RESUMO
BACKGROUND: The Diplolepideae are the larger group within the Arthrodontae mosses, characterized by peristomes formed from residual cell walls. It is now understood that these peristomes exhibit diverse hygroscopic movements, playing a crucial role in spore release. However, the exact mechanism behind this movement remains unclear, lacking direct evidence. This study investigated the microscopic and submicroscopic structures of the peristomes in three Diplolepideae species: Hypopterygium fauriei (Besch.), Pylaisia levieri (Müll. Hal.) Arikawa and Regmatodon declinatus (Hook.) Brid. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to reveal the differences in their hygroscopic movement mechanisms. RESULTS: The three species exhibited distinct responses upon wetting: H. fauriei's exostome closed inwards, P. levieri' opened outwards, and R. declinatus' elongated significantly. These differences are attributed to the varying microfibril deposition in the exostome layers. Uniform deposition in the inner layer and minimal deposition in the outer layer enabled exostome opening upon wetting and closing when dry. Our findings suggest that the diastole and contraction of fine microfibrils in the exostome plates and ridges are the key drivers of hygroscopic movement. CONCLUSIONS: This study provides further evidence at both the structural and submicroscopic levels, contributing to the unraveling of the hygroscopic movement mechanism in Diplolepideae peristomes. This enhanced understanding sheds light on the relationship between peristome structure and function.
Assuntos
Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Molhabilidade , MovimentoRESUMO
Bauxite residue (BR) is a large volume by-product generated during bauxite smelting process and metal pollution problem is becoming increasingly prominent in residue areas. Accumulation and transfer of metals in six vascular plants were analyzed and soil environment was evaluated. Results found levels of Al (2,110-26,280 mg kg-1), Fe (990 to 9,880 mg kg-1), Ca (8,020 to 49,250 mg kg-1), Mg (2,060 to 17,190 mg kg-1), K (16,840 to 39,670 mg kg-1), and Ti (80 to 1,240 mg kg-1) in plants. Metal concentrations in soils exceeded background levels. Bioconcentration factor (BCF) found that Al, Fe, and Ti in plants (roots, stems, and leaves) were relatively depleted (BCF <1). Transfer factor (TF) of Al, Fe, Ca, K, and Ti in plants was distinctly higher than 1 and mainly concentrated in stems and leaves. Pollution indices revealed that soil environment was at moderated to serious contaminated risk. Principal components analysis (PCA) showed that Artemisia caruifolia Buch. and Siegesbeckia orientalis L. plants had a good ability to absorb Al and Fe, which can be used as biological indicators and restoration materials.
Currently, soil environment was exposed to moderated to serious contaminated risk from Wachangping karst bauxite residue areas.Bioconcentration factor (BCF) analysis found that Al, Fe, and Ti in six vascular plants (roots, stems, and leaves) were relatively depleted (BCF <1).Transfer factor (TF) of Al, Fe, Ca, K, and Ti in vascular plants was distinctly higher than 1, which mainly concentrated in stems and leaves.PCA revealed that Artemisia caruifolia Buch. and Siegesbeckia orientalis L. plants had a good ability to absorb Al and Fe, which can be used as biological indicators and ecological restoration materials.
Assuntos
Óxido de Alumínio , Poluentes do Solo , Poluentes do Solo/metabolismo , Poluentes do Solo/análise , Bioacumulação , Biodegradação Ambiental , China , Solo/química , Metais/metabolismo , Metais Pesados/metabolismo , Metais Pesados/análise , Monitoramento Ambiental , Folhas de Planta/metabolismoRESUMO
Vitex negundo has strong antioxidant activity, but its primary antioxidant components are not clear. In this study, the antioxidant components were screened by offline two-dimensional liquid chromatography coupled with electrochemical detection (2D-LC-ECD) and subsequently assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification, radical scavenging capacity, and molecular docking. Various fractions were isolated from Vitex negundo leaves, and 39 antioxidant components were screened and identified. All of the fractions containing the antioxidant components exhibited certain antioxidant activity. Correlation analysis revealed a strong correlation between the response of LC-ECD and the in vitro antioxidant activity of the fractions. Molecular docking demonstrated that components with high response to LC-ECD exhibited robust interaction with antioxidant-related target proteins. The main antioxidant components of Vitex negundo leaves were isoorientin, chlorogenic acid, agnuside, cynaroside, and scutellarin. The 2D-LC-ECD combined with LC-MS/MS was rapid and effective in screening the antioxidant components in Vitex negundo leaves and could also provide technical support for the discovery of antioxidant components with different polarities and contents in other medicinal and edible plants.
Assuntos
Antioxidantes , Simulação de Acoplamento Molecular , Folhas de Planta , Espectrometria de Massas em Tandem , Vitex , Vitex/química , Folhas de Planta/química , Espectrometria de Massas em Tandem/métodos , Antioxidantes/química , Antioxidantes/análise , Cromatografia Líquida/métodos , Extratos Vegetais/química , Espectrometria de Massa com Cromatografia LíquidaRESUMO
CONTEXT: Periplaneta americana L. (Blattariae) is used as a treatment for ulcerative colitis (UC) in Chinese traditional medicine. OBJECTIVE: To evaluate the antioxidative activity of P. americana whole body ethanol extract (PAE) on UC mice and whether glycine and proline could be used for quality control and identification of active PAE components. MATERIALS AND METHODS: NCM460 cells were pre-incubated in PAE, AA-L, AA-M, and AA-H (low, high and medium doses of proline and glycine), then treated with recombinant human TNF-α. The glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen (ROS) levels were determined. UC mice were fed with water containing 2.5% dextran sulfate sodium (w/v) after pre-treatment with different doses of PAE once a day for 7 days. ELISA was used to detect the concentrations of inflammation-related factors. Colon tissues of mice were used to detect the activity of myeloperoxidase (MPO), GSH, MDA, and SOD. Histological changes were observed using H&E staining. The expression of target proteins was determined by western blotting. RESULTS: In vivo, PAE treatment reduced the DAI score more than in the model group, restoring the weight and colonic length. It also reduced the severity of colitis, and inflammatory and oxidative stress intensity. Additionally, western blotting showed that the Nrf2 pathway was activated by PAE. In vitro PAE significantly alleviated TNF-α-induced cell damage and oxidative stress, which is relevant to the activation of the Nrf2 pathway. CONCLUSIONS: PAE may relieve oxidative stress through the Nrf2 signaling pathway, and proline and glycine may be used as active components of its antioxidative stress activity.
Assuntos
Colite Ulcerativa , Periplaneta , Camundongos , Humanos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Antioxidantes/uso terapêutico , Periplaneta/metabolismo , Sulfato de Dextrana/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Colo , Superóxido Dismutase/metabolismo , Modelos Animais de DoençasRESUMO
This work developed an electrochemical impedance spectroscopy (EIS) sensor for detection of EGFR (epidermal growth factor receptor)-overexpressing tumor cell and preliminary estimation of EGFR expression. Here, EGFR antibodies as the specific antibodies for cancer cells were conjugated on magnetic gold-decorated graphene oxide nanocomposites, which were used to capture the EGFR-overexpressing tumor cells. The magnetically responsive tumor cells were enriched and immobilized on a magnetic glassy carbon electrode (mGCE) surface, leading to increased electron-transfer resistance (Ret) utilized for determination of cells and preliminary evaluation of EGFR expression level. This strategy enables the enrichment, fixation and detection of tumor cells to be accomplished in a facile way. An excellent linearity in the range of 2.0 × 102 - 3.0 × 105 cell mL-1 with the detection limit of 152 cell mL-1 for MDA-MB-231 cells was obtained. Investigation on the expression levels of EGFR on various types of cells was conducted. MDA-MB-231 cells showed a distinctly higher EGFR expression, compared with MHCC97-L and L02 cells, providing the possibility for the EGFR-targeted therapy of the tumors. It is expected that the proposed sensor has the potential to be applied for cancer monitoring.
Assuntos
Técnicas Biossensoriais , Técnicas Eletroquímicas , Nanocompostos/química , Carbono/química , Eletrodos , Receptores ErbB/biossíntese , Receptores ErbB/metabolismo , Ouro/química , Grafite/química , Humanos , Fenômenos Magnéticos , Células Tumorais CultivadasRESUMO
The human A53T mutant of α-synuclein tends to aggregate and leads to neurotoxicity in familial Parkinson's disease (PD). The aggregation of α-synuclein is also found in sporadic PD. Thus, targeting α-synuclein clearance could be used as a drug-discovery strategy for PD treatment. Caffeic acid (CA) has shown neuroprotection in Alzheimer's disease or cerebral ischaemia; however, it is unclear whether CA confers neuroprotection in α-synuclein-induced PD models. Here we focus on whether and how A53T α-synuclein is affected by CA. We assessed the effect of CA on cell viability in SH-SY5Y cells overexpressing A53T α-synuclein. Pathway-related inhibitors were used to identify the autophagy mechanisms. Seven-month-old A53T α-synuclein transgenic mice (A53T Tg mice) received CA daily for eight consecutive weeks. Behaviour tests including the buried food pellet test, the pole test, the Rotarod test, open field analysis, and gait analysis were used to evaluate the neuroprotective effect of CA. Tyrosine hydroxylase and α-synuclein were assessed by immunohistochemistry or western blot in the substantia nigra (SN). We found that CA alleviated the cell damage induced by overexpressing A53T α-synuclein and that CA reduced A53T α-synuclein by activating the JNK/Bcl-2-mediated autophagy pathway. The efficacy of CA on A53T α-synuclein degradation was reversed by the autophagy inhibitor bafilomycin A1 and the JNK inhibitor SP600125. In A53T Tg mice, CA improved behavioural impairments, attenuated loss of dopaminergic neurons, enhanced autophagy and reduced α-synuclein in the SN. Thus, the results provide scientific evidence for the neuroprotective effect of CA in PD. Our work lays the foundation for CA clinical trials to treat PD in the future.
Assuntos
Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , MAP Quinase Quinase 4/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , alfa-Sinucleína/metabolismo , Animais , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Marcha/efeitos dos fármacos , Humanos , Masculino , Camundongos Transgênicos , Doença de Parkinson , Transtornos Parkinsonianos/metabolismo , alfa-Sinucleína/genéticaRESUMO
Sox17, an antagonist of canonical Wnt/ß-catenin signaling, inhibits several malignant carcinogenesis and progression. However, little is known about Sox17 in hepatocellular carcinoma (HCC). Here, we found that Sox17 is downregulated in HCC tissue. Furthermore, Sox17 inhibits cell proliferation and migration in HCC. KIF14, a member of kinesin superfamily protein (KIFs), is an oncogene in a variety of malignant tumors including HCC. We demonstrated that Sox17 is negatively related to KIF14 expression in HCC tissue and Sox17 inhibits HCC cell proliferation and migration by transcriptional downregulation of KIF14 expression. Our results may provide a strategy for blocking HCC carcinogenesis and progression.
Assuntos
Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Cinesinas/genética , Neoplasias Hepáticas/patologia , Proteínas Oncogênicas/genética , Fatores de Transcrição SOXF/metabolismo , Adulto , Apoptose , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Imunoprecipitação da Cromatina , Progressão da Doença , Feminino , Humanos , Cinesinas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Luciferases/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/metabolismo , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOXF/antagonistas & inibidores , Fatores de Transcrição SOXF/genética , Células Tumorais CultivadasRESUMO
Background: Factor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk. Objectives: The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. Methods: Mouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities. Results: A humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability. Conclusion: As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.
RESUMO
OBJECTIVE: To establish and verify the validity of a three-dimensional finite element model of the thoracolumbal segments T12-L2; the stress distribution of the model was analyzed, providing a theoretical basis for finite element analysis of thoracolumbal segment fracture as well as a surgical model. METHODS: A healthy female volunteer with no history of lumbar spine injury was selected to obtain CT scan data of the T12-L2 vertebral bodies. Mimics 3D reconstruction software was used to generate the T12-L2 3D model, and surface mesh and body mesh were generated by smoothing treatment and mesh division. The normal finite element model of the T12-L2 vertebral bodies and the finite element model of osteoporosis were established with Ansys finite element software. Under a loading force of 500 N vertically downward and a load of 7.5 Nâ¢m bending moment, seven operating conditions were simulated to analyze the displacement and stress distribution of each vertebral body and intervertebral disc, and to verify the effectiveness of the model. RESULTS: There were 31,901 nodes and 64,244 elements in the thoracolumbar T12-L2 three-dimensional finite element model. These results were similar to the conclusions found in a review of the domestic and global literature, and the finite element model was validated. CONCLUSIONS: The results of this experiment can provide a practical reference for clinical work and help to establish a three-dimensional finite element model of the thoracolumbar junction.
RESUMO
The effect of unilateral and bilateral bone-filling mesh containers (BFC) on osteoporotic vertebral compression fracture (OVCF) was analyzed by the finite element method. The CT scan data of the T12-L2 vertebral body were obtained from a healthy female volunteer with no history of lumbar spine injury or obvious abnormality of vertebral body morphology. The normal finite element model of the T12-L2 vertebral body and the finite element model of osteoporosis were established, and the models were validated. The L1 in the normal model of the vertebral body was used to simulate the vertebral compression fracture, after which the unilateral and bilateral BFC were simulated to establish models representing the two surgical approaches. We analyzed changes in the deformation and von Mises stress in vertebral bodies and intervertebral discs in the two models under seven working conditions (axial direction, anteflexion, rear protraction, left-side bending, right-side bending, left rotation, and right rotation) and found that the unilateral and bilateral approaches are biomechanically comparable, with no statistical difference between the two overall models.
Assuntos
Fraturas por Compressão , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Fenômenos Biomecânicos , Feminino , Análise de Elementos Finitos , Fraturas por Compressão/cirurgia , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/lesões , Vértebras Lombares/cirurgia , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/cirurgia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Telas CirúrgicasRESUMO
OBJECTIVE: To evaluate the biomechanical characteristics of percutaneous anterograde and retrograde screw implantation for superior ramus pubis fractures. METHODS: Mimics software was used to reconstruct the normal pelvis. 3-Matic software was used to establish a model for superior ramus pubis fracture, and percutaneous anterograde/retrograde screw implantation was used to simulate the treatment of a superior ramus pubis fracture. After material assignment by Mimics software, Ansys software simulated the force of a standing position with a 600 N load on an S1 vertebral endplate and then compared the mechanical stability. RESULTS: After simulating the fracture at five points, the effect of anterograde and retrograde screw implantation on the displacement and stress of the pelvis and the left pubic bone were found to be similar. When anterograde screw implantation was used, screw displacement at each point was 1.10 mm, 1.04 mm, 1.10 mm, 1.10 mm, and 1.07 mm; the stress at each point was 14.95 MPa, 11.50 MPa, 18.60 MPa, 18.07 MPa, and 18.37 MPa. When retrograde screw implantation was used, screw displacement at each point was 0.62 mm, 0.62 mm, 0.70 mm, 0.76 mm, and 0.87 mm; and the stress at each point was 5.13 MPa, 4.03 MPa, 6.61 MPa, 9.74 MPa, and 11.55 MPa respectively. CONCLUSIONS: When assessing the treatment of superior ramus pubis fractures from a biomechanical perspective, we found that if the distance between the fracture line and the insertion point is less than 70 mm, it is recommended to use retrograde screw implantation.
RESUMO
A major sign of aging is wrinkles (dynamic lines and static lines) on the surface of the skin. In spite of Botulinum toxin's favorable therapeutic effect today, there have been several reports of its toxicity and side effects. Therefore, the development of an effective and safe wrinkle-fighting compound is imperative. An antioxidant-wrinkle effect was demonstrated by the peptide that we developed and synthesized, termed Skin Peptide. Aiming at the intrinsic defects of the peptide such as hydrolysis and poor membrane penetration, we developed a general approach to transform the Skin Peptide targeting intracellular protein-protein interaction into a bioavailable peptide-gold spherical nano-hybrid, Skin Pcluster. As expected, the results revealed that Skin Pcluster reduced the content of acetylcholine released by neurons in vitro, and then inhibit neuromuscular signal transmission. Additionally, human experiments demonstrated a significant de-wrinkle effect. Moreover, Skin Pcluster is characterized by a reliable safety profile. Consequently, anti-wrinkle peptides and Skin Pcluster nanohybrids demonstrated innovative anti-wrinkle treatments and have significant potential applications.
RESUMO
OBJECTIVE: We aimed to evaluate the advantages of preoperative digital design of skin flaps to repair fingertip defects during the COVID-19 pandemic. We combined digital design with a 3D-printed model of the affected finger for preoperative communication with fingertip defect patients under observation in a buffer ward. METHODS: From December 2019 to January 2021, we obtained data from 25 cases of 30 fingertip defects in 15 males and 10 females, aged 20-65 years old (mean 35 ± 5 years). All cases were treated by digitally designing preoperative fingertip defect flaps combined with a 3D-printed model. Preoperative 3D Systems Sense scanning was routinely performed, 3-matic 12.0 was used to measure the fingertip defect area ranging from 1.5 cm × 3.5 cm to 2.0 cm × 5.0 cm, and the skin flap was designed. The flap area was 1.6 cm × 3.6 cm to 2.1 cm × 5.1 cm. CURA 15.02.1 was used to set parameters, and the 3D model of the affected finger was printed prior to the operation. Full-thickness skin grafts were taken from donor areas for repair. RESULTS: No vascular crises occurred in any of the 25 cases, and all flaps survived. The postoperative follow-up occurred over 3-12 months. All patients were evaluated 3 months after operation according to the trial standard of hand function evaluation of the Chinese Hand Surgery Society. The results showed that 20 cases had excellent outcomes (80%), four cases had good outcomes (16%), and one case had a fair outcome (4%). The excellent and good rate was 96%. CONCLUSIONS: During the COVID-19 epidemic, fingertip defects were treated with preoperative digital design of fingertip defect flaps combined with 3D printing. Precision design saves surgery time and improves the success rate of surgery and the survival rates of skin flaps. In addition, 3D model simulations improve preoperative communication efficiency, and the personalized design improves patient satisfaction.
Assuntos
COVID-19/epidemiologia , Traumatismos dos Dedos/cirurgia , Dedos/cirurgia , Pandemias , Procedimentos de Cirurgia Plástica/métodos , Cuidados Pré-Operatórios/métodos , Transplante de Pele/métodos , Adulto , Idoso , COVID-19/psicologia , China/epidemiologia , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Anatômicos , Impressão Tridimensional/instrumentação , Procedimentos de Cirurgia Plástica/psicologia , SARS-CoV-2/patogenicidade , Transplante de Pele/psicologia , Retalhos Cirúrgicos/irrigação sanguínea , Retalhos Cirúrgicos/inervação , Resultado do Tratamento , Cicatrização/fisiologiaRESUMO
Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson's disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant α-synuclein treated with MPP+/MPTP in vitro and in vivo. Nuclear-localized HDAC4 repressed cAMP response element-binding protein (CREB) and myocyte enhancer factor 2A (MEF2A), altered neuronal gene expression, and promoted neuronal apoptosis. Furthermore, cytoplasm-to-nucleus shuttling of HDAC4 was determined by its phosphorylation status, which was regulated by PP2A and PKCε. Treatment with PKCε-specific activators, DCP-LA or Bryostatin 1, provided neuroprotection against MPP+ toxicity in a dose-dependent manner. In summary, our research illustrated that intracellular trafficking of HDAC4 contributes to the vulnerability of cells expressing pathogenic α-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKCε activators that may serve as therapeutic agents for Parkinson's disease.
Assuntos
Núcleo Celular/enzimologia , Histona Desacetilases/metabolismo , Neurotoxinas/metabolismo , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Núcleo Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos Transgênicos , Mutação/genética , Células PC12 , Fosforilação/efeitos dos fármacos , Proteína Quinase C-épsilon/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Transcrição Gênica/efeitos dos fármacos , alfa-Sinucleína/genéticaRESUMO
Brain ischemic preconditioning (PC) provides vital insights into the endogenous protection against stroke. Genomic and epigenetic responses to PC condition the brain into a state of ischemic tolerance. Notably, PC induces the elevation of histone acetylation, consistent with evidence that histone deacetylase (HDAC) inhibitors protect the brain from ischemic injury. However, less is known about the specific roles of HDACs in this process. HDAC3 has been implicated in several neurodegenerative conditions. Deletion of HDAC3 confers protection against neurotoxicity and neuronal injury. Here, we hypothesized that inhibition of HDAC3 may contribute to the neuronal survival elicited by PC. To address this notion, PC and transient middle cerebral artery occlusion (MCAO) were conducted in Sprague-Dawley rats. Additionally, primary cultured cortical neurons were used to identify the modulators and effectors of HDAC3 involved in PC. We found that nuclear localization of HDAC3 was significantly reduced following PC in vivo and in vitro. Treatment with the HDAC3-specific inhibitor, RGFP966, mimicked the neuroprotective effects of PC 24 h and 7 days after MCAO, causing a reduced infarct volume and less Fluoro-Jade C staining. Improved functional outcomes were observed in the neurological score and rotarod test. We further showed that attenuated recruitment of HDAC3 to promoter regions following PC potentiates transcriptional initiation of genes including Hspa1a, Bcl2l1, and Prdx2, which may underlie the mechanism of protection. In addition, PC-activated calpains were implicated in the cleavage of HDAC3. Pretreatment with calpeptin blockaded the attenuated nuclear distribution of HDAC3 and the protective effect of PC in vivo. Collectively, these results demonstrate that the inhibition of HDAC3 preconditions the brain against ischemic insults, indicating a new approach to evoke endogenous protection against stroke.
RESUMO
Daily stress is associated with increased risk for various diseases, and numerous studies have provided evidence that environmental stress leads to deleterious effects on the central nervous system. However, it remains unclear whether chronic stress exacerbates the progression of Parkinson's disease (PD). To investigate this hypothesis, we determined the effect of chronic mild stress (CMS) on the pathogenesis of PD in a transgenic mice line that overexpresses the human A53T mutant α-synuclein (A53T Tg mice). We show that when exposed to CMS, male, but not female, A53T Tg mice developed profound motor disabilities and exhibited olfactory sensitivity deficits. Pathological analysis also identified robust dopaminergic neuron degeneration and strong reduction of dopamine levels in A53T Tg male mice who underwent CMS treatment. Systematic examination of the abnormal aggregation of α-synuclein revealed a profound increase of inclusion in A53T Tg male mice subject to CMS resembling key pathological changes of PD. An insight into the mechanism underlying stress leading to the acceleration of neurodegeneration in those with genetic susceptibility, was revealed by evidence of microglia activation and elevated pro-inflammatory factor levels in A53T Tg male mice following CMS. Notably, these effects of CMS on the pathogenesis of PD showed a remarkable sexual dimorphism: only male A53T Tg mice exhibited exacerbation of the progression of PD. However, the molecular and cellular bases for this difference remains to be elucidated. Our results indicate a causative role for chronic mild stress using a PD animal model. Based on these findings, we propose that CMS acts as an environmental risk factor that leads to neuroinflammation and progressive neurodegeneration on a background of PD susceptibility.
Assuntos
Predisposição Genética para Doença , Mutação/genética , Doença de Parkinson/etiologia , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , alfa-Sinucleína/genética , Animais , Peso Corporal/genética , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Corpo Estriado/patologia , Corticosterona/sangue , Citocinas/metabolismo , Progressão da Doença , Comportamento Exploratório/fisiologia , Feminino , Preferências Alimentares , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/genética , Neurotransmissores/metabolismo , Transtornos do Olfato/etiologia , Transtornos do Olfato/genética , Doença de Parkinson/genética , Estresse Psicológico/sangue , Substância Negra/patologia , Fatores de Tempo , Ubiquitina/metabolismo , CaminhadaRESUMO
Persistent organic pollutants (POPs) have aroused environmentalists and public concerns due to their toxicity, bioaccumulation and persistency in the environment. However, monitoring atmospheric POPs using conventional instrumental methods is difficult and expensive, and POP levels in air samples represent an instantaneous value at a sampling time. Biomonitoring methods can overcome this limitation, because biomonitors can accumulate POPs, serve as long-term integrators of POPs and provide reliable information to assess the impact of pollutants on the biota and various ecosystems. Recently, mosses are increasingly employed to monitor atmospheric POPs. Mosses have been applied to indicate POP pollution levels in the remote continent of Antarctica, trace distribution of POPs in the vicinity of pollution sources, describe the spatial patterns at the regional scale, and monitor the changes in the pollution intensity along time. In the future, many aspects need to be improved and strengthened: (i) the relationship between the concentrations of POPs in mosses and in the atmosphere (different size particulates and vapor phases); and (ii) the application of biomonitoring with mosses in human health studies.