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1.
Mol Neurobiol ; 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34984583

RESUMO

Parkinson's disease (PD) is an incurable neurodegenerative disease characterized by aggregation of pathological alpha-synuclein (α-syn) and loss of dopaminergic neuron in the substantia nigra. Inhibition of phosphorylation of the α-syn has been shown to mediate alleviation of PD-related pathology. Protein phosphatase 2A (PP2A), an important serine/threonine phosphatase, plays an essential role in catalyzing dephosphorylation of the α-syn. Here, we identified and validated cancerous inhibitor of PP2A (CIP2A), as a potential diagnostic biomarker for PD. Our data showed that plasma CIP2A concentrations in PD patients were significantly lower compared to age- and sex-matched controls, 1.721 (1.435-2.428) ng/ml vs 3.051(2.36-5.475) ng/ml, p < 0.0001. The area under the curve of the plasma CIP2A in distinguishing PD from the age- and sex-matched controls was 0.776. In addition, we evaluated the role of CIP2A in PD-related pathogenesis in PD cellular and MPTP-induced mouse model. The results demonstrated that CIP2A is upregulated in PD cellular and MPTP-induced mouse models. Besides, suppression of the CIP2A expression alleviates rotenone induced aggregation of the α-syn as well as phosphorylation of the α-syn in SH-SY5Y cells, which is associated with increased PP2A activity. Taken together, our data demonstrated that CIP2A plays an essential role in the mechanisms related to PD development and might be a novel PD biomarker.

2.
Front Immunol ; 12: 719807, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691027

RESUMO

According to emerging studies, the excessive activation of microglia and the subsequent release of pro-inflammatory cytokines play important roles in the pathogenesis and progression of Parkinson's disease (PD). However, the exact mechanisms governing chronic neuroinflammation remain elusive. Findings demonstrate an elevated level of NLRP3 inflammasome in activated microglia in the substantia nigra of PD patients. Activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Abnormal protein aggregation of α-synuclein (α-syn), a pathologically relevant protein of PD, were reported to activate the NLRP3 inflammasome of microglia through interaction with toll-like receptors (TLRs). This eventually releases pro-inflammatory cytokines through the translocation of nuclear factor kappa-B (NF-κB) and causes an impairment of mitochondria, thus damaging the dopaminergic neurons. Currently, therapeutic drugs for PD are primarily aimed at providing relief from its clinical symptoms, and there are no well-established strategies to halt or reverse this disease. In this review, we aimed to update existing knowledge on the role of the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis and microglial activation in PD. In addition, this review summarizes recent progress on the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis of microglia as a potential target for PD treatment by inhibiting microglial activation.

3.
Front Aging Neurosci ; 13: 657095, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34393753

RESUMO

The pathogenesis of Parkinson's disease (PD) is currently unclear. Recent studies have suggested a correlation between vitamin D and PD. Vitamin D and its analogs have protective effects in animal models of PD, but these studies have not clarified the mechanism. Parthanatos is a distinct type of cell death caused by excessive activation of poly (ADP-ribose) polymerase-1 (PARP1), and the activation of PARP1 in PD models suggests that parthanatos may exist in PD pathophysiology. 1,25-Dihydroxyvitamin D3 (calcitriol) is a potential inhibitor of PARP1 in macrophages. This study aimed to investigate whether calcitriol treatment improves PD models and its effects on the parthanatos pathway. A 1-methyl-4-phenylpyridinium (MPP+)-induced cell model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute animal model were selected as the in vitro and in vivo PD models, and calcitriol was applied in these models. Results showed that parthanatos existed in the MPP+-induced cell model and pretreatment with calcitriol improved cell viability, reduced the excessive activation of PARP1, and relieved parthanatos. The application of calcitriol in the MPTP subacute animal model also improved behavioral tests, restored the damage to dopamine neurons, and reduced the activation of PARP1-related signaling pathways. To verify whether calcitriol interacts with PARP1 through its vitamin D receptor (VDR), siRNA, and overexpression plasmids were used to downregulate or overexpress VDR. Following the downregulation of VDR, the expression and activation of PARP1 increased and PARP1 was inhibited when VDR was overexpressed. Coimmunoprecipitation verified the combination of VDR and PARP1. In short, calcitriol can substantially improve parthanatos in the MPP+-induced cell model and MPTP model, and the protective effect might be partly through the VDR/PARP1 pathway, which provides a new possibility for the treatment of PD.

4.
Brain ; 144(7): 2024-2037, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-33792662

RESUMO

Increasing evidence suggests that microglial activation is strongly linked to the initiation and progression of Parkinson's disease. Cell-to-cell propagation of α-synuclein pathology is a highlighted feature of Parkinson's disease, and the focus of such research has been primarily on neurons. However, recent studies as well as the data contained herein suggest that microglia, the primary phagocytes in the brain, play a direct role in the spread of α-synuclein pathology. Recent data revealed that plasma exosomes derived from Parkinson's disease patients (PD-EXO) carry pathological α-synuclein and target microglia preferentially. Hence, PD-EXO are likely a key tool for investigating the role of microglia in α-synuclein transmission. We showed that intrastriatal injection of PD-EXO resulted in the propagation of exosomal α-synuclein from microglia to neurons following microglia activation. Toll-like receptor 2 (TLR2) in microglia was activated by exosomal α-synuclein and acted as a crucial mediator of PD-EXO-induced microglial activation. Additionally, partial microglia depletion resulted in a significant decrease of exogenous α-synuclein in the substantia nigra. Furthermore, exosomal α-synuclein internalization was initiated by binding to TLR2 of microglia. Excessive α-synuclein phagocytosis may induce the inflammatory responses of microglia and provide the seed for microglia-to-neuron transmission. Consistently, TLR2 silencing in microglia mitigated α-synuclein pathology in vivo. Overall, the present data support the idea that the interaction of exosomal α-synuclein and microglial TLR2 contribute to excessive α-synuclein phagocytosis and microglial activation, which lead to the further propagation and spread of α-synuclein pathology, thereby highlighting the pivotal roles of reactive microglia in α-synuclein transmission.


Assuntos
Exossomos/metabolismo , Microglia/metabolismo , Doença de Parkinson/metabolismo , Receptor 2 Toll-Like/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley
5.
New Phytol ; 229(1): 284-295, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32761622

RESUMO

Traits are critical in predicting decomposition that fuels carbon and nutrient cycling in ecosystems. However, our understanding of root trait-decomposition linkage, and especially its dependence on mycorrhizal type and environmental context, remains limited. We explored the control of morphological and chemical (carbon- and nutrient-related) traits over decomposition of absorptive roots in 30 tree species associated with either arbuscular mycorrhizal (AM) or ectomycorrhizal (ECM) fungi in temperate and subtropical forests in China. Carbon-related traits (acid-unhydrolysable residue (AUR) and cellulose concentrations) had predominant control of root decomposition in AM species while nutrient-related traits (magnesium concentration) predominately controlled that in ECM species. Thicker absorptive roots decomposed faster in AM species as a result of their lower AUR concentrations, but more slowly in ECM angiosperm species potentially as a result of their higher magnesium concentrations. Root decomposition was linked to root nutrient economy in both forests while root diameter-decomposition coordination emerged only in the subtropical forest where root diameter and decomposition presented similar cross-species variations. Our findings suggest that root trait-decomposition linkages differ strongly with mycorrhizal type and environment, and that root diameter can predict decomposition but in opposing directions and with contrasting mechanisms for AM and ECM species.


Assuntos
Micorrizas , China , Ecossistema , Florestas , Nitrogênio , Raízes de Plantas , Árvores
6.
Tree Physiol ; 41(3): 403-415, 2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33079181

RESUMO

Hydraulic capacitance and carbohydrate storage are two drought adaptation strategies of woody angiosperms. However, we currently lack information on their associations and how they are associated with species' degree of isohydry. We measured total stem xylem nonstructural carbohydrate (NSC) concentration in the dry and wet seasons, xylem hydraulic capacitance, native leaf water potentials, pressure-volume curve parameters and photosynthetic performance in 24 woody understory species differing in their degree of isohydry. We found a trade-off between xylem water and carbohydrate storage both in storage capacitance and along a spectrum of isohydry. Species with higher hydraulic capacitance had lower native NSC storage. The less isohydric species tended to show greater NSC depletion in the dry season and have more drought-tolerant leaves. In contrast, the more isohydric species had higher hydraulic capacitance, which may enhance their drought avoidance capacity. In these species, leaf flushing in the wet season and higher photosynthetic rates in the dry season resulted in accumulation rather than depletion of NSC in the dry season. Our results provide new insights into the mechanisms through which xylem storage functions determine co-occurring species' drought adaptation strategies and improve our capacity to predict community assembly processes under drought.


Assuntos
Árvores , Água , Carboidratos , Secas , Folhas de Planta , Xilema
7.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-399154

RESUMO

A novel multitope protein-peptide vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and disease is described in this report. The initial development and characterization experiments are presented along with proof-of-concept studies for the vaccine candidate UB-612. UB-612 consists of eight components rationally designed for induction of potently neutralizing antibodies and broad T cell responses against SARS-CoV-2: the S1-RBD-sFc fusion protein, six synthetic peptides (one universal peptide and five SARS-CoV-2-derived peptides), a proprietary CpG TLR-9 agonist at low concentration as an excipient, and aluminum phosphate adjuvant. Through immunogenicity studies in Guinea pigs and rats, we optimized the design of protein/peptide immunogens and selected an adjuvant system, yielding a vaccine that provides excellent S1-RBD binding and high neutralizing antibody responses, robust cellular responses, and a Th1-oriented response at low doses. In challenge studies, UB- 612 vaccination reduced viral load and prevented development of disease in mouse and non-human primate challenge models. With a Phase 1 trial completed, a Phase 2 trial ongoing in Taiwan, and additional trials planned to support global authorizations, UB-612 is a highly promising and differentiated vaccine candidate for prevention of SARS-CoV-2 infection and COVID-19 disease. Author SummarySARS-CoV-2 virus, the causative agent of Coronavirus Disease 2019 (COVID-19), has spread globally since its origin in 2019, causing an unprecedented public health crisis that has resulted in greater than 4.7 million deaths worldwide. Many vaccines are under development to limit disease spread and reduce the number of cases, but additional candidates that promote a robust immune response are needed. Here, we describe a multitope protein-peptide vaccine platform that is unique among COVID-19 vaccines. The advantages of our approach are induction of both high levels of neutralizing antibodies as well as a Th/CTL response in the vaccinated host, which mimics the immune response that occurs after natural infection with SARS-CoV-2. We demonstrate that our vaccine is immunogenic and effective in preventing disease in several animal models, including AAV- hACE-2 transduced mice, and both rhesus and cynomolgus macaques. Importantly, no immunopathology was observed in the lungs of immunized animals, therefore showing that antibody-dependent enhancement (ADE) does not occur. Our study provides an additional, novel vaccine candidate for advancement in clinical trials to treat and prevent SARS-CoV-2 infection and COVID-19 disease.

8.
Sleep Med ; 75: 428-433, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32980664

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is adversely affecting sleep quality and mental health, especially in individuals with chronic disease such as Parkinson's disease (PD). METHODS: We conducted a quantitative study, which included 119 Chinese PD patients who had been treated in an outpatient neurology clinic in Wuhan and 169 age- and sex-matched healthy controls. The questionnaire survey focused on the impact of the COVID-19 pandemic on sleep, mental status, symptoms, and daily life and medical treatment of PD patients. RESULTS: Compared to healthy controls, PD patients had significantly higher scores in both the Pittsburgh Sleep Quality Index (PSQI) (8.13 vs 5.36, p < 0.001) and the Hospital Anxiety and Depression Scale (HADS) -Depression (4.89 vs 3.82, p = 0.022), as well as a higher prevalence of sleep disturbances with PSQI > 5 points (68.9% vs 44.4%, p < 0.001). Sleep disturbance was identified in 68.9% of PD patients. A logistic regression analysis showed that sleep disturbance of PD patients was independently associated with exacerbation of PD symptoms (OR = 3.616, 95%CI= (1.479, 8.844), p = 0.005) and anxiety (OR = 1.379, 95%CI= (1.157, 1.642), p < 0.001). Compared to male PD patients, female ones had higher PSQI scores (9.28 ± 4.41 vs 7.03 ± 4.01, p = 0.009) and anxiety (32.8% vs 0.1%, p = 0.002) and depression prevalence (34.5% vs 11.5%, p = 0.003). CONCLUSION: The findings of the present study emphasize the importance of mental and sleep health interventions in PD patients during the COVID-19 pandemic. Additional attention should be paid to the difficulty encountered by PD patients in seeking medical treatment.


Assuntos
Ansiedade/epidemiologia , COVID-19/psicologia , Depressão/epidemiologia , Pandemias , Doença de Parkinson/epidemiologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Idoso , Estudos de Casos e Controles , China , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/psicologia , Pesquisa Qualitativa , Inquéritos e Questionários
9.
Elife ; 92020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32589142

RESUMO

Plant species diversity affects carbon and nutrient cycling during litter decomposition, yet the generality of the direction of this effect and its magnitude remains uncertain. With a meta-analysis including 65 field studies across the Earth's major forest ecosystems, we show here that decomposition was faster when litter was composed of more than one species. These positive biodiversity effects were mostly driven by temperate forests but were more variable in other forests. Litter mixture effects emerged most strongly in early decomposition stages and were related to divergence in litter quality. Litter diversity also accelerated nitrogen, but not phosphorus release, potentially indicating a decoupling of nitrogen and phosphorus cycling and perhaps a shift in ecosystem nutrient limitation with changing biodiversity. Our findings demonstrate the importance of litter diversity effects for carbon and nutrient dynamics during decomposition, and show how these effects vary with litter traits, decomposer complexity and forest characteristics.


Assuntos
Biodiversidade , Florestas , Solo , Carbono/metabolismo , Modelos Biológicos , Nutrientes/metabolismo , Folhas de Planta , Análise Espaço-Temporal
10.
Front Chem ; 8: 309, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32391330

RESUMO

Due to the shuttle effect and low conductivity of sulfur (S), it has been challenging to realize the application of lithium-sulfur (Li-S) batteries with high performance and long cyclability. In this study, a high catalytic active CNTs@FeOOH composite is introduced as a functional interlayer for Li-S batteries. Interestingly, the existence of oxygen vacancy in FeOOH functions electrocatalyst and promotes the catalytic conversion of intercepted lithium polysulfides (LiPS). As a result, the optimized CNTs@FeOOH interlayer contributed to a high reversible capacity of 556 mAh g-1 at 3,200 mA g-1 over 350 cycles. This study demonstrates that enhanced catalytic effect can accelerate conversion efficiency of polysulfides, which is beneficial of boosting high performance Li-S batteries.

11.
New Phytol ; 226(6): 1656-1666, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32096212

RESUMO

The degree of plant iso/anisohydry is a popular framework for characterising species-specific drought responses. However, we know little about associations between below-ground and above-ground hydraulic traits as well as the broader ecological implications of this framework. For 24 understory shrub species in seasonally dry subtropical coniferous plantations, we investigated contributions of the degree of isohydry to species' resource economy strategies, abundance, and importance value, and quantified the hydraulic conductance (Kh ) of above-ground and below-ground organs, magnitude of deep water acquisition (WAdeep ), shallow absorptive root traits (diameter, specific root length, tissue density), and resource-use efficiencies (Amax , maximum photosynthesis rate; PNUE, photosynthetic nitrogen-use efficiency). The extreme isohydric understory species had lower wood density (a proxy for higher growth rates) because their higher WAdeep and whole-plant Kh allowed higher Amax and PNUE, and thus did not necessarily show lower abundance and importance values. Although species' Kh was coordinated with their water foraging capacity in shallow soil, the more acquisitive deep roots were more crucial than shallow roots in shaping species' extreme isohydric behaviour. Our results provide new insights into the mechanisms through which below-ground hydraulic traits, especially those of deep roots, determine species' degree of isohydry and economic strategies.


Assuntos
Pinus , Secas , Solo , Água , Madeira
12.
New Phytol ; 225(1): 222-233, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247133

RESUMO

Strategies for deep soil water acquisition (WAdeep ) are critical to a species' adaptation to drought. However, it is unknown how WAdeep determines the abundance and resource economy strategies of understorey shrub species. With data from 13 understorey shrub species in subtropical coniferous plantations, we investigated associations between the magnitude of WAdeep , the seasonal plasticity of WAdeep , midday leaf water potential (Ψmd ), species abundance and resource economic traits across organs. Higher capacity for WAdeep was associated with higher intrinsic water use efficiency, but was not necessary for maintaining higher Ψmd in the dry season nor was it an ubiquitous trait possessed by the most common shrub species. Species with higher seasonal plasticity of WAdeep had lower wood density, indicating that fast species had higher plasticity in deep soil resource acquisition. However, the magnitude and plasticity of WAdeep were not related to shallow fine root economy traits, suggesting independent dimensions of soil resource acquisition between deep and shallow soil. Our results provide new insights into the mechanisms through which the magnitude and plasticity of WAdeep interact with shallow soil and aboveground resource acquisition traits to integrate the whole-plant economic spectrum and, thus, community assembly processes.


Assuntos
Pinus/fisiologia , Folhas de Planta/fisiologia , Solo/química , Água/metabolismo , Secas , Isótopos de Oxigênio/análise , Fenótipo , Pinus/anatomia & histologia , Folhas de Planta/anatomia & histologia , Raízes de Plantas/anatomia & histologia , Raízes de Plantas/fisiologia , Estações do Ano , Madeira
13.
Ying Yong Sheng Tai Xue Bao ; 31(6): 1980-1988, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34494752

RESUMO

We measured the activities of six kinds of enzyme, including ß-glucosidase (BG), ß-N-acetyl-glucosaminidase (NAG), leucine aminopeptidase (LAP), acid phosphatase (AP), polyphenol oxidase (POX), peroxidase (POD), as well as enzyme stoichiometric ratios and soil physical and chemical properties at 0-10 and 10-20 cm layers across typical Pinus massoniana plantation, Pinus elliottii plantation and mixed plantation of P. massoniana and Schima superba (broadleaved-conifer mixed plantation) in mid-subtropical China. Key factors driving the variation in soil enzyme activity and stoichiometry among different stand types were investigated. The results showed that the activities of soil BG and LAP were significantly affected by stand type. Soil BG activity at 10-20 cm soil layer was significantly higher in P. elliottii plantation than in P. massoniana plantation, while the activity of LAP was highest in the P. massoniana plantation. Soil BG/(NAG+LAP) and BG/AP at 10-20 cm layer of P. elliottii plantation were significantly higher than those of P. massoniana plantation, while (NAG+LAP)/AP of P. massoniana plantation was significantly higher than those of P. elliottii plantation and mixed plantation. The vector length of enzyme stoichiometry at 10-20 cm soil layer was significantly different among stand type, with an order of P. elliottii plantation > broadleaved-conifer mixed plantation > P. massoniana. The vector angles of enzyme stoichiometry in the three plantations were greater than 45°, with the vector angle in the P. elliottii plantation at 10-20 cm soil layer being significantly greater than that of the P. massoniana plantation. Results from redundancy analysis showed that soil carbon quality index and the ratio of soil organic carbon to total phosphorus (C/P), soil water content and C/P were the key factors affecting soil enzyme activity and stoichiometry at 0-10 and 10-20 cm soil layers, respectively. The quantity and quality of soil carbon and phosphorus, and soil water content played a key role in regulating nutrient cycling in mid-subtropical plantation ecosystem.


Assuntos
Pinus , Solo , Carbono/análise , China , Ecossistema , Nitrogênio/análise
14.
Front Neurol ; 10: 812, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447756

RESUMO

A 47-year-old HIV-seronegative woman with autoimmune hemolytic anemia (AIHA) was treated with corticosteroids for 8 months. She developed central nervous system dysfunction and was diagnosed with cryptococcal meningitis (CM) after detecting cryptococcus neoformans in the cerebrospinal fluid. The patient's clinical symptoms were worsened and unusual MRI findings of white matter lesions were noticed even after adequate treatment, which were quite unusual compared with typical characteristics of CM. This led us to carry out further investigations. Similar cases have been reported previously in published literature. Combined with clinical symptoms and MRI findings, the most likely diagnosis was Cryptococcal Meningitis-Immune Reconstitution Inflammatory Syndrome. Unfortunately, the patient deteriorated and died of respiratory failure. Cryptococcal Meningitis-Immune Reconstitution Inflammatory Syndrome may have MRI changes during the early onset of the disease (bilateral basal ganglia). We propose that close monitoring of the condition, meticulous MRI follow-up and brain biopsies should be indicated in such cases for treating them actively, so as to avoid worsening of the patients' condition.

15.
Biochem Biophys Res Commun ; 513(2): 306-312, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30954223

RESUMO

Hyposmia occurs during the prodromal phase of Parkinson's disease (PD), while the underlying mechanisms remain unclear. Discussed are altered dopamine content and impairment of neurogenesis of olfactory bulbs (OB), which has been suggested to be linked to olfactory dysfunction. Given that mouse with reduced vesicular monoamine transporter 2 (VMAT2) expression is now deemed as a relatively new PD animal model simulating motor and nonmotor symptoms, it may provide a new insight into investigating the mechanisms of hyposmia in the context of PD. In this study, we examined the effect of subacute administration of MPTP on mice with a reduced expression of VMAT2, focusing on the histopathological and biochemical alterations, specifically, TH expression level, dopamine content as well as neurogenesis in OB. Interestingly, mice with a reduced VMAT2 expression displayed more obvious olfactory impairment in response to MPTP administration accompanied by markedly decreased dopaminergic interneurons in OB. Furthermore, neurogenesis in OB was also further impaired after MPTP due to reduced VMAT2 expression. We therefore demonstrated that reduced expression of VMAT2 contributed to the impairment of hyposmia, pathologically, the degeneration of extranigral systems and reduced neurogenesis might be the underlying mechanisms.


Assuntos
Regulação para Baixo , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/fisiopatologia , Proteínas Vesiculares de Transporte de Monoamina/genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Interneurônios/patologia , Ventrículos Laterais/patologia , Ventrículos Laterais/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Neurogênese , Bulbo Olfatório/patologia , Bulbo Olfatório/fisiopatologia , Doença de Parkinson Secundária/patologia
16.
Front Neurol ; 10: 271, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949126

RESUMO

Although the pathogenic mechanisms of Parkinson's disease (PD) remain unclear, ample empirical evidence suggests that oxidative stress is involved in the pathogenesis of this disease. The nuclear factor E2-related factor 2 (Nrf2) is known to activate several antioxidant response element (ARE)-driven antioxidative genes that prevents oxidative stress in vitro and in vivo. Moreover, it was documented that hydralazine is a potent Nrf2 activator. In this study, we tested whether hydralazine can attenuate 1-Methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced neurotoxicity in vitro and in vivo by activating Nrf2 and its downstream network of antioxidative genes. We found that treatment with hydralazine attenuated MPP+ or H2O2-induced loss of cell viability in human neuroblastoma cell line (SH-SY5Y). In addition, hydralazine significantly promoted the nuclear translocation of Nrf2, and upregulated the expression of its downstream antioxidative genes. Further, knockout of Nrf2 abolished the protection conferred by hydralazine on MPP+ -induced cell death. Similar findings were observed in vivo. Before, during, and after MPTP 30 mg/kg (i.p.) administration for 7 days, the mice were given hydralazine (Hyd) 51.7 mg/kg per day by oral gavage for 3 weeks. Oral administration of hydralazine ameliorated oxidative stress, MPTP-induced behavioral disorder, and loss of neurons of dopaminergic system in the substantia nigra (SN) and striatum, all of which were attributed to its ability to activate the Nrf2-ARE pathway. Hydralazine increased the migration of Nrf2 to the nucleus in dopaminergic neurons, enhanced the expression of its downstream antioxidative genes. Together, these datasets show that the Nrf2-ARE pathway mediates the protective effects of hydralazine on Parkinson's disease.

17.
Front Neurol ; 10: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740086

RESUMO

Cluster headache is generally considered to be a primary headache; secondary cluster-like headache is quite rare, while cluster-like headache secondary to meningioma is even rarer. Here, we describe an unusual case with cluster-like headache 2.5 years after sphenoid ridge meningioma surgery. The cluster-like headache and meningioma were on the same side, and even at the same position. Furthermore, the cluster-like headache lasted for 6 months. In addition, the patient did not respond well to conventional treatments for cluster headache, such as oxygen inhalation, carbamazepine, and tramadol. Brain magnetic resonance imaging demonstrated a softening lesion, glial hyperplasia, and localized thickening and enhancement of the dura in the left frontal-temporal lobe. However, positron-emission computed tomography showed reduced metabolism in the left frontal-temporal lobe. Although the possibility of a primary headache cannot be completely eliminated, the association between cluster-like headache and probable tumor recurrence or postoperative changes should be considered.

18.
Cell Death Dis ; 10(3): 174, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787269

RESUMO

Recent researches regarding to exosomal involvement in alpha-synuclein (α-syn) transmission relating to the pathological process of Parkinson's disease (PD) have attracted considerable attention. It is highly desirable to make clear the diffusion process and cellular uptake of α-syn-associated exosomes and the underlying mechanism of exosomes-involved communication in the synucleinopathy pathogenesis. To determine the contribution of α-syn-associated exosomes to the initiation and progression of PD, plasma exosomes derived from PD patients were stereotaxically injected into the striatum of mice brains. Exosomes extracted from plasma diagnosed with PD contained monomeric and oligomeric α-syn. Here, we found that microglia display a high potency for uptake of plasma exosomes derived from PD patients, and therefore could be activated by exogenous exosomes in vitro and in vivo. In addition, immunofluorescent double staining verified the transfer of exogenous human exosomal α-syn to neurons. The release of human exosomal α-syn from microglia may facilitate this propagation. Finally, we described a mechanism underlying this potential role of microglia in the transmission of exosomal α-syn. Specifically, exogenous exosomes were found to dysregulate autophagy of the BV2 mouse microglia cell line with presentation of increased accumulation of intracellular α-syn and accelerated secretion of α-syn into extracellular space. These results suggest that microglia play a crucial role in the transmission of α-syn via exosomal pathways, in additional to idea that the progression of PD may be altered by the modulation of exosome secretion and/or microglial states.


Assuntos
Exossomos/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Autofagia , Linhagem Celular , Córtex Cerebelar/metabolismo , Corpo Estriado/metabolismo , Exossomos/ultraestrutura , Feminino , Humanos , Masculino , Camundongos , Microglia/citologia , Pessoa de Meia-Idade , Substância Negra/metabolismo , alfa-Sinucleína/genética
19.
New Phytol ; 221(4): 2228-2238, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30320883

RESUMO

Timing (phenology) and amount (production) are two integral facets of root growth, and their shifts have profound influences on below-ground resource acquisition. However, the environmental control and the effects of nitrogen (N) deposition on the production and phenology of ectomycorrhizal (ECM) roots remain unclear. Using a 4 yr minirhizotron experiment, we explored the control of the production and three phenophases (initiation, peak, and cessation of growth) of ECM roots in two soil layers and investigated their dynamic responses to N addition in a seasonally dry subtropical Pinus elliottii forest. We found a stronger control of water availability on the production and a stronger control of temperature on the phenology of ECM roots under ambient conditions. Temperature was correlated positively with initiation and negatively with cessation, especially in the shallow layer. N addition did not affect the phenology of ECM roots but increased their production by modifying N and phosphorus (P) stoichiometry in the soil and foliage. Our findings suggest a greater sensitivity of production than phenology of ECM roots to N addition. The increased production of ECM roots under N addition could be driven by N-induced P limitation or some combination of below-ground resources (P, N, water).


Assuntos
Micorrizas/fisiologia , Nitrogênio/farmacologia , Pinus/microbiologia , Micorrizas/efeitos dos fármacos , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/fisiologia , Estações do Ano , Solo/química
20.
Front Aging Neurosci ; 10: 370, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524265

RESUMO

Parkinson's disease (PD) is one of the synucleinopathies spectrum of disorders typified by the presence of intraneuronal protein inclusions. It is primarily composed of misfolded and aggregated forms of alpha-synuclein (α-syn), the toxicity of which has been attributed to the transition from an α-helical conformation to a ß-sheetrich structure that polymerizes to form toxic oligomers. This could spread and initiate the formation of "LB-like aggregates," by transcellular mechanisms with seeding and subsequent permissive templating. This hypothesis postulates that α-syn is a prion-like pathological agent and responsible for the progression of Parkinson's pathology. Moreover, the involvement of the inflammatory response in PD pathogenesis has been reported on the excessive microglial activation and production of pro-inflammatory cytokines. At last, we describe several treatment approaches that target the pathogenic α-syn protein, especially the oligomers, which are currently being tested in advanced animal experiments or are already in clinical trials. However, there are current challenges with therapies that target α-syn, for example, difficulties in identifying varying α-syn conformations within different individuals as well as both the cost and need of long-duration large trials.

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