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1.
NPJ Vaccines ; 9(1): 140, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39112515

RESUMEN

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.

2.
Sci Adv ; 7(8)2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33597231

RESUMEN

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.


Asunto(s)
Enfermedad de Parkinson , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/metabolismo , Humanos , Mesencéfalo , Mutación , Organoides/metabolismo , Enfermedad de Parkinson/metabolismo , Fenotipo
3.
EMBO Mol Med ; 13(2): e12188, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33428332

RESUMEN

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.


Asunto(s)
Células Madre Pluripotentes Inducidas , Enfermedad de Parkinson , alfa-Sinucleína , Neuronas Dopaminérgicas , Código de Histonas , Humanos , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética
4.
Neurosci Lett ; 740: 135425, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33075422

RESUMEN

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.


Asunto(s)
Intoxicación por MPTP/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Animales , Ácido Ascórbico/sangre , Ácido Ascórbico/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Intoxicación por MPTP/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Degeneración Nerviosa/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/patología , Equilibrio Postural/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Sustancia Negra/patología
5.
Asian J Surg ; 44(1): 66-71, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33262045

RESUMEN

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.


Asunto(s)
Cabeza Femoral/diagnóstico por imagen , Fijación Interna de Fracturas/métodos , Fracturas de Cadera/diagnóstico por imagen , Fracturas de Cadera/cirugía , Monitoreo Intraoperatorio/métodos , Adulto , Anteversión Ósea/diagnóstico por imagen , Cadáver , Femenino , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Adulto Joven
6.
Front Neurosci ; 14: 583097, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33071750

RESUMEN

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.

7.
Int J Mol Sci ; 21(11)2020 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-32486013

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Mitocondrias/patología , Enfermedad de Alzheimer/metabolismo , Animales , Línea Celular , Supervivencia Celular , Femenino , Genotipo , Hipocampo/metabolismo , Hipocampo/patología , Procesamiento de Imagen Asistido por Computador , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Neurogénesis , Neuronas/metabolismo
8.
Aging Dis ; 11(3): 705-724, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32489714

RESUMEN

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.

9.
Int J Mol Sci ; 21(1)2019 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-31861329

RESUMEN

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.


Asunto(s)
Células Madre Adultas/metabolismo , Ciclo Celular/genética , Hipocampo/citología , Células-Madre Neurales/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Células Madre Adultas/efectos de los fármacos , Amodiaquina/farmacología , Animales , Biomarcadores , Ciclo Celular/efectos de los fármacos , Proliferación Celular , Giro Dentado/metabolismo , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Regulación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Ratones , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neurogénesis/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Ratas
10.
EMBO J ; 38(24): e101196, 2019 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-31750563

RESUMEN

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.


Asunto(s)
Enfermedad de Parkinson/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/fisiología , Sustancia Negra/metabolismo , Animales , Conducta Animal , Trasplante de Células , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/fisiología , Células Madre Embrionarias/fisiología , Edición Génica , Predisposición Genética a la Enfermedad , Humanos , Células Madre Pluripotentes Inducidas/fisiología , Células Madre Pluripotentes Inducidas/trasplante , Ratones , Ratones Noqueados , Mutación , Células-Madre Neurales/fisiología , Células-Madre Neurales/trasplante , Enfermedad de Parkinson/genética , Ratas , Trasplante de Células Madre
11.
Aging Dis ; 10(2): 307-328, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31435482

RESUMEN

Alzheimer's disease (AD), which is the most major cause of dementia, is a progressive neurodegenerative disease that affects cognitive functions. Even though the prevalence of AD is continuously increasing, few drugs including cholinesterase inhibitors and N-methyl D-aspartate-receptor antagonists were approved to treat AD. Because the clinical trials of AD drugs with single targets, such as ß-amyloid and tau, have failed, the development of multi-target drugs that ameliorate many of the symptoms of AD is needed. Thus, recent studies have investigated the effects and underlying mechanisms of herbal formulae consisting of various herb combinations used to treat AD. This review discusses the results of clinical and nonclinical studies of the therapeutic efficacy in AD and underlying mechanisms of the herbal formulae of traditional Oriental medicines and bioactive compounds of medicinal plants.

12.
Ageing Res Rev ; 55: 100945, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31434007

RESUMEN

Ghrelin, which has many important physiological roles, such as stimulating food intake, regulating energy homeostasis, and releasing insulin, has recently been studied for its roles in a diverse range of neurological disorders. Despite the several functions of ghrelin in the central nervous system, whether it works as a therapeutic agent for neurological dysfunction has been unclear. Altered levels and various roles of ghrelin have been reported in Alzheimer's disease (AD), which is characterized by the accumulation of misfolded proteins resulting in synaptic loss and cognitive decline. Interestingly, treatment with ghrelin or with the agonist of ghrelin receptor showed attenuation in several cases of AD-related pathology. These findings suggest the potential therapeutic implications of ghrelin in the pathogenesis of AD. In the present review, we summarized the roles of ghrelin in AD pathogenesis, amyloid beta (Aß) homeostasis, tau hyperphosphorylation, neuroinflammation, mitochondrial deficit, synaptic dysfunction and cognitive impairment. The findings from this review suggest that ghrelin has a novel therapeutic potential for AD treatment. Thus, rigorously designed studies are needed to establish an effective AD-modifying strategy.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Ghrelina/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Mitocondrias/metabolismo , Proteínas tau/metabolismo
13.
Transl Oncol ; 12(9): 1264-1270, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31302474

RESUMEN

Immune checkpoint inhibitors (ICIs) have become an effective therapeutic option for colorectal cancer and studies on these drugs have therefore increased greatly. Efficacy assessments of ICIs in preclinical orthotopic colorectal cancer using MRI have not been reported however due to the difficulties in conducting colorectal imaging. The purpose of this present study was to investigate the feasibility of using magnetic resonance colonography (MRC) to evaluate the efficacy of an ICI, an anti-PD-L1 antibody, in an orthotopic colorectal cancer mouse model. The mouse model was generated by the engraftment of colorectal cancer cells into the submucosal layer of the colon. Anti-cancer efficacy was assessed by tumor volume and metastatic tumor number analyses, and these values were significantly lower in the PD-L1 antibody-treated group compared to the controls. Histological analyses using H&E and Ki-67 immunohistochemical staining confirmed a highly efficacious tumor growth inhibition and enhanced infiltration by CD4+ and CD8+ lymphocytes in the PD-L1 antibody-treated group. We conclude that MRC has the potential to be used for ICI efficacy assessments against orthotopic colorectal cancer mouse model.

14.
Int J Mol Sci ; 20(12)2019 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-31234321

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Mitocondrias/efectos de los fármacos , Panax , Preparaciones de Plantas/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Panax/química , Preparaciones de Plantas/química
15.
Nanomedicine ; 17: 297-307, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30794963

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Portadores de Fármacos/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Proteína de Unión a Vitamina D/administración & dosificación , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Masculino , Ratones , Ratones Transgénicos , Nanopartículas/química , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Proteína de Unión a Vitamina D/uso terapéutico
16.
Int J Mol Sci ; 19(12)2018 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-30551564

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Agregado de Proteínas/efectos de los fármacos , Administración Oral , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Femenino , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Ratones , Mutación , Neurogénesis
17.
Neurochem Int ; 121: 114-124, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30291956

RESUMEN

One of the pathological hallmarks of Alzheimer's disease (AD) is the abnormal aggregation of amyloid beta (Aß) peptides. Uncaria rhynchophylla (UR), one of the Uncaria species, has long been used to treat neurodegenerative disease. In particular, it has been reported that UR inhibits aggregation of Aß in vitro. However, little is known about the histological effects of UR treatment on Aß pathology in AD animal models. In the present study, we investigated the effect of UR on Aß aggregation, Aß-mediated pathologies and adult hippocampal neurogenesis in the brain of 5XFAD mice. First, using the thioflavin T assay and amyloid staining, we demonstrated that UR treatment effectively inhibited Aß aggregation and accumulation in the cortex and subiculum. Second, immunofluorescence staining showed that administration of UR attenuated gliosis and neurodegeneration in the subiculum and cortex. Third, UR treatment ameliorated impaired adult hippocampal neurogenesis. The present results indicate that UR significantly alleviates Aß deposition and Aß-mediated neuropathology in the brain in 5XFAD mice, suggesting the potency of UR as a preventive and therapeutic agent for AD.


Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Extractos Vegetales/farmacología , Uncaria , Animales , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Transgénicos , Extractos Vegetales/aislamiento & purificación
18.
Injury ; 49(10): 1912-1921, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30060889

RESUMEN

INTRODUCTION: Local delivery of high dose antibiotics in the form of antibiotic impregnated polymethyl methacrylate (PMMA) cement beads or coated rods is commonly used in the management of long bone infections. The downsides of antibiotic cement beads for intramedullary long bone infections are associated with difficulty in removal from the medullary canal, bead breakage, and lack of stability. Antibiotic cement-coated smooth flexible guide wires, rods and nails can have complications such as delamination or debonding of the cement. In addition, the current techniques for cement rod insertion have a risk of iatrogenic joint contamination. To improve upon this technique and decrease potential complications, we propose the use of an antibiotic cement-coated hinged threaded rod as a temporary intramedullary spacer. This technique utilizes both an antegrade and retrograde insertion of the threaded rod into the medullary canal through the bony defect site with connection at the hinge to treat intramedullary long bone infections and infected nonunions. MATERIAL AND METHODS: A total of 40 patients were included in the study. The details in making the cement rod were well documented. The shape of cement rod and the integrity of the cement at the time of rod insertion and rod removal were compared to identify any cement debonding or delamination. Potential postoperative complications including iatrogenic joint infection, displacement or breakage of the threaded cement rods, and fracture displacement were all carefully documented. The preliminary biological effect of the initial debridement and antibiotic cement rod placement was determined using the negative conversion rate of intraoperative cultures. RESULTS: A single antibiotic coated threaded rod was inserted in 18 cases. Two separate antibiotic coated threaded rods were inserted and connected via hinge in 22 cases. There were zero cases of rod breakage and no secondary loss of reduction from antibiotic rod placement to the definitive staged operation. There were zero iatrogenic joint infections. There were zero cases of cement debonding or delamination from the rod. The conversion rate to a negative culture after initial debridement and antibiotic rod placement was 85% (34/40 cases). CONCLUSIONS: The use of an antibiotic coated cement threaded rod with a hinge as an intramedullary spacer provides the benefits of local antibiotic delivery, offers improved construct stability, makes implant removal easier without delamination of the cement mantle, and utilizes the versatility of a hinge to prevent violation of native joints when treating infected nonunions and intramedullary long bone infections.


Asunto(s)
Antibacterianos/administración & dosificación , Sistemas de Liberación de Medicamentos/instrumentación , Fracturas del Fémur/cirugía , Fijación Intramedular de Fracturas/efectos adversos , Fracturas no Consolidadas/cirugía , Osteomielitis/tratamiento farmacológico , Complicaciones Posoperatorias/microbiología , Fracturas de la Tibia/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Cementos para Huesos/farmacología , Clavos Ortopédicos , Desbridamiento , Femenino , Fracturas del Fémur/microbiología , Curación de Fractura/fisiología , Fracturas no Consolidadas/microbiología , Humanos , Masculino , Persona de Mediana Edad , Osteomielitis/prevención & control , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Fracturas de la Tibia/microbiología , Resultado del Tratamiento
19.
PLoS One ; 13(1): e0187063, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29370209

RESUMEN

PURPOSE: Targeting of vascular endothelial growth factor receptors (VEGFRs) has potential anti-angiogenic effects because VEGFR-2 is the major signaling regulator of VEGF/VEGFR pathways. We aimed to elucidate the drug mechanism and anti-tumor efficacy of TTAC-0001, a novel, fully human anti-VEGFR-2/KDR monoclonal antibody, in mouse orthotopic breast cancer model using multi-modal bioimaging. MATERIALS AND METHODS: We used orthotopic xenograft tumor model in which human breast cancer cells (MDA-MB-231) were injected into the right mammary fat pad of Balb/c nude mice. We investigated its biodistribution using serial fluorescence imaging after injecting fluorescent-labelled-drug and mode of action using Matrigel plug angiogenesis assays. The anti-tumor efficacy of drug was assessed using ultrasonography and bioluminescence imaging. Histopathologic analyses, including hematoxylin and eosin staining and immunohistochemistry with anti-CD31 and anti-Ki-67 antibodies, were performed. Each experiment had four groups: control, bevacizumab 10 mg/kg (BVZ-10 group), TTAC-0001 2 mg/kg (TTAC-2 group), and TTAC-0001 10 mg/kg (TTAC-10 group). RESULTS: The TTAC-10 group showed good tumor targeting that lasted for at least 6 days and had a good anti-angiogenic effect with decreased hemoglobin content and fewer CD31-positive cells in the Matrigel plug. Compared with BVZ-10 and TTAC-2 groups, the TTAC-10 group showed the strongest anti-tumor efficacy, inhibiting tumor growth as detected by ultrasonography and bioluminescence imaging. The TTAC-10 group also showed the lowest viable tumor and micro-vessel areas and the lowest Ki-67 index in histopathologic analyses. CONCLUSION: We firstly demonstrated that TTAC-0001 effectively inhibited tumor growth and neovascularization in mouse orthotopic breast cancer model. It may provide a future treatment option for breast cancer.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Modelos Animales de Enfermedad , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/diagnóstico por imagen , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Imagen Multimodal , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
20.
Arch Orthop Trauma Surg ; 138(2): 195-202, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29058078

RESUMEN

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.


Asunto(s)
Hilos Ortopédicos , Fijación Interna de Fracturas/métodos , Fracturas Conminutas/cirugía , Rótula/lesiones , Rótula/cirugía , Adulto , Anciano , Femenino , Fracturas Conminutas/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Rótula/diagnóstico por imagen
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