Our results highlight salient aspects of microglial aging at the level of protein interactions and demonstrate a potential role of polyphenols as therapeutics for age-associated dysfunction.


Assuntos
Envelhecimento/fisiologia , Suplementos Nutricionais , Microglia/metabolismo , Polifenóis/farmacologia , Transdução de Sinais , Animais , Dieta , Ontologia Genética , Masculino , Microglia/efeitos dos fármacos , Proteoma/metabolismo , Ratos Endogâmicos F344 , Transdução de Sinais/efeitos dos fármacos
2.
J Neuroinflammation ; 17(1): 242, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32799878

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most prevalent movement disorder characterized by up to 80% loss of dopamine (DA) neurons and accumulation of Lewy body deposits composed of α-synuclein (α-syn). Accumulation of α-syn is associated with microglial activation, leading to a pro-inflammatory environment linked with the pathogenesis of PD. Along with microglia, CD4 and CD8 T cells are observed in SNpc. The contribution of T-cells to PD development remains unclear with studies demonstrating that they may mediate neurodegeneration or act in a neuroprotective manner. METHODS: Here, we assessed the contribution of T cells to PD neurodegeneration using an adeno-associated virus (AAV) coding human wild-type α-syn or GFP injected into the substantia nigra pars compacta (SNpc) in T cell deficient (athymic nude) and T cell competent (heterozygous) rats. The rats were behaviorally assessed with cylinder test to test paw bias. Following behavior testing, brains were collected and analyzed for markers of dopamine neuron, microglial activation, T cells, and α-syn expression. RESULTS: Injection of AAV9-α-syn unilaterally into the SN of T cell competent rats resulted in a significant paw bias in comparison to the controls at 60 days post-injection. Conversely, T cell-deficient rats injected with AAV9-α-syn showed no deficit in paw bias. As expected, injected T cell competent rats demonstrated a significant increase in microglial activation (MHCII staining) as well as significant dopaminergic neuron loss. In contrast, the T cell-deficient counterparts did not show a significant increase in microglial activation or significant neuron loss compared to the control animals. We also observed CD4 and CD8 T cells in SNpc following microglial MHCII expression and dopaminergic neuron loss. The time course of T cell entry correlates with upregulation of MHCII and the peak loss of TH+ cells in the SNpc. CONCLUSION: These data demonstrate that T cell infiltration and microglial upregulation of MHCII are involved in α-synuclein-mediated DA neuron loss in this rat model of PD.


Assuntos
Microglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Linfócitos T/metabolismo , Regulação para Cima , alfa-Sinucleína/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Masculino , Microglia/patologia , Neurônios/patologia , Doença de Parkinson/patologia , Ratos , Ratos Nus , Substância Negra/metabolismo , Substância Negra/patologia , Linfócitos T/patologia , alfa-Sinucleína/metabolismo
3.
J Neuroinflammation ; 15(1): 204, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30001722

RESUMO

BACKGROUND: Neuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Exosomes from adipose-derived stem cells (hASCs) containing the long noncoding RNA MALAT1 are a novel, cell-free regenerative approach to long-term recovery after traumatic brain injury (TBI) that have the potential to modulate inflammation at the genomic level. The long noncoding RNA MALAT1 has been shown to be an important component of the secretome of hASCs. METHODS: We isolated exosomes from hASC containing or depleted of MALAT1. The hASC-derived exosomes were then administered intravenously to rats following a mild controlled cortical impact (CCI). We followed the rats with behavior, in vivo imaging, histology, and RNA sequencing (RNA Seq). RESULTS: Using in vivo imaging, we show that exosomes migrate into the spleen within 1 h following administration and enter the brain several hours later following TBI. Significant recovery of function on motor behavior as well as a reduction in cortical brain injury was observed after TBI in rats treated with exosomes. Treatment with either exosomes depleted of MALAT1 or conditioned media depleted of exosomes showed limited regenerative effects, demonstrating the importance of MALAT1 in exosome-mediated recovery. Analysis of the brain and spleen transcriptome using RNA Seq showed MALAT1-dependent modulation of inflammation-related pathways, cell cycle, cell death, and regenerative molecular pathways. Importantly, our data demonstrates that MALAT1 regulates expression of other noncoding RNAs including snoRNAs. CONCLUSION: We demonstrate that MALAT1 in hASC-derived exosomes modulates multiple therapeutic targets, including inflammation, and has tremendous therapeutic potential for treatment of TBI.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Encefalite/tratamento farmacológico , Encefalite/etiologia , Exossomos/metabolismo , RNA Longo não Codificante/metabolismo , Regeneração/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Análise por Conglomerados , Modelos Animais de Doenças , Membro Anterior/fisiopatologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Transtornos Motores/etiologia , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Equilíbrio Postural/efeitos dos fármacos , RNA Longo não Codificante/genética , Ratos , Ratos Endogâmicos F344 , Regeneração/fisiologia , Fatores de Tempo
4.
Mol Ther ; 23(1): 17-23, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25195598

RESUMO

In Parkinson's disease, α-synuclein is known to activate microglia and this activation has been proposed as one of the mechanisms of neurodegeneration. There are several signals produced by neurons that have an anti-inflammatory action on microglia, including CX3CL1 (fractalkine). We have shown that a soluble form of CX3CL1 is required to reduce neuron loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that fractalkine agonism can reduce neuron loss in a 6-hydroxydopamine lesion model. Here, we show that fractalkine can reduce α-synuclein-mediated neurodegeneration in rats. Rats that received fractalkine showed abrogated loss of tyrosine hydroxylase and Neu-N staining. This was replicated in animals where we expressed fractalkine from astrocytes with the glial fibrillary acid protein (GFAP) promoter. Interestingly, we did not observe a reduction in MHCII expression suggesting that soluble fractalkine is likely altering the microglial state to a more neuroprotective one rather than reducing antigen presentation.


Assuntos
Quimiocina CX3CL1/genética , Terapia Genética/métodos , Doença de Parkinson Secundária/terapia , Transtornos Parkinsonianos/terapia , alfa-Sinucleína/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Apresentação de Antígeno , Astrócitos/metabolismo , Astrócitos/patologia , Quimiocina CX3CL1/agonistas , Quimiocina CX3CL1/metabolismo , Dependovirus/genética , Regulação da Expressão Gênica , Vetores Genéticos , Proteína Glial Fibrilar Ácida , Antígenos de Histocompatibilidade Classe II/genética , Masculino , Camundongos , Microglia/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/metabolismo , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Regiões Promotoras Genéticas , Ratos , Transdução de Sinais , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/metabolismo
5.
J Neuroinflammation ; 12: 174, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26376629

RESUMO

BACKGROUND: Aging is associated with a decline in stem cell proliferation that is thought to be a result of dysregulated signaling in the neurogenic niche. This results in a diminished and less efficient pool of progenitors. The Wnt pathway plays a key role in the proliferation and differentiation of progenitor cells. Recent publications suggest that the age-related decline in the function of Wnt is a contributor to age-dependent decline in neural progenitors. Similarly, the aged neurogenic niche is characterized by higher levels of inflammatory cytokines. This increased inflammation contributes to the declining function of neural progenitor cells. NT-020, a proprietary blend of polyphenols, has been shown to increase proliferation of neural progenitors and improve cognitive function in aged rats. PURPOSE AND METHODS: In this study, we examined the neurogenic niche in the subgranular zone of the dentate gyrus (SGZ) and the subventricular zone (SVZ) of young and aged rats to determine if dietary supplementation with NT-020 could regulate inflammation and oxidative stress response pathways in neurons, astrocytes, and microglia. Further, we examined NT-020's ability to modulate Wnt signaling in the aged neurogenic niche. To accomplish this, we utilized gene PCR arrays and immunohistochemistry. RESULTS: We observed an increase in nuclear localization of immunopositive labeling of ß-catenin, HO-1, and Nrf2 in all subsets of cell types in both young and aged rats in the SGZ and SVZ following NT-020 treatment. NeuN-positive cells showed a basal increase in nuclear ß-catenin in the aged rats, which was not observed in doublecortin (DCX)-labeled cells, microglia, or astrocytes. Reverse transcription polymerase chain reaction (RT-PCR) analysis of isolated hippocampal tissue revealed that a significant percent of genes involved with inflammation are affected by treatment with NT-020. In addition, several genes that regulate Wnt activity were affected by supplementation. CONCLUSIONS: The results suggest that NT-020 activates oxidative stress response pathways and supports pro-neurogenic gene expression in the hippocampus. This may represent the mechanism by which the NT-020 formula enhances performance in learning and memory tasks in aged mice.


Assuntos
Envelhecimento , Carnosina/uso terapêutico , Colecalciferol/uso terapêutico , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/uso terapêutico , Via de Sinalização Wnt/fisiologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Carnosina/farmacologia , Proliferação de Células/efeitos dos fármacos , Colecalciferol/farmacologia , Biologia Computacional , Citocinas/genética , Citocinas/metabolismo , Giro Denteado/citologia , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/efeitos dos fármacos , Neuropeptídeos/metabolismo , Extratos Vegetais/farmacologia , Ratos , Ratos Endogâmicos F344 , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
6.
Aust J Rural Health ; 21(4): 208-15, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24033521

RESUMO

OBJECTIVE: To obtain information about aged care services in rural New South Wales public hospitals, and to describe key operational aspects of their service delivery models. DESIGN: A mixed methods design was used to combine data collected from: (i) a survey of public hospitals and (ii) qualitative site visits in a sample of eleven rural sites. SETTING: Rural public hospitals in NSW, Australia. PARTICIPANTS: Qualitative data were collected from multidisciplinary clinicians, managers and community service providers who participated in site visits in 2010 and from surveys of NSW public hospitals in 2009/10 about aged care and dementia services. RESULTS: Survey and site visit findings demonstrated that rural hospitals have fewer secure beds for managing patients with disturbed behaviour due to dementia and delirium and fewer speciality aged care staff than metropolitan hospitals. Site visit participants also described how secure environments can aid care for people with dementia even in the absence of clinical specialists. CONCLUSION: The care of people with dementia in rural hospitals is constrained by access to specialist aged care staff and the physical environment of the hospital. Clinicians are adept at maximising resources to manage diagnosis and transitions for people with dementia. Further understanding of how key operational aspects of clinical leadership and environmental modifications impact on a range of patient outcomes would be valuable.


Assuntos
Demência/terapia , Hospitais Rurais/organização & administração , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , New South Wales
7.
Sci Rep ; 13(1): 317, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609440

RESUMO

Shifts in normal aging set stage for neurodegeneration and dementia affecting 1 in 10 adults. The study demonstrates that lncRNA GAS5 is decreased in aged and Alzheimer's disease brain. The role and targets of lncRNA GAS5 in the aging brain were elucidated using a GAS5-targeting small molecule NPC86, a frontier in lncRNA-targeting therapeutic. Robust techniques such as molecular dynamics simulation of NPC86 binding to GAS5, in vitro functional assays demonstrating that GAS5 regulates insulin signaling, neuronal survival, phosphorylation of tau, and neuroinflammation via toll-like receptors support the role of GAS5 in maintaining healthy neurons. The study demonstrates the safety and efficacy of intranasal NPC86 treatment in aged mice to improve cellular functions with transcriptomic analysis in response to NPC86. In summary, the study demonstrates that GAS5 contributes to pathways associated with neurodegeneration and NPC86 has tremendous therapeutic potential to prevent the advent of neurodegenerative diseases and dementias.


Assuntos
MicroRNAs , RNA Longo não Codificante , Camundongos , Animais , Insulina/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Doenças Neuroinflamatórias , Transdução de Sinais , Modelos Animais de Doenças , Neurônios/metabolismo , MicroRNAs/genética
8.
J Neurosci ; 31(45): 16241-50, 2011 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-22072675

RESUMO

The protective/neurotoxic role of fractalkine (CX3CL1) and its receptor CX3C chemokine receptor 1 (CX3CR1) signaling in neurodegenerative disease is an intricate and highly debated research topic and it is becoming even more complicated as new studies reveal discordant results. It appears that the CX3CL1/CX3CR1 axis plays a direct role in neurodegeneration and/or neuroprotection depending on the CNS insult. However, all the above studies focused on the role of CX3CL1/CX3CR1 signaling in pathological conditions, ignoring the relevance of CX3CL1/CX3CR1 signaling under physiological conditions. No approach to date has been taken to decipher the significance of defects in CX3CL1/CX3CR1 signaling in physiological condition. In the present study we used CX3CR1⁻/⁻, CX3CR1⁺/⁻, and wild-type mice to investigate the physiological role of CX3CR1 receptor in cognition and synaptic plasticity. Our results demonstrate for the first time that mice lacking the CX3CR1 receptor show contextual fear conditioning and Morris water maze deficits. CX3CR1 deficiency also affects motor learning. Importantly, mice lacking the receptor have a significant impairment in long-term potentiation (LTP). Infusion with IL-1ß receptor antagonist significantly reversed the deficit in cognitive function and impairment in LTP. Our results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1ß.


Assuntos
Transtornos Cognitivos/patologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração/genética , Receptores de Interleucina-8A/deficiência , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Biofísica , Bromodesoxiuridina/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Cerebelo/metabolismo , Transtornos Cognitivos/genética , Condicionamento Psicológico/fisiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica , Ensaio de Imunoadsorção Enzimática/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Comportamento Exploratório/fisiologia , Medo/fisiologia , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/patologia , Atividade Motora/genética , Neurogênese/genética , Técnicas de Patch-Clamp , Teste de Desempenho do Rota-Rod
9.
J Neuroinflammation ; 8: 9, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21266082

RESUMO

BACKGROUND: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS), and nitric oxide (NO). The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 is constitutively expressed. It is not known if addition of exogenous CX3CL1 beyond otherwise physiologically normal levels could decrease microglia activation and thereby minimize the secondary neurodegeneration following a neurotoxic insult. METHODS: The intrastriatal 6-hydroxydopamine (6-OHDA) rat model of Parkinson disease, was used to test the hypothesis that exogenous CX3CL1 could be neuroprotective. Treatment with recombinant CX3CL1 was delivered to the striatum by an osmotic minipump for 28 days beginning 7 days after the initial insult. Unbiased stereological methods were used to quantify the lesion size in the striatum, the amount of neuronal loss in the substantia nigra, and the amount of microglia activation. RESULTS: As hypothesized, CX3CL1 was able to suppress this microglia activation. The reduced microglia activation was found to be neuroprotective as the CX3CL1 treated rats had a smaller lesion volume in the striatum and importantly significantly fewer neurons were lost in the CX3CL1 treated rats. CONCLUSION: These findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic target for many neurodegenerative diseases, including Parkinson disease and Alzheimer disease, where inflammation plays an important role.


Assuntos
Quimiocina CX3CL1/farmacologia , Quimiocina CX3CL1/toxicidade , Microglia/efeitos dos fármacos , Microglia/fisiologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Animais , Quimiocina CX3CL1/genética , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Humanos , Masculino , Microglia/citologia , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Oxidopamina/farmacologia , Doença de Parkinson/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia
11.
J Drugs Dermatol ; 10(2): 158-64, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21283920

RESUMO

BACKGROUND: Psoriasis is a hyperproliferative and inflammatory skin disorder that affects roughly 2 percent of the worldwide population. Clobetasol propionate is the most common corticosteroid used to treat moderate-to-severe psoriasis but the potential for side effects limits its long-term use. Topical vitamin D, which is used to treat mild-to-moderate psoriasis, has been shown to be safe when used daily for up to 52 weeks. To date, very few studies exist evaluating the use of clobetasol propionate in a regimen with calcitriol to manage moderate-to-severe disease over time. OBJECTIVES: To evaluate the efficacy and assess safety of a regimen of sequential topical treatments with clobetasol propionate 0.05% spray for up to four weeks followed by calcitriol 3 µg/g ointment for eight weeks in the management of moderate-to-severe plaque psoriasis. METHODS: This was a multi-center, open-label study in subjects aged 18-80 years with moderate-to-severe plaque psoriasis at baseline. Subjects applied clobetasol propionate 0.05% spray twice daily for up to four weeks. At the end of four weeks, if the subject's overall disease severity (ODS) was assessed as clear, almost clear, mild or moderate, subjects started treatment with calcitriol 3 µg/g ointment twice daily. Twice-daily treatment with calcitriol 3 µg/g ointment continued for eight weeks (until week 12) or unless the subject's ODS was assessed as severe or returned to the baseline score, at which time it was discontinued. Subjects were evaluated at baseline and at weeks 2, 4, 8 and 12. RESULTS: Of the 305 subjects enrolled, 170 subjects completed the full 12-week study with no major protocol deviations and comprised the per-protocol (PP) study population. Treatment success, defined as at least one grade improvement in ODS at week 12 compared to baseline, was achieved in 84.1 percent of subjects. The percent body surface area affected (% BSA) decreased from 7.1 percent at baseline to 3.9 percent at week 12 (P<0.001). The sequential treatment regimen was well tolerated with no unexpected adverse events. Most reported adverse events and cutaneous irritations were mild in severity. CONCLUSIONS: The results of this study indicate that the 12-week regimen of clobetasol propionate 0.05% spray treatment for four weeks immediately followed by an eight-week treatment phase with calcitriol 3 µg/g ointment is efficacious and safe for the management of moderate-to-severe plaque psoriasis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Calcitriol/administração & dosagem , Clobetasol/administração & dosagem , Psoríase/tratamento farmacológico , Vitaminas/administração & dosagem , Administração Cutânea , Anti-Inflamatórios/efeitos adversos , Calcitriol/efeitos adversos , Clobetasol/efeitos adversos , Progressão da Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Fatores de Tempo , Resultado do Tratamento , Vitaminas/efeitos adversos
12.
J Drugs Dermatol ; 10(8): 885-92, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21818510

RESUMO

BACKGROUND: Clobetasol propionate 0.05% spray is available for treating moderate-to-severe plaque psoriasis; however, there is limited information with plaque psoriasis of the scalp. OBJECTIVE: Evaluate the efficacy, safety, and quality-of-life impact of clobetasol propionate 0.05% spray in patients with moderate to severe plaque psoriasis of the scalp. METHODS: Multicenter, randomized, double-blind, vehicle-controlled study involving 81 men and women with moderate-to-severe (Global Severity Score [GSS] = 3 or 4) plaque psoriasis of the scalp. Eligible patients were treated with clobetasol propionate 0.05% spray or vehicle spray, which was applied twice daily for up to four weeks. The primary efficacy end point was the GSS of psoriasis of the scalp after four weeks. Safety assessments included local tolerability, presence of Cushing's syndrome, and adverse events. RESULTS: At the end of treatment, 85 percent (35/41) of patients in the clobetasol propionate 0.05% spray group achieved success (GSS clear or almost clear), compared with 13 percent (5/40) in the vehicle spray group (P is less than .001). The proportion of patients treated with clobetasol propionate 0.05% spray who achieved a rating of clear (GSS = 0) after two weeks and at the end of treatment was 12 percent and 51 percent, respectively. Clobetasol propionate 0.05% spray was well tolerated, and there were no serious adverse events or reported cases of folliculitis or Cushing's syndrome. CONCLUSION: Treatment with clobetasol propionate 0.05% spray for up to four weeks is effective and well tolerated for moderate-to-severe plaque psoriasis of the scalp.


Assuntos
Anti-Inflamatórios/uso terapêutico , Clobetasol/uso terapêutico , Psoríase/tratamento farmacológico , Couro Cabeludo/efeitos dos fármacos , Administração Tópica , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Clobetasol/administração & dosagem , Clobetasol/farmacologia , Síndrome de Cushing/etiologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/psicologia , Qualidade de Vida , Resultado do Tratamento
13.
Cutis ; 88(1): 46-51, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21877508

RESUMO

Psoriasis is a chronic condition with serious quality-of-life ramifications. Dermatologists seek alternative treatments of patients with plaque psoriasis that provide both efficacy and safety while minimizing exposure to high-potency steroids that can have adverse effects following long-term use. We report an open-label, multicenter study designed to evaluate a morning/evening (AM/PM) treatment regimen involving clobetasol propionate spray 0.05% and calcitriol ointment 3 microg/g for moderate plaque psoriasis. Participants applied clobetasol propionate spray 0.05% in the morning and calcitriol ointment 3 microg/g in the evening for up to 4 weeks. Participants were evaluated at baseline, week 2, and week 4. The results of this study indicate that a 4-week regimen of clobetasol propionate spray 0.05% treatment in the morning and calcitriol ointment 3 microg/g in the evening is efficacious and without unexpected safety issues for the management of moderate plaque psoriasis.


Assuntos
Calcitriol/administração & dosagem , Clobetasol/administração & dosagem , Glucocorticoides/administração & dosagem , Psoríase/tratamento farmacológico , Vitaminas/administração & dosagem , Administração Cutânea , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pomadas , Psoríase/patologia , Resultado do Tratamento , Adulto Jovem
14.
Cutis ; 88(4): 201-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22106730

RESUMO

High-potency topical corticosteroids are the cornerstone of psoriasis therapy. Although highly effective, long-term use of topical steroids can cause adverse side effects. Additionally, steroids alone do not address the multiple pathophysiologic factors that cause the disease. Psoriasis regimens that utilize high-potency steroids combined with nonsteroid-containing products such as vitamin D analogs have been used for many years to manage the disease, not only for the short-term treatment of the disease but also for long-term treatment to minimize the recurrence of symptoms. We report an open-label, multicenter study designed to evaluate a weekday/ weekend treatment regimen involving calcitriol ointment 3 microg/g and clobetasol propionate spray 0.05% for moderate plaque psoriasis. Participants applied calcitriol ointment 3 microg/g twice daily on the weekdays and clobetasol propionate spray 0.05% twice daily on the weekends for up to 4 weeks. Participants were evaluated at baseline, week 2, and week 4. The results of this study demonstrate that a 4-week regimen of calcitriol ointment 3 microg/g treatment on weekdays and clobetasol propionate spray 0.05% on weekends is effective and well-tolerated for the treatment of moderate plaque psoriasis.


Assuntos
Calcitriol/uso terapêutico , Clobetasol/uso terapêutico , Psoríase/tratamento farmacológico , Administração Cutânea , Adolescente , Adulto , Idoso , Calcitriol/administração & dosagem , Calcitriol/efeitos adversos , Clobetasol/administração & dosagem , Clobetasol/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pomadas , Satisfação do Paciente , Psoríase/patologia , Resultado do Tratamento , Vitaminas/administração & dosagem , Vitaminas/efeitos adversos , Vitaminas/uso terapêutico , Adulto Jovem
15.
Neurochem Int ; 150: 105173, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34453976

RESUMO

The neuroprotective role of human adipose-derived stems cells (hASCs) has raised great interest in regenerative medicine due to their ability to modulate their surrounding environment. Our group has demonstrated that exosomes derived from hASC (hASCexo) are a cell-free regenerative approach to long term recovery following traumatic brain injury (TBI). Previously, we demonstrated the efficacy of exosome treatment with intravenous delivery at 3 h post TBI in rats. Here, we show efficacy of exosomes through intranasal delivery at 48 h post TBI in mice lengthening the therapeutic window of treatment and therefore increasing possible translation to clinical studies. Our findings demonstrate significant recovery of motor impairment assessed by an elevated body swing test in mice treated with exosomes containing MALAT1 compared to both TBI mice without exosomes and exosomes depleted of MALAT1. Significant cognitive improvement was seen in the reversal trial of 8 arm radial arm water maze in mice treated with exosomes containing MALAT1. Furthermore, cortical damage was significantly reduced in mice treated with exosomes containing MALAT1 as well as decreased MHCII+ staining of microglial cells. Mice without exosomes or treated with exosomes depleted of MALAT1 did not show similar recovery. Results demonstrate both inflammation related genes and NRTK3 (TrkC) are target genes modulated by hASC exosomes and further that MALAT1 in hASC exosomes regulates expression of full length TrkC thereby activating the MAPK pathway and promoting recovery. Exosomes are a promising therapeutic approach following TBI with a therapeutic window of at least 48 h and contain long noncoding RNA's, specifically MALAT1 that play a vital role in the mechanism of action.


Assuntos
Tecido Adiposo/transplante , Lesões Encefálicas Traumáticas/terapia , Disfunção Cognitiva/terapia , Exossomos/transplante , Transtornos Motores/terapia , Transplante de Células-Tronco/métodos , Tecido Adiposo/metabolismo , Administração Intranasal , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Células Cultivadas , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Exossomos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Motores/metabolismo , Transtornos Motores/patologia , RNA Longo não Codificante/administração & dosagem , Tempo para o Tratamento
16.
Eur J Mass Spectrom (Chichester) ; 26(3): 187-194, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31969004

RESUMO

The question of whether [CH2OH]+ should be described as the hydroxymethyl cation, +CH2OH, or protonated formaldehyde, CH2=OH+, is reconsidered in the light of experimental information and new computational evidence. Previous arguments that the charge distribution in [CH2OH]+ may be probed by considering the incremental stabilisation of [CH2OH]+ induced by homologation on carbon (to give [CH3CHOH]+) or oxygen (to produce [CH2OCH3]+) are critically examined. Cation stabilisation energies are shown to be better indicators of the nature of these oxonium ions. Further insight into the structure of larger CnH2n+1O+ oxonium ions is obtained by considering the site of protonation of enol ethers and related species. Computational information, including AIM (Atoms and Molecules) and NBA (Natural Bond Analysis) charges on the carbon and oxygen atoms in [CH2OH]+ and related species, is considered critically. Particular attention is focused on the calculated bond lengths and barriers to rotation about the C-O bond(s) in [CH2OH]+, [CH3CHOH]+, [(CH3)2COH]+, CH3OH and [CH2OCH3]+ and the C-N bond in [CH2NH2]+. Trends in these data are consistent with appreciable π-bonding only in the C-O connections which correspond to the C=O bond in the parent aldehyde or ketone from which the oxonium ion may be considered to be derived by protonation or alkyl cationation.

17.
Geroscience ; 42(2): 703-713, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157596

RESUMO

Aging is associated with many pathophysiological changes that could lead to the onset of degenerative disease. Some of the physiological changes that occur with aging include increased inflammation and decreased stem cell proliferation, leading to decreased capacity for tissue regeneration and loss of function. In previous studies, we and others have found nutraceutical intervention to ameliorate some of the deleterious effects associated with aging. In particular, we have previously shown that NT-020, a supplement composed of a proprietary blend of blueberries, green tea, vitamin D3, and carnosine, is able to rescue age-related cognitive deficits, impaired neurogenesis, and inflammation in rats. We have also previously demonstrated that stem cells cultured with old serum showed decreased proliferation; however, when stem cells were cultured in serum from old rats given a diet supplemented with NT-020, proliferation did not differ from that of cells cultured with serum from young rats. While it is clear that NT-020 is exerting a therapeutic, anti-aging effect, the mechanisms of action were yet to be fully elucidated.To that end, in the present study, we conducted a bioinformatics experiment to examine the rat proteome of serum from young and old control rats and young and old rats given a diet supplemented with NT-020. Serum from old rats showed an increase in some inflammatory and pro-aging factors while serum from old rats given a diet supplemented with NT-020 showed an increase in some anti-aging factors, most notably proteins associated with the complement system and autophagy. A number of immune functions that increase with age were shown to be downregulated with NT-020 treatment.


Assuntos
Suplementos Nutricionais , Neurogênese , Envelhecimento , Animais , Proteínas Sanguíneas/metabolismo , Ratos , Ratos Endogâmicos F344
18.
Geroscience ; 41(1): 77-87, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30739297

RESUMO

The incidence of neurodegenerative disorders and cognitive impairment is increasing. Rising prevalence of age-related medical conditions is associated with a dramatic economic burden; therefore, developing strategies to manage these health concerns is of great public health interest. Nutritionally based interventions have shown promise in treatment of these age-associated conditions. Astaxanthin is a carotenoid with reputed neuroprotective properties in the context of disease and injury, while emerging evidence suggests that astaxanthin may also have additional biological activities relating to neurogenesis and synaptic plasticity. Here, we investigate the potential for astaxanthin to modulate cognitive function and neural plasticity in young and aged mice. We show that feeding astaxanthin to aged mice for 1 month improves performance on several hippocampal-dependent cognitive tasks and increases long-term potentiation. However, we did not observe an alteration in neurogenesis, nor did we observe a change in microglial-associated IBA1 immunostaining. This demonstrates the potential for astaxanthin to modulate neural plasticity and cognitive function in aging.


Assuntos
Envelhecimento/efeitos dos fármacos , Cognição/efeitos dos fármacos , Suplementos Nutricionais , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Envelhecimento/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/dietoterapia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Inflamação/dietoterapia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/fisiologia , Doenças Neurodegenerativas/dietoterapia , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Xantofilas/administração & dosagem , Xantofilas/farmacologia , Xantofilas/uso terapêutico
19.
BMC Neurosci ; 9: 22, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18275610

RESUMO

BACKGROUND: Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. RESULTS: We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. CONCLUSION: The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.


Assuntos
Envelhecimento/patologia , Sangue Fetal/fisiologia , Hipocampo/citologia , Neurônios/citologia , Regeneração/fisiologia , Células-Tronco/citologia , Animais , Ciclo Celular/fisiologia , Proliferação de Células , Senescência Celular/fisiologia , Humanos , Injeções Intravenosas , Leucócitos Mononucleares/citologia , Masculino , Microglia/citologia , Fenótipo , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley
20.
J Am Soc Mass Spectrom ; 19(10): 1491-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18657443

RESUMO

1,2-Eliminations are a varied and extensive set of dissociations of ions in the gas phase. To understand better such dissociations, elimination of CH(2)=CH(2) and CH(3)CH(3) from (CH(3))(2)NH(+)CH(2)CH(3) (1) and of CH(4) from (CH(3))(2)NH(2)(+) are characterized by quantum chemical calculations. Stretching of the CN bond to ethyl is followed by shift of an H from methyl to the bridging position in ethyl and then to N to reach (CH(3))(2)NH(2)(+) + CH(2)=CH(2) from 1. CH(3)CH(3) elimination by H-transfer to C(2)H(5)(+) to form CH(3)NH(+)=CH(2) + CH(3)CH(3) also takes place. (CH(3))(2)NH(2)(+) eliminates methane by CN bond extension followed by beta-H-transfer to give CH(2)=NH(+) + CH(4). Low-energy reactions resembling complex-mediated 1,2-eliminations occur and constitute a hitherto largely unrecognized type of reaction. As in many complex-mediated reactions, these reactions transfer H between incipient fragments. They are distinguished from complex-mediated processes by the fragments not being able to rotate freely relative to each other near the transition state for reaction, as they do in complexes. Most 1,2-eliminations are ion-neutral complex-mediated, occur by the just described lower energy reactions, have 1,1-like transition states, or utilize highly asynchronous 1,2 transition states. All of these avoid synchronized 1,2-transition states that would violate conservation of orbital symmetry.


Assuntos
Dimetilaminas/química , Etilaminas/química , Gases/química , Cátions Monovalentes/química , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Teoria Quântica , Compostos de Amônio Quaternário/química , Termodinâmica
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