RESUMO
Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.
Assuntos
Doença de Parkinson/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , Substância Negra/metabolismo , Animais , Comportamento Animal , Transplante de Células , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Células-Tronco Embrionárias/fisiologia , Edição de Genes , Predisposição Genética para Doença , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Células-Tronco Pluripotentes Induzidas/transplante , Camundongos , Camundongos Knockout , Mutação , Células-Tronco Neurais/fisiologia , Células-Tronco Neurais/transplante , Doença de Parkinson/genética , Ratos , Transplante de Células-TroncoRESUMO
It has been reported that damage to the mitochondria affects the progression of Alzheimer's disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In this study, we aimed to (1) identify mitigating effects of endogenous omega-3 on mitochondrial deficits and AD pathology induced by amyloid beta (Aß) in fat-1 mice, a transgenic omega-3 polyunsaturated fatty acids (PUFAs)-producing animal; (2) identify if docosahexaenoic acid (DHA) improves mitochondrial deficits induced by Aß in HT22 cells; and (3) verify improvement effects of DHA administration on mitochondrial deficits and AD pathology in B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD), a transgenic Aß-overexpressing model. We found that omega-3 PUFAs significantly improved Aß-induced mitochondrial pathology in fat-1 mice. In addition, our in vitro and in vivo findings demonstrate that DHA attenuated AD-associated pathologies, such as mitochondrial impairment, Aß accumulation, neuroinflammation, neuronal loss, and impairment of adult hippocampal neurogenesis.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Mitocôndrias/patologia , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular , Feminino , Genótipo , Hipocampo/metabolismo , Hipocampo/patologia , Processamento de Imagem Assistida por Computador , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Neurogênese , Neurônios/metabolismoRESUMO
The aggregation and accumulation of amyloid beta (Aß) peptide is believed to be the primary cause of Alzheimer's disease (AD) pathogenesis. Vitamin D-binding protein (DBP) can attenuate Aß aggregation and accumulation. A biocompatible polymer poly (D,L-lactic acid-co-glycolic acid) (PLGA) can be loaded with therapeutic agents and control the rate of their release. In the present study, a PLGA-based drug delivery system was used to examine the therapeutic effects of DBP-PLGA nanoparticles in Aß-overexpressing (5XFAD) mice. DBP was loaded into PLGA nanoparticles and the characteristics of the DBP-PLGA nanoparticles were analyzed. Using a thioflavin-T assay, we observed that DBP-PLGA nanoparticles significantly inhibited Aß aggregation in vitro. In addition, we found that intravenous injection of DBP-PLGA nanoparticles significantly attenuated the Aß accumulation, neuroinflammation, neuronal loss and cognitive dysfunction in the 5XFAD mice. Collectively, our results suggest that DBP-PLGA nanoparticles could be a promising therapeutic candidate for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteína de Ligação a Vitamina D/administração & dosagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Masculino , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Proteína de Ligação a Vitamina D/uso terapêuticoRESUMO
Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.
Assuntos
Células-Tronco Adultas/metabolismo , Ciclo Celular/genética , Hipocampo/citologia , Células-Tronco Neurais/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Células-Tronco Adultas/efeitos dos fármacos , Amodiaquina/farmacologia , Animais , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Proliferação de Células , Giro Denteado/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , RatosRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aß) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aß-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aß-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aß accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aß-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aß deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Mitocôndrias/efeitos dos fármacos , Panax , Preparações de Plantas/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Panax/química , Preparações de Plantas/químicaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease, which is accompanied by memory loss and cognitive dysfunction. Although a number of trials to treat AD are in progress, there are no drugs available that inhibit the progression of AD. As the aggregation of amyloid-ß (Aß) peptides in the brain is considered to be the major pathology of AD, inhibition of Aß aggregation could be an effective strategy for AD treatment. Jowiseungchungtang (JWS) is a traditional oriental herbal formulation that has been shown to improve cognitive function in patients or animal models with dementia. However, there are no reports examining the effects of JWS on Aß aggregation. Thus, we investigated whether JWS could protect against both Aß aggregates and Aß-mediated pathology such as neuroinflammation, neurodegeneration, and impaired adult neurogenesis in 5 five familial Alzheimer's disease mutations (5XFAD) mice, an animal model for AD. In an in vitro thioflavin T assay, JWS showed a remarkable anti-Aß aggregation effect. Histochemical analysis indicated that JWS had inhibitory effects on Aß aggregation, Aß-induced pathologies, and improved adult hippocampal neurogenesis in vivo. Taken together, these results suggest the therapeutic possibility of JWS for AD targeting Aß aggregation, Aß-mediated neurodegeneration, and impaired adult hippocampal neurogenesis.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Agregados Proteicos/efeitos dos fármacos , Administração Oral , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camundongos , Mutação , NeurogêneseRESUMO
INTRODUCTION: We present the surgical technique of rim-plate-augmented separate vertical wiring for comminuted inferior pole fracture of the patella and report the clinical outcomes. MATERIALS AND METHODS: Between July 2013 and January 2016, 13 patients (7 male and 6 female) who were diagnosed with comminuted inferior pole fracture of the patella in preoperative computed tomography and underwent a minimum of 1 year of follow-up were enrolled in this study. Mean patient age was 57.7 years (range 28-72 years). All patients underwent open reduction and internal fixation by rim-plate-augmented separate vertical wiring. Bony union, complications, range of motion and Bostman score were the clinical outcomes. RESULTS: Bony union was achieved in all cases at an average of 10 weeks after surgery (range 8-12). There was no loss of reduction and fixative failure during follow-up. The average range of motion was 127° (range 120°-130°). The mean Bostman score at last follow-up was 29.6 points (range 27-30) and graded excellent in 12 patients. CONCLUSION: Rim-plate-augmented separate vertical wiring demonstrated secure fixation and favorable clinical outcomes. This study provides evidence for its effectiveness as a fixation method for treating displaced, comminuted inferior pole fracture of the patella.
Assuntos
Fios Ortopédicos , Fixação Interna de Fraturas/métodos , Fraturas Cominutivas/cirurgia , Patela/lesões , Patela/cirurgia , Adulto , Idoso , Feminino , Fraturas Cominutivas/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Patela/diagnóstico por imagemRESUMO
PURPOSE: To review available approaches and fixation methods for posterolateral fracture fragment (PLF) in tibial plateau fracture, and to propose an algorithm to treat various types of plateau fractures which all involve the PLF. METHODS: This article reviews multiple surgical approaches for PLF and suggests an algorithm for suitable approach and fixation method according to PLF with combined plateau fracture. RESULTS: The modified anterolateral approach is a suitable single approach for fractures with a PLF combined with an anterolateral plateau fracture and for isolated posterolateral fracture fragments. For a multicolumn tibia plateau fracture involving the lateral, medial and posterior columns, dual approaches (modified anterolateral and posteromedial approach) can be used to access the entire plateau area. CONCLUSIONS: When considering approaches of this complex fracture pattern, one must consider local soft tissue condition, plateau fracture morphology, associated injuries, and fixation options. After review of multiple approaches described in the literature for PLF fixation, we can suggest an algorithm for the approach and fixation to treat tibial plateau fractures with posterolateral fracture fragments.
Assuntos
Placas Ósseas/efeitos adversos , Fixação Interna de Fraturas/métodos , Fraturas Intra-Articulares/cirurgia , Fraturas da Tíbia/cirurgia , Adulto , Algoritmos , Feminino , Humanos , Traumatismos do Joelho/cirurgia , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Tíbia/cirurgiaRESUMO
INTRODUCTION: Periprosthetic fractures are difficult to manage. Plating technique has been considered a reliable form of management of periprosthetic fractures with a well-fixed stem, but a dependable and stable method of plate fixation to the bone is lacking. This study reports the clinical results using a locking attachment plate (LAP) instead of cable fixation to fix locking plates to a periprosthetic femoral shaft fracture. MATERIALS AND METHODS: Nineteen patients with periprosthetic femoral shaft fractures around well-fixed stemmed implants were studied between August 2012 and December 2014. Patients were followed up for at least 1 year postoperatively. Median age was 74 years (range 56-96 years). Fractures were classified according to the Unified Classification System, Vancouver classification, and Su classification. PROCEDURE: Open reduction was performed under minimal incision and the locking plate was fixed to the lateral cortex of the femoral shaft. The part of the shaft without a stem was fixed to the plate using 5.0-mm locking screws, and the part with an underlying stem was fixed using 3.5-mm locking screws through the LAP instead of cables. Postoperatively, patients were managed using general principles for femoral shaft fractures. RESULTS: Average follow-up was 16 months (range 12-36 months). All cases achieved fracture healing without loss of reduction. There were no cases of implant breakage or stem loosening at final follow-up. The average number of LAPs per fixation construct was 2.1 (range 1-4), and the average number of 3.5-mm locking screws through each LAP was 3.3 (range 2-4). The average value of plate screw density was 0.55 (range 0.37-0.8), and the average working length was four holes (range 2-8). CONCLUSIONS: Using the LAP to manage periprosthetic fractures with a well-fixed stem could obviate the need for cable around the stem area and yield acceptable outcomes.
Assuntos
Placas Ósseas , Fraturas do Fêmur/cirurgia , Redução Aberta/instrumentação , Redução Aberta/métodos , Fraturas Periprotéticas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Fêmur/cirurgia , Seguimentos , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Hirayama disease is a slowly progressing benign motor neuron disease that affects the distal upper limb. A 29-year-old man visited the hospital with a 1-year history of weakened left proximal upper limb. He was diagnosed with Hirayama disease 9 years ago, while there was no further progression of the muscle weakness afterward. Atrophy and weakness was detected in proximal upper limb muscles. Magnetic resonance imaging and somatosensory evoked potentials were normal. Needle electromyography showed abnormal findings in proximal upper limb muscles. Our patient had Hirayama disease involving the proximal portion through secondary progression. Clinical manifestation and accurate electromyography may be useful for diagnosis. Rare cases with progression patterns as described here are helpful and have clinical meaning for clinicians.
Assuntos
Debilidade Muscular/fisiopatologia , Atrofias Musculares Espinais da Infância/diagnóstico , Adulto , Eletromiografia , Potenciais Somatossensoriais Evocados/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/diagnóstico por imagem , Extremidade Superior/diagnóstico por imagemRESUMO
A3 intertrochanteric fracture has a higher incidence of intraoperative re-displacement than A1 and 2. The authors have also experienced difficulty with maintenance of reduction in A3 intertrochanteric fractures, as the technique depends on manual effort and can fail easily during the procedure. It induced us to develop this surgical technique to ease the surgical procedure and improve clinical outcomes. This paper introduces a modified provisional guide pin fixation technique applicable to even AO/OTA A3 intertrochanteric fractures, and presents preliminary results of 11 patients who were treated by provisional pin fixation-assisted nailing in A3 intertrochanteric fractures. Using this technique, we have reduced the chances of intraoperative reduction loss and achieved favorable clinical outcomes.
Assuntos
Pinos Ortopédicos/efeitos adversos , Fixação Intramedular de Fraturas/métodos , Fraturas do Quadril/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Fixação Intramedular de Fraturas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-OperatóriasRESUMO
A randomized, active-controlled, double-blind, first-in-human, phase 1 study was conducted in healthy Korean adults to evaluate the safety, tolerability, and immunogenicity of EuNmCV-5, a new pentavalent meningococcal vaccine targeting serogroups A, C, W, X, and Y. Sixty participants randomly received a single dose of either EuNmCV-5 or MenACWY-CRM, a quadrivalent vaccine containing serogroups A, C, W, and Y. Safety was assessed through monitoring anaphylactic reactions, adverse events for 28 days, and serious adverse events over 180 days. Immunogenicity was assessed via rabbit complement-dependent serum bactericidal antibody (rSBA) assay. EuNmCV-5 was safe, well-tolerated, and elicited a substantial antibody titer increase. The seroprotection rates exceeded 96.7%, and the seroconversion rates were over 85% for all the targeted serogroups. It showed higher seroconversion rates against serogroups A and C (p = 0.0016 and 0.0237, respectively) and elicited a substantial increase in GMT for all targeted serogroups compared to the MenACWY-CRM.ClinicalTrials.gov identifier: NCT05739292.
RESUMO
Most of the clinical studies on the results of MIPO (minimally invasive plate osteosynthesis) with the use of anatomically preshaped locking plates for the complex distal femoral fractures have shown favorable results. In the application of bridge plating, placement of lag screws to the butterfly fragments is usually not recommended because it may make the whole construct too stiff. Recently, problems of nonunion related to excessive stiffness after MIPO using a locked plate were reported but the only solution suggested was reoperation with a bone graft. We herein report a case of nonunion after MIPO of the distal femoral fracture where we applied a concept of "dynamization of the plate-bone construct" to make it less stiff and in turn to get fracture healing with bridging callus formation. A 58-year-old woman sustained a simple oblique fracture of the distal femur (AO-OTA 33A1). We performed MIPO procedure using a locking compression plate-distal femur. To get the alignment, we have placed a conventional screw across the fracture line through the dynamic compression unit (DCU) of the combination hole. Postoperative radiographs revealed 7-8 mm gap across the entire fracture surface which was not obvious on the intra-operative C-arm images. Radiographs taken 6 months after operation showed almost no callus formation with shuttle marginal resorption. We interpreted the situation that the construct was too stiff to allow motion across the fracture site due to the lag screw. We thought we have used it as a reduction screw but it acted as a lag screw, preventing motion at the fracture site. Given this analysis, we have only taken the lag screw out to make the construct less stable. It caused the situation of absolute stability with a significant gap to turn into the one of relative stability with acceptable gap. Fracture has solidly healed with bridging callus formation 6 months after lag screw removal under local anesthesia. We would like to call this strategy as "dynamization" of the locked plating.
Assuntos
Placas Ósseas , Fraturas do Fêmur/cirurgia , Fixação Interna de Fraturas/métodos , Fenômenos Biomecânicos , Parafusos Ósseos , Desenho de Equipamento , Feminino , Fluoroscopia , Humanos , Articulação do Joelho/fisiopatologia , Pessoa de Meia-Idade , Amplitude de Movimento ArticularRESUMO
Epigenetic deregulation of α-synuclein plays a key role in Parkinson's disease (PD). Analysis of the SNCA promoter using the ENCODE database revealed the presence of important histone post-translational modifications (PTMs) including transcription-promoting marks, H3K4me3 and H3K27ac, and repressive mark, H3K27me3. We investigated these histone marks in post-mortem brains of controls and PD patients and observed that only H3K4me3 was significantly elevated at the SNCA promoter of the substantia nigra (SN) of PD patients both in punch biopsy and in NeuN-positive neuronal nuclei samples. To understand the importance of H3K4me3 in regulation of α-synuclein, we developed CRISPR/dCas9-based locus-specific H3K4me3 demethylating system where the catalytic domain of JARID1A was recruited to the SNCA promoter. This CRISPR/dCas9 SunTag-JARID1A significantly reduced H3K4me3 at SNCA promoter and concomitantly decreased α-synuclein both in the neuronal cell line SH-SY5Y and idiopathic PD-iPSC derived dopaminergic neurons. In sum, this study indicates that α-synuclein expression in PD is controlled by SNCA's histone PTMs and modulation of the histone landscape of SNCA can reduce α-synuclein expression.
Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , alfa-Sinucleína , Neurônios Dopaminérgicos , Código das Histonas , Humanos , Doença de Parkinson/genética , alfa-Sinucleína/genéticaRESUMO
Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Oxidative stress has been identified as one of the major causes of nigrostriatal degeneration in PD. Ascorbic acid plays a role as an efficient antioxidant to protect cells from free radical damage, but it is easily oxidized and loses its antioxidant activity. To overcome this limitation, we have recently developed NXP031, a single-stranded DNA aptamer that binds to ascorbic acid with excellent specificity, reducing its oxidation and increasing its efficacy. This study investigated the neuroprotective effects of NXP031 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. Acute degeneration of nigral dopaminergic neurons was induced by four consecutive treatments of MPTP (20 mg/kg) in male C57BL/6 J mice. NXP031 (Vitamin C/Aptamin C 200 mg/4 mg/kg) was administered intraperitoneally for 5 days following MPTP. We observed that the administration of NXP031 ameliorated MPTP-induced loss of dopaminergic neurons in the SN and exhibited improvement of MPTP-mediated motor impairment. We further found that NXP031 increased plasma ascorbic acid levels and inhibited microglia activation-induced neuroinflammation in the SN, which might contribute to the protective effects of NXP031 on nigrostriatal degeneration. Our findings suggest that NXP031 could be a potential therapeutic intervention in PD.
Assuntos
Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Animais , Ácido Ascórbico/sangue , Ácido Ascórbico/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Degeneração Neural/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Substância Negra/patologiaRESUMO
The incidence of intertrochanteric femoral fractures has rapidly increased with the extended lifespan of the elderly population. Surgery enables early ambulation by achieving anatomic reduction and stable internal fixation. However, reduction usually involves postoperative evaluation. Here, we present reliable parameters obtained from analyses of three-dimensional computed tomography images from cadavers to serve as guidelines during the reduction of intertrochanteric fractures. We included 184 three-dimensional modeling samples from cadavers placed in two standardized positions, similar to C-arm imaging. We recorded the level of the orthogonal line from the greater trochanter (GT) tip to the femoral head (GT orthogonal line [GTOL]) in the anteroposterior view and the line along the anterior femoral cortex passing through the femoral head (anterior cortical line) in the axial view. Correlations between these lines and angular alignments were statistically determined. The GTOL passed above the femoral head center at mean 2.36 mm in all patients; 77.17% of such instances were in the upper second quadrant of the femoral head. The anterior cortical line passed under the femoral head center at mean 10.82 mm; 73.37% of such instances were in the inferior one-third of the femoral head. Consistent correlations were found between the GTOL and neck-shaft angle and between the anterior cortical line and anteversion. The GTOL and anterior cortical line passed through a constant level of the femoral head in most samples and were correlated with angular alignments. The intraoperative use of these simple imaginary lines improves the intertrochanteric fracture reduction quality.
Assuntos
Cabeça do Fêmur/diagnóstico por imagem , Fixação Interna de Fraturas/métodos , Fraturas do Quadril/diagnóstico por imagem , Fraturas do Quadril/cirurgia , Monitorização Intraoperatória/métodos , Adulto , Anteversão Óssea/diagnóstico por imagem , Cadáver , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
Loss-of-function mutations of DNAJC6, encoding HSP40 auxilin, have recently been identified in patients with early-onset Parkinson's disease (PD). To study the roles of DNAJC6 in PD pathogenesis, we used human embryonic stem cells with CRISPR-Cas9-mediated gene editing. Here, we show that DNAJC6 mutations cause key PD pathologic features, i.e., midbrain-type dopamine (mDA) neuron degeneration, pathologic α-synuclein aggregation, increase of intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions in human midbrain-like organoids (hMLOs). In addition, neurodevelopmental defects were also manifested in hMLOs carrying the mutations. Transcriptomic analyses followed by experimental validation revealed that defects in DNAJC6-mediated endocytosis impair the WNT-LMX1A signal during the mDA neuron development. Furthermore, reduced LMX1A expression during development caused the generation of vulnerable mDA neurons with the pathologic manifestations. These results suggest that the human model of DNAJC6-PD recapitulates disease phenotypes and reveals mechanisms underlying disease pathology, providing a platform for assessing therapeutic interventions.
Assuntos
Doença de Parkinson , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Mesencéfalo , Mutação , Organoides/metabolismo , Doença de Parkinson/metabolismo , FenótipoRESUMO
BACKGROUND AND AIM: Revaprazan is a novel acid pump antagonist. The aim of this study was to investigate the inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects. METHODS: In a double-blind, three-way cross-over study, 30 healthy male volunteers were randomized to 100, 150 or 200 mg of oral revaprazan daily for 7 days. Serum gastrin concentration was measured, and 24-h intragastric pH was recorded at baseline and on days 1 and 7 of each administration period. Serial blood samples were processed for pharmacokinetics. RESULTS: Median intragastric pH over 24 h and mean percentage time that pH was > 4 increased in a dose-dependent manner and were significantly higher on days 1 and 7 compared with baseline in all groups (P < 0.05). The antisecretory effect of revaprazan was rapid and nearly maximal on day 1 in all groups. Serum gastrin levels were rapidly normalized by 100 and 150 mg/day of revaprazan on days 1 and 7, but were significantly higher in the 200 mg/day revaprazan group. The pharmacokinetic effect was rapidly absorbed and eliminated on days 1 and 7 in all groups. CONCLUSIONS: Revaprazan rapidly and effectively inhibits gastric acid secretion in healthy male subjects. Therefore, revaprazan can be used as an effective drug for acid-related disease.
Assuntos
Esofagite Péptica/tratamento farmacológico , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Úlcera Péptica/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esofagite Péptica/metabolismo , Seguimentos , Determinação da Acidez Gástrica , Humanos , Masculino , Úlcera Péptica/metabolismo , Valores de Referência , Estômago/efeitos dos fármacosRESUMO
Several studies have revealed that the transcription factor nuclear receptor related 1 (Nurr1) plays several roles not only in the regulation of gene expression related to dopamine synthesis, but also in alternative splicing, and miRNA targeting. Moreover, it regulates cognitive functions and protects against inflammation-induced neuronal death. In particular, the role of Nurr1 in the pathogenesis of Parkinson's disease (PD) has been well investigated; for example, it has been shown that it restores behavioral and histological impairments in PD models. Although many studies have evaluated the connection between Nurr1 and PD pathogenesis, the role of Nurr1 in Alzheimer's disease (AD) remain to be studied. There have been several studies describing Nurr1 protein expression in the AD brain. However, only a few studies have examined the role of Nurr1 in the context of AD. Therefore, in this review, we highlight the overall effects of Nurr1 under the neuropathologic conditions related to AD. Furthermore, we suggest the possibility of using Nurr1 as a therapeutic target for AD or other neurodegenerative disorders.
RESUMO
Although the major causative factors of Alzheimer's disease (AD) are the accumulation of amyloid ß and hyperphosphorylated tau, AD can also be caused by metabolic dysfunction. The major clinical symptom of AD is cognitive dysfunction. However, AD is also accompanied by various secondary symptoms such as depression, sleep-wake disturbances, and abnormal eating behaviors. Interestingly, the orexigenic hormone ghrelin has been suggested to have beneficial effects on AD-related metabolic syndrome and secondary symptoms. Ghrelin improves lipid distribution and alters insulin sensitivity, effects that are hypothesized to delay the progression of AD. Furthermore, ghrelin can relieve depression by enhancing the secretion of hormones such as serotonin, noradrenaline, and orexin. Moreover, ghrelin can upregulate the expression of neurotrophic factors such as brain-derived neurotrophic factor and modulate the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1ß. Ghrelin alleviates sleep-wake disturbances by increasing the levels of melatonin, melanin-concentrating hormone. Ghrelin reduces the risk of abnormal eating behaviors by increasing neuropeptide Y and γ-aminobutyric acid. In addition, ghrelin increases food intake by inhibiting fatty acid biosynthesis. However, despite the numerous studies on the role of ghrelin in the AD-related pathology and metabolic disorders, there are only a few studies that investigate the effects of ghrelin on secondary symptoms associated with AD. In this mini review, our purpose is to provide the insights of future study by organizing the previous studies for the role of ghrelin in AD-related pathology and metabolic disorders.