RESUMEN
The incidence and prevalence of Parkinson's disease (PD) is expected to raise dramatically over the next decades. Gender-related differences are not yet widely recognized, particularly regarding the response to dopaminergic medications. To analyse gender differences in the clinical effects of safinamide, compared to placebo, in Chinese PD patients of the pivotal XINDI trial. The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Patients were followed for 16 weeks receiving safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson's Disease Rating Scale and Parkinson's Disease Questionnaire-39 items. A post-hoc analysis was performed to describe the efficacy of safinamide in both genders on motor symptoms, motor fluctuations and quality of life. 128 (42%) out of 305 patients enrolled were women and 177 (58%) men. Our additional analyses of the XINDI study have shown that safinamide, compared to placebo, was associated with improvements in motor symptoms, motor fluctuations and quality of life in both genders, with some differences in the response that did not reach statistical significance, possibly due to sample size limitation and post-hoc design of the study. The changes from baseline at week 16 were > 50% higher in the females compared to males for the total daily OFF time (- 1.149 h vs - 0.764 h in males), the total daily ON time (1.283 h vs 0.441 h in males), the UPDRS total score (- 8.300 points vs - 5.253 points in males) and the UPDRS part II score (- 2.574 points vs - 1.016 points in males). The changes from baseline at week 16 were higher in the females compared to males in the "ADL" domain (- 6.965 points vs - 5.772 points in males), the "Emotional well-being" domain (- 6.243 points vs - 4.203 in males), the "Stigma" domain (- 6.185 points vs - 4.913 points in males) and the "Bodily discomfort" domain (- 5.196 points vs 1.099 points in males), while were higher in males in the "Mobility" score (- 6.523 points vs - 4.961 points in females) and the "Communication" score (- 3.863 points vs - 1.564 points in females). Safinamide was shown to improve PD symptoms and quality of life in both male and female Chinese patients. Possible differences in the response between genders need to be further studied in larger and different ethnic populations.
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Antiparkinsonianos , Enfermedad de Parkinson , Femenino , Humanos , Masculino , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Método Doble Ciego , Pueblos del Este de Asia , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/complicaciones , Calidad de VidaRESUMEN
Background: MFN2 gene encodes the protein Mitofusin 2, involved in essential mitochondrial functions such as fusion, trafficking, turnover, and cellular interactions. We describe a family carrying a novel MFN2 mutation associated with ALS-frontotemporal dementia (FTD) clinical phenotype in the mother and Charcot-Marie-Tooth disease type 2A (CMT2A) in her son. Case presentation: The mother, a 67-year-old woman, referred to us for a three year-history of mood disturbance and gait impairment, and a more recent hypophonia, dysarthria, dysphagia, and diffuse muscle wasting. Family history was positive for psychiatric disorders and gait disturbances. Brain 18F-FDG PET showed severe hypometabolism in the fronto-temporal brain cortex bilaterally. Electrodiagnostic studies (EDX) showed severe motor axonopathy in the bulbar, cervical and lumbosacral districts. Her 41-year-old son had a history of mood depression and sensory disturbances in the limbs, along with mild muscle wasting, weakness, and reduced reflexes. Nerve conduction studies revealed a moderate sensory-motor polyneuropathy, while brain MRI was normal. Whole exome sequencing of the patients' DNA identified the novel MFN2 (NM_014874.4) variant c.581A>C p.(Asp194Ala). Conclusion: Our findings provide evidence of heterogenous clinical manifestations in family members sharing the same MFN2 molecular defect. Additionally, we present the first documented case of ASL-FTD associated with an MFN2 mutation, thereby expanding the range of MFN-related disorders. Further research involving larger cohorts of patients will be needed to better understand the role of MFN2 as a contributing gene in the development of ALS-FTD.
RESUMEN
Gender is an important factor influencing epidemiological and clinical features of Parkinson's disease (PD). We aimed to evaluate gender differences in the expression of a panel of miRNAs (miR-34a-5p, miR-146a, miR-155, miR-29a, miR-106a) possibly involved in the pathophysiology or progression of disease. Serum samples were obtained from 104 PD patients (58 men and 46 women) never treated with levodopa. We measured levels of miRNAs using quantitative PCR. Correlations between miRNA expression and clinical data were assessed using the Spearman's correlation test. We used STRING to evaluate co-expression relationship among target genes. MiR-34a-5p was significantly upregulated in PD male patients compared to PD female patients (fc: 1.62; p < 0.0001). No correlation was found with age, BMI, and disease severity, assessed by UPDRS III scale, in male and female patients. MiR-146a-5p was significantly upregulated in female as compared to male patients (fc: 3.44; p < 0.0001) and a significant correlation was also observed between disease duration and mir-146a-5p. No differences were found in the expression of miR-29a, miR-106a-5p and miR-155 between genders. Predicted target genes for miR-34a-5p and miR-146-5p and protein interactions in biological processes were reported. Our study supports the hypothesis that there are gender-specific differences in serum miRNAs expression in PD patients. Follow-up of this cohort is needed to understand if these differences may affect disease progression and response to treatment.
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MicroARNs , Enfermedad de Parkinson , Humanos , Masculino , Femenino , Levodopa/uso terapéutico , Factores Sexuales , Biomarcadores , MicroARNs/genética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genéticaRESUMEN
Diagnosis of multiple system atrophy (MSA) may be improved by using multimodal imaging approaches. We investigated the use of T1-weighted/T2-weighted (T1w/T2w) images ratio combined with voxel-based morphometry to evaluate brain tissue integrity in MSA compared to Parkinson's disease (PD) and healthy controls (HC). Twenty-six patients with MSA, 43 patients with PD and 56 HC were enrolled. Whole brain voxel-based and local regional analyses were performed to evaluate gray and white matter (GM and WM) tissue integrity and mean regional values were used for patients classification using logistic regression. Increased mean regional values of T1w/T2w in bilateral putamen were detected in MSA-P compared to PD and HC. The combined use of regional GM and T1w/T2w values in the right and left putamen showed the highest accuracy in discriminating MSA-P from PD and good accuracy in discriminating MSA from PD and HC. A good accuracy was also found in discriminating MSA from PD and HC by either combining regional GM and T1w/T2w values in the cerebellum or regional WM and T1w/T2w in the cerebellum and brainstem. The T1w/T2w image ratio alone or combined with validated MRI parameters can be further considered as a potential candidate biomarker for differential diagnosis of MSA.
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Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Anciano , Biomarcadores/análisis , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Sustancia Gris/patología , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Sustancia Blanca/patologíaRESUMEN
BACKGROUND AND PURPOSE: Parkinson disease (PD) patients are classically classified according to two alternative motor subtyping methods: (i) tremor-dominant versus postural instability and gait disorder; (ii) tremor-dominant versus akinetic-rigid. The degree of overlap between the two classification systems at diagnosis of PD and their temporal stability, as well as the correspondence between the two systems, were examined over a follow-up period of 4 years. METHODS: Newly diagnosed, untreated PD patients were classified as tremor-dominant versus postural instability and gait disorder and tremor-dominant versus akinetic-rigid at baseline and after 2 and 4 years. RESULTS: There was a poor overlap between the two classification systems at any time point and baseline subtype status could not predict 4-year subtype membership. In fact, about half of our cohort shifted category during the first 2 years, regardless of the classification scheme adopted. A lower rate of shift was observed from 2- to 4-year follow-up. CONCLUSIONS: The two classical motor subtyping methods of PD poorly overlap, which implies that a patient can be categorized as tremor-dominant in one classification system but not in the other. Moreover, their temporal instability undermines their prognostic value in the early stage of PD.
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Trastornos Neurológicos de la Marcha/fisiopatología , Hipocinesia/fisiopatología , Enfermedad de Parkinson/fisiopatología , Equilibrio Postural/fisiología , Temblor/fisiopatología , Anciano , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Hipocinesia/etiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/clasificación , Enfermedad de Parkinson/complicaciones , Temblor/etiologíaRESUMEN
BACKGROUND AND PURPOSE: Very little is known about the progression of non-motor symptoms (NMSs) in Parkinson's disease (PD) and there are no longitudinal studies exploring this topic from the earliest stage, when patients receive the diagnosis. We here report on the progression of NMSs over 4 years from diagnosis in a cohort of de-novo, previously untreated, patients with PD. METHODS: Consecutive de-novo (disease duration < 2 years), untreated patients with PD were enrolled in this observational study. Evaluations were then scheduled every 2 years and included assessment of motor and non-motor features as well as of quality of life measures. RESULTS: Sixty-one patients were prospectively followed-up for 4 years from diagnosis. The majority of NMSs increased over time and significantly affected quality of life, whereas motor disability did not. There was no significant association between NMSs and dopaminergic therapy in terms of both drug class and total levodopa-equivalent daily dosage. Excessive daytime sleepiness was the only NMS correlating with therapy with dopamine agonists. Female patients were more likely to have worse quality of life. CONCLUSIONS: Non-motor symptoms significantly increase over time, with a different progression rate for each one. NMSs significantly affect quality of life in PD and we here demonstrated that this was especially the case when patients were in their (motor) honeymoon period. Future trials should target non-dopaminergic networks and consider NMSs in their outcomes.
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Enfermedad de Parkinson/diagnóstico , Calidad de Vida , Progresión de la Enfermedad , Agonistas de Dopamina/uso terapéutico , Femenino , Humanos , Levodopa/uso terapéutico , Estudios Longitudinales , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Factores Sexuales , Evaluación de SíntomasRESUMEN
BACKGROUND AND PURPOSE: Oxidative stress is a central pathogenic mechanism of Parkinson's disease (PD), and the heme oxygenase (HO) bilirubin pathway is one of the main mammalian antioxidative defences. Indeed, there is growing evidence of HO-bilirubin upregulation from early phases of PD. Our aim was to investigate bilirubin as a possible biomarker of PD diagnosis and progression. METHODS: A cross-sectional case-control study was performed to evaluate differences in bilirubin levels between newly diagnosed, drug-naïve PD subjects and controls. Afterwards, PD subjects were included in a 2-year longitudinal study to evaluate disease progression in relation to baseline bilirubin levels. RESULTS: Seventy-five de novo PD subjects were selected and matched with 75 controls by propensity score. Analysis of variance showed higher bilirubin levels in PD patients compared with controls (P < 0.001). Linear regression analysis failed to show a relationship between bilirubin and Unified Parkinson's Disease Rating Scale (UPDRS) part III (P = 0.283) at baseline evaluation. At 2-year follow-up, indirect relationships between bilirubin levels and UPDRS part III (P = 0.028) and between bilirubin levels and levodopa-equivalent daily dosage (P = 0.012) were found. CONCLUSIONS: Parkinson's disease subjects showed higher levels of bilirubin compared with controls. Bilirubin increase might be due to HO overexpression as a compensatory response to oxidative stress occurring from early stages of PD.
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Bilirrubina/sangre , Enfermedad de Parkinson/sangre , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Mild cognitive impairment (MCI) is a common feature in Parkinson's disease (PD). We performed an exploratory study to investigate dopaminergic nigrostriatal innervation and its cognitive correlates in early untreated PD patients with MCI as compared to cognitively intact patients. PATIENTS AND METHODS: A consecutive series of 34-de-novo, drug-naïve patients with PD were enrolled. They underwent [123-I] FP-CIT SPECT and comprehensive neuropsychological battery. MCI was identified in 15 of 34 patients with PD. RESULTS: The two groups did not show any statistically significant difference in age, sex, disease duration, education, lateralization, and H&Y and Hospital Anxiety and Depression Scale scores. Logistic regression analysis showed that UPDRS-III was weakly associated with MCI (P = 0.034). Partial correlation analysis controlling for UPDRS-III and age suggested that in PD patients with MCI reduced V3â³ values in the more affected caudate were correlated with reduced performances in frontal assessment battery, Trail Making Test: part B minus Part A and copy task of the Rey-Osterrieth complex figure test. Reduced V3â³ values in the more and less affected putamen were significantly related with reduced performance in frontal assessment battery and in copy task of Rey-Osterrieth complex figure test, respectively. No correlation was found between neuropsychological scores and DAT availability in PD patients without MCI. CONCLUSIONS: Although preliminary, our results suggest that striatal dopamine depletion may contribute to some cognitive deficit in early never treated PD patients with MCI.
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Disfunción Cognitiva/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Enfermedad de Parkinson/diagnóstico por imagen , Anciano , Disfunción Cognitiva/etiología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Escalas de Valoración Psiquiátrica , Tomografía Computarizada de Emisión de Fotón Único/métodos , TropanosRESUMEN
BACKGROUND AND PURPOSE: Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinson's disease (PD). The aim of the present study was to determine the progression of cognitive impairment in drug-naïve untreated PD patients with or without clinically significant apathy. METHODS: Sixty-two PD patients with a disease duration <2 years and without history of present or past therapy with pro-dopaminergic agents were included and underwent the Apathy Evaluation Scale (S-AES), a clinical interview based on diagnostic criteria for apathy and a comprehensive neuropsychological battery to assess memory, frontal functions and visuospatial functions. Two years after the first assessment, all patients were re-evaluated on the S-AES, a clinical interview and neuropsychological tests. RESULTS: According to the cut-off value of the S-AES and diagnostic criteria for apathy, eight patients experienced apathy at both baseline and follow-up (A+A+), nine patients had apathy only at follow-up (A-A+), 37 patients never experienced apathy (A-A-) and eight patients showed apathy at the baseline only (A+A-). Cognitive performance significantly declined in all four groups. At both baseline and follow-up A+A+ performed worse than A-A- on visuospatial and frontal tests; A-A+ had lower scores than A-A- on the interference task of the Stroop test (IT-ST). Regression analysis showed that poor performance on the IT-ST at baseline was the only independent predictor of onset of apathy at follow-up. CONCLUSIONS: The results indicated a relationship between apathy and dysexecutive syndrome in early PD. Reduced scores on the IT-ST may predict development of apathy in PD patients.
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Apatía/fisiología , Trastornos del Conocimiento/etiología , Función Ejecutiva/fisiología , Enfermedad de Parkinson/complicaciones , Anciano , Trastornos del Conocimiento/fisiopatología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatologíaRESUMEN
BACKGROUND AND PURPOSE: Uric acid (UA) has been studied extensively as a valuable biomarker of Parkinson's disease (PD), but its relationship with non-motor symptoms (NMS) in de novo PD has been poorly investigated. Our aim was to evaluate the usefulness of baseline serum UA as a marker of NMS progression in newly diagnosed PD. METHODS: Sixty-nine newly diagnosed PD patients were enrolled. At baseline, all patients completed the NMS questionnaire (NMSQuest), and serum UA levels were measured. After 2 years, the NMSQuest was completed again and patients were categorized into four groups: NMS improvement (domain involvement at baseline but not at 2-year follow-up visit), NMS absence (domain not involved at baseline or 2-year follow-up visits), NMS presence (domain involvement both at baseline and 2-year follow-up visits) and NMS worsening (domain not involved at baseline but involved at 2-year follow-up). RESULTS: ANOVA with post hoc Bonferroni correction showed that patients with NMS absence presented significantly higher UA values than patients with NMS presence with regard to the attention/memory (P = 0.023), depression/anxiety (P = 0.028) and cardiovascular domains (P = 0.002), whilst no differences were found with regard to both the NMS improvement and worsening groups. In addition, multinomial regression analysis showed that the lowest tertile of NMS progression presented higher UA levels (P = 0.023; odds ratio 0.488) compared with patients with greater NMS progression. CONCLUSIONS: This is the first report of a relationship between serum UA and presence/progression of multiple NMS in de novo PD, providing additional evidence of the reliability of UA as a biomarker of PD and opening new insights on PD neuroprotection.
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Progresión de la Enfermedad , Enfermedad de Parkinson/fisiopatología , Ácido Úrico/sangre , Adulto , Anciano , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/clasificaciónRESUMEN
Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.
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Encéfalo/patología , Encéfalo/fisiopatología , Síndrome de Kallmann/patología , Síndrome de Kallmann/fisiopatología , Adolescente , Adulto , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Imagen de Difusión Tensora , Globo Pálido/patología , Globo Pálido/fisiopatología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Corteza Motora/patología , Corteza Motora/fisiopatología , Desempeño Psicomotor/fisiología , Tractos Piramidales/patología , Tractos Piramidales/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: Akt and its downstream signalling pathways contribute to the aetiology and progression of colorectal carcinoma (CRC). Targeting the Akt pathway is an attractive strategy but few chemotherapeutic drugs have been used to treat CRC with only limited success. BI-69A11, a small molecule inhibitor of Akt, efficiently inhibits growth in melanoma cells. Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 promotes cancer-selective apoptosis when delivered by a tropism-modified replication incompetent adenovirus (Ad.5/3-mda-7). However, Ad.5/3-mda-7 displays diminished antitumour efficacy in several CRC cell lines, which correlates with the expression of K-RAS. METHODS: The individual and combinatorial effect of BI-69A11 and Ad.5/3-mda-7 in vitro was studied by cell viability, cell cycle, apoptosis and invasion assays in HT29 and HCT116 cells containing wild type or mutant K-ras, respectively. In vivo HT29 tumour xenografts were used to test the efficacy of the combination treatment. RESULTS: BI-69A11 inhibited growth and induced apoptosis in CRC. However, combinatorial treatment was more effective compared with single treatment. This combination showed profound antitumour and anti angiogenic effects in vitro and in vivo by downregulating Akt activity. CONCLUSIONS: BI-69A11 enhances the antitumour efficacy of Ad.5/3-mda-7 on CRC overexpressing K-RAS by inducing apoptosis and regulating Akt activity thereby warranting further evaluation in treating CRC.
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Bencimidazoles/farmacología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Interleucinas/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Quinolonas/farmacología , Adenoviridae/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/genética , Línea Celular Tumoral , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Células HCT116 , Células HT29 , Humanos , Interleucinas/biosíntesis , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND PURPOSE: Cognitive impairment is common in Parkinson's disease (PD), even in the early stages. We aimed to assess the relationship between insulin-like growth factor-1 (IGF-1) and cognitive functions in early, drug-naïve patients with PD. METHODS: Serum IGF-1 was measured in 65 early, drug-naïve patients with PD that underwent a complete neuropsychological battery at baseline and after 2â years. Linear regression analysis was used to evaluate the relationships between neuropsychological scores and IGF-1. Repeated-measures anova was applied to assess changes in neuropsychological variables over time. RESULTS: At baseline, IGF-1 levels were related to phonological fluency. At follow-up, IGF-1 levels were associated with the Rey auditory verbal learning test (RAVLT) - immediate and delayed recall, Frontal Assessment Battery, verbal span and Benton judgement of the line orientation test. Patients with low IGF-1 levels at baseline showed a significantly faster decline of performances than patients with high IGF-1 levels on immediate and delayed recall of the RAVLT and interference task of the Stroop test. CONCLUSIONS: Low serum IGF-1 levels are related to poor performance on executive tasks in early, drug-naïve patients with PD, and may predict poor performance on attention/executive and verbal memory tasks after a 2-year follow-up.
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Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/complicaciones , Estimulación Acústica , Análisis de Varianza , Femenino , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Análisis de Regresión , Aprendizaje Verbal/fisiologíaRESUMEN
Phosphoinositide-dependent kinase-1 (PDK1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and protein kinase C (PKC), and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. PDK1 expression suffices for its activity, owing to auto-activation, or elevated phosphorylation by phosphoinositide 3'-OH-kinase (PI3K). Selective inactivation of Pdk1 in the melanocytes of Braf(V600E)::Pten(-/-) or Braf(V600E)::Cdkn2a(-/-)::Pten(-/-) mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-hydroxytamoxifen. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in Braf(V600E)::Pten(-/-) mice. Pdk1(-/-) melanomas exhibit a marked decrease in the activity of AKT, P70S6K and PKC. Notably, PDKi was as effective in inhibiting AGC kinases and colony forming efficiency of melanoma with Pten wild-type (WT) genotypes. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes, and inhibition of FOXO3a restored proliferation and colony formation of Pdk1(-/-) melanoma cells. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression.
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Neoplasias Pulmonares/genética , Melanoma Experimental/genética , Fosfohidrolasa PTEN/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Animales , Carcinogénesis/metabolismo , Línea Celular Tumoral , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Técnicas de Inactivación de Genes , Humanos , Indazoles/farmacología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/secundario , Metástasis Linfática , Melanoma Experimental/enzimología , Melanoma Experimental/secundario , Ratones , Ratones Noqueados , Mutación Missense , Fosfohidrolasa PTEN/deficiencia , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirimidinas/farmacología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Transducción de Señal , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Análisis de Matrices TisularesRESUMEN
Canonical endoplasmic reticulum (ER) stress, which occurs in many physiological and disease processes, results in activation of the unfolded protein response (UPR). We now describe a new, evolutionarily conserved cellular stress response characterised by a striking, but reversible, reorganisation of ER membranes that occurs independently of the UPR, resulting in impaired ER transport and function. This reorganisation is characterised by a dramatic redistribution and clustering of ER membrane proteins. ER membrane aggregation is regulated, in part, by anti-apoptotic BCL-2 family members, particularly MCL-1. Using connectivity mapping, we report the widespread occurrence of this stress response by identifying several structurally diverse chemicals from different pharmacological classes, including antihistamines, antimalarials and antipsychotics, which induce ER membrane reorganisation. Furthermore, we demonstrate the potential of ER membrane aggregation to result in pathological consequences, such as the long-QT syndrome, a cardiac arrhythmic abnormality, arising because of a novel trafficking defect of the human ether-a-go-go-related channel protein from the ER to the plasma membrane. Thus, ER membrane reorganisation is a feature of a new cellular stress pathway, clearly distinct from the UPR, with important consequences affecting the normal functioning of the ER.
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Retículo Endoplásmico/metabolismo , Animales , Línea Celular , Estrés del Retículo Endoplásmico , Canales de Potasio Éter-A-Go-Go/metabolismo , Gosipol/análogos & derivados , Gosipol/farmacología , Células HeLa , Humanos , Células MCF-7 , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
The BH3-interacting domain death agonist (Bid) is a pro-apoptotic member of the B-cell lymphoma-2 (Bcl-2) protein family. Previous studies have shown that stress reduces levels of Bcl-2 in brain regions implicated in the pathophysiology of mood disorders, whereas antidepressants and mood stabilizers increase Bcl-2 levels. The Bcl-2 protein family has an essential role in cellular resilience as well as synaptic and neuronal plasticity and may influence mood and affective behaviors. This study inhibited Bid in mice using two pharmacological antagonists (BI-11A7 and BI-2A7); the selective serotonin reuptake inhibitor citalopram was used as a positive control. These agents were studied in several well-known rodent models of depression-the forced swim test (FST), the tail suspension test (TST), and the learned helplessness (LH) paradigm-as well as in the female urine sniffing test (FUST), a measure of sex-related reward-seeking behavior. Citalopram and BI-11A7 both significantly reduced immobility time in the FST and TST and attenuated escape latencies in mice that underwent the LH paradigm. In the FUST, both agents significantly improved duration of female urine sniffing in mice that had developed helplessness. LH induction increased the activation of apoptosis-inducing factor (AIF), a caspase-independent cell death constituent activated by Bid, and mitochondrial AIF expression was attenuated by chronic BI-11A7 infusion. Taken together, the results suggest that functional perturbation of apoptotic proteins such as Bid and, alternatively, enhancement of Bcl-2 function, is a putative strategy for developing novel therapeutics for mood disorders.
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Compuestos de Anilina/uso terapéutico , Antidepresivos/uso terapéutico , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/antagonistas & inhibidores , Citalopram/uso terapéutico , Depresión/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/psicología , Sulfonamidas/uso terapéutico , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/farmacología , Animales , Antidepresivos/administración & dosificación , Antidepresivos/farmacología , Factor Inductor de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis , Conducta Animal/efectos de los fármacos , Proteínas Portadoras/metabolismo , Citalopram/administración & dosificación , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Infusiones Intraventriculares , Masculino , Ratones , Ratones Endogámicos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Sulfuros/administración & dosificación , Sulfuros/farmacología , Sulfuros/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacologíaRESUMEN
Sleep disturbances are common in patients with Parkinson's disease (PD). We aimed to evaluate prevalence and severity of nighttime sleep disturbances in Italian PD patients and to validate the Italian version of the Parkinson's disease sleep scale. A total of 221 PD patients and 57 healthy controls participated in a cross-sectional study with retest. PDSS, Epworth Sleepiness Scale (ESS), Hamilton Depression Rating Scale, Unified Parkinson's Disease Rating Scale (UPDRS), and Hoehn and Yahr staging were applied. PDSS total and individual items scores from patients were significantly lower than those in controls. Internal consistency of PDSS scale was satisfactory and intraclass correlation coefficient for test-retest reliability was 0.96 for total PDSS score. A significant negative correlation was found between total PDSS and ESS scores, and between total PDSS and HDRS scores. PDSS scores were also related to UPDRS sections II, III and IV, and H&Y stage. PDSS and ESS scores were not related to levodopa equivalent dose. Daytime sleepiness, depressive symptoms and disease severity correlate with sleep disturbances in Italian PD patients. The PDSS is a valid and reliable tool to evaluate sleep disturbances in Italian patients.
Asunto(s)
Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , Índice de Severidad de la Enfermedad , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/epidemiología , Anciano , Estudios Transversales , Femenino , Humanos , Italia/epidemiología , Masculino , Escala del Estado Mental , Persona de Mediana Edad , ObservaciónRESUMEN
OBJECTIVE: To characterize brain metabolic changes associated with mild cognitive impairment (MCI) in drug-naive patients with Parkinson disease (PD) using (18)F-fluorodeoxyglucose (FDG) and PET (FDG-PET). METHODS: This cross-sectional study included newly diagnosed patients with PD with MCI in single or multiple domain (PD-MCI; n =12) and without MCI (PD-nMCI; n =12), and healthy controls (n =12). The groups were matched for age. Moreover, the patient groups were matched for motor disability. All subjects underwent a FDG-PET study. Cerebral regional relative metabolic maps were compared in PD-MCI, PD-nMCI, and controls using regions of interest analysis (ROIs) and voxel-based analysis with statistical parametric mapping. RESULTS: ROIs and voxel-based analyses revealed significant relative hypometabolism in the prefrontal, superior/inferior parietal, and associative occipital cortices as well as in the striatum in patients with PD-MCI relative to controls (p < 0.05) and to a lesser extent in patients with PD-nMCI. In contrast, patients with PD-nMCI did not show significant metabolic changes as compared to controls. CONCLUSION: MCI in patients with PD is associated with cortical hypometabolism since the earliest stage, independent of therapy or motor disability. The early involvement of posterior cortical region, a pattern shared by advanced stages of PD-MCI and PD with dementia, could represent an early marker of dementia. The relevance of this pattern in predicting prodromal dementia has to be evaluated in longitudinal studies.