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1.
J Alzheimers Dis ; 73(4): 1585-1595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31958084

RESUMO

CCL23 is a chemokine implicated in inflammation and host defense responses. It has been recently associated with acquired brain damage and stroke outcomes. In this study, we reported the role of CCL23 in Alzheimer's disease (AD). We evaluated the levels of CCL23 in 659 individuals: cognitively normal, mild cognitive impaired (MCI), and AD patients. Two cross-sectional (study 1, n = 53; study 2, n = 200) and two longitudinal (study 3, n = 74; study 4, n = 332) studies were analyzed separately. CCL23 levels in the blood and/or cerebrospinal fluid (CSF) of each study were measured by immunoassays. Globally, our results suggest a predictive role of CCL23 protein levels both in the plasma in study 3 (hazard ratio (HR) = 2.5 (confidence interval (CI) 95% : 1.2-5.3), p = 0.02) and in the CSF in study 4 (HR = 3.05 (CI 95% : 1.02-5), p = 0.04) in cases of MCI that progress to AD. Moreover, we observed that the APOEɛ4 allele was associated with higher levels of CCL23 in study 2 (470.33 pg/mL (interquartile range (IQR): 303.33-597.76) versus 377.94 pg/mL (IQR: 267.16-529.19), p = 0.01) (APOE genotypes were available in studies 2 and 4). Together, these findings support the role of CCL23 in neuroinflammation in the early stages of AD, suggesting that CCL23 might be a candidate blood biomarker for MCI to AD progression.

3.
Surg Neurol Int ; 10: 83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31528421

RESUMO

Background: Myxopapillary ependimoma (MPE) is a benign slow-growing tumor, and it has been designated histologically as a Grade I neoplasm according to the 2016 World Health Organization classification. Despite the benign character, dissemination and metastasis have occasionally been reported. The retrograde dissemination to other levels of the neuraxis is extremely rare, being more frequent to the intracranial compartment. Case Description: We hereby present a case of medullary metastasis of cauda equina MPE, with a history of having undergone a subtotal resection and postoperative adjuvant radiotherapy. The patient presents complaints of night dorsal pain attributable to intradural metastasis twenty-one years after the first surgical intervention. Conclusion: The case reported highlights the importance of long follow-up in patients with MPE, since the possibility of secondary seeding to distant craniospinal sites or local spinal sites after surgery, and radiotherapy should be considered in metastatic disease.

4.
ACS Chem Neurosci ; 10(9): 4076-4101, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31441641

RESUMO

Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).

5.
Mov Disord ; 34(10): 1547-1561, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31433872

RESUMO

BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.

6.
Pediatr Dev Pathol ; : 1093526619865641, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31335286

RESUMO

Human parvovirus B19 represents the most common etiology of myocarditis in the pediatric population. Although it usually causes a benign exanthematic viral infection, parvovirus B19 may also present as disseminated disease with tropism for the myocardium, causing heart failure with high mortality. We present the case of a 2-year-old patient with fulminating acute myocarditis in whom the histological, immunophenotypic, and microbiological findings in necropsy showed multiorgan involvement caused by parvovirus B19. The autopsy revealed changes due to infection with parvovirus B19 as well as hypoxic-ischemic and secondary autoimmune changes. Medullary aplasia was observed, transmural lymphocyte myocarditis, lymphocytosis in the dermis with endothelial cells positive for parvovirus B19 in immunohistochemistry, cholestatic hepatitis due to ischemia and autoimmune hepatitis, lymphadenitis, and signs of hemophagocytosis. We also found hypoxic-ischemic encephalopathy.

7.
Nat Commun ; 10(1): 2798, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243268

RESUMO

Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.


Assuntos
Cálcio/metabolismo , Biblioteca Gênica , Proteínas Sensoras de Cálcio Neuronal/metabolismo , Animais , Catálise , Células Cultivadas , Técnicas de Química Combinatória , Drosophila/fisiologia , Imagem por Ressonância Magnética , Masculino , Membranas Artificiais , Camundongos , Proteínas Sensoras de Cálcio Neuronal/genética , Neurônios/metabolismo , Palmitoil-CoA Hidrolase , Permeabilidade , Conformação Proteica , Proteínas
8.
Cell Rep ; 27(9): 2690-2708.e10, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141692

RESUMO

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer.

9.
Front Neurol ; 10: 187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918495

RESUMO

Cerebral amyloid angiopathy (CAA) is a common cause of lobar intracerebral hemorrhage (ICH) in elderly individuals and it is the result of the cerebrovascular deposition of beta-amyloid (Aß) protein. CAA is frequently found in patients with Alzheimer's disease (AD), although it has an independent contribution to the cognitive deterioration associated with age. Specific apolipoproteins (Apo) have been associated with Aß fibrillization and clearance from the brain. In this regard, in the present study, we analyzed the brain levels of ApoE, ApoA-I, and ApoJ/clusterin in autopsy brains from 20 post-mortem cases with CAA type I, CAA type II, with parenchymal Aß deposits or without Aß deposits. Our objective was to find a possible differential pattern of apolipoproteins distribution in the brain depending on the CAA pathological presentation. The protein expression levels were adjusted by the APOE genotype of the patients included in the study. We found that ApoE and ApoJ were abundantly present in meningeal, cortical, and capillary vessels of the brains with vascular Aß accumulation. ApoE and ApoJ also deposited extracellularly in the parenchyma, especially in cases presenting Aß diffuse and neuritic parenchymal deposits. In contrast, ApoA-I staining was only relevant in capillary walls in CAA type I cases. On the other hand, ICH was the principal cause of death among CAA patients in our cohort. We found that CAA patients with ICH more commonly had APOEε2 compared with CAA patients without ICH. In addition, patients who suffered an ICH presented higher vascular ApoE levels in brain. However, higher ApoE presence in cortical arteries was the only independent predictor of suffering an ICH in our cohort after adjusting by age and APOE genotype. In conclusion, while ApoE and ApoJ appear to be involved in both vascular and parenchymal Aß pathology, ApoA-I seems to be mainly associated with CAA, especially in CAA type I pathology. We consider that our study helps to molecularly characterize the distribution subtypes of Aß deposition within the brain.

10.
PLoS One ; 14(2): e0212215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30789925

RESUMO

In obstructive cholestasis, there is an integral adaptive response aimed to diminish the bile flow and minimize the injury of bile ducts caused by increased intraluminal pressure and harmful levels of bile salts and bilirrubin. Canalicular bicarbonate secretion, driven by the anion exchanger 2 (AE2), is an influential determinant of the canalicular bile salt-independent bile flow. In this work, we ascertained whether AE2 expression and/or activity is reduced in hepatocytes from rats with common bile duct ligation (BDL), as part of the adaptive response to cholestasis. After 4 days of BDL, we found that neither AE2 mRNA expression (measured by quantitative real-time PCR) nor total levels of AE2 protein (assessed by western blot) were modified in freshly isolated hepatocytes. However, BDL led to a decrease in the expression of AE2 protein in plasma membrane fraction as compared with SHAM control. Additionally, AE2 activity (JOH-, mmol/L/min), measured in primary cultured hepatocytes from BDL and SHAM rats, was decreased in the BDL group versus the control group (1.9 ± 0.3 vs. 3.1 ± 0.2, p<0.005). cAMP-stimulated AE2 activity, however, was not different between SHAM and BDL groups (3.7 ± 0.3 vs. 3.5 ± 0.3), suggesting that cAMP stimulated insertion into the canalicular membrane of AE2-containing intracellular vesicles, that had remained abnormally internalized after BDL. In conclusion, our results point to the existence of a novel adaptive mechanism in cholestasis aimed to reduce biliary pressure, in which AE2 internalization in hepatocytes might result in decreased canalicular HCO3- output and decreased bile flow.


Assuntos
Bicarbonatos/metabolismo , Antiportadores de Cloreto-Bicarbonato/biossíntese , Cloretos/metabolismo , Colestase/metabolismo , Regulação para Baixo , Hepatócitos/metabolismo , Animais , Colestase/patologia , Modelos Animais de Doenças , Hepatócitos/patologia , Transporte de Íons , Masculino , Ratos , Ratos Wistar
11.
Nefrologia ; 39(4): 355-361, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30704753

RESUMO

Hereditary renal hypouricemia is a rare autosomal recessive genetic disorder that involves an isolated defect in uric acid reabsorption at the renal tubules. Patients present with serum uric acid concentrations of less than 2mg/dl (119 micromol/L) with increased fractional excretion above 10%. Most of the patients are asymptomatic and are detected incidentally. However, complications such us nephrolithiasis, hematuria, acute renal failure exercise-induced or after dehydration for acute gastroenteritis, or posterior reversible encephalopaty syndrome (PRES) may develop. Hereditary renal hypouricemia is confirmed by molecular genetic analysis of the two genes which codify the uric acid transport in the kidney tubules. The renal hypouricemia type 1 (OMIM 220150) is characterized by loss-of-function mutations in the SLC22A12 gene which encodes URAT 1 transporter, and the hypouricemia type 2 (OMIM 612076) is caused by defects in the SLC2A9 gene. Homozygous mutations of SLC2A9 cause the most severe forms of the disease. Most mutations have been identified in Japanese adults, and only a few in children. We describe three asyntomatic pediatric Spanish patients with renal hypouricemia, with genetic confirmation, and we make a revision of all of the pediatric cases with genetic study published in the literature.

12.
Histopathology ; 75(1): 4-19, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30667539

RESUMO

Malignant tumours show a marked degree of morphological, molecular and proteomic heterogeneity. This variability is closely related to microenvironmental factors and the location of the tumour. The activation of genetic alterations is very tissue-dependent and only few tumours have distinct genetic alterations. Importantly, the activation state of proteins and signaling factors is heterogeneous in the primary tumour and in metastases and recurrences. The molecular diagnosis based only on genetic alterations can lead to treatments with unpredictable responses, depending on the tumour location, such as the tumour response in melanomas versus colon carcinomas with BRAF mutations. Therefore, we understand that the correct evaluation of tumours requires a system that integrates both morphological, molecular and protein information in a clinical and pathological context, where intratumoral heterogeneity can be assessed. Thus, we propose the term 'tissunomics', where the diagnosis will be contextualised in each tumour based on the complementation of the pathological, molecular, protein expression, environmental cells and clinical data.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Carcinogênese/genética , Aprendizado Profundo , Feminino , Humanos , Masculino , Mutação , Neoplasias/genética , Especificidade de Órgãos , Proteômica , Biologia de Sistemas , Transcriptoma , Microambiente Tumoral/imunologia
13.
EMBO J ; 38(2)2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30530526

RESUMO

Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia. However, anti-inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann-Pick disease type A (NPA). We establish that an NPA patient and the acid sphingomyelinase knockout (ASMko) mouse model show amoeboid microglia in neurodegeneration-prone areas. In vivo microglia ablation worsens disease progression in ASMko mice. We demonstrate the coexistence of different microglia phenotypes in ASMko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build-up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASMko mice. Similar microglia phenotypes occur in a Niemann-Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSDs and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSDs and other demyelinating diseases.


Assuntos
Catepsina B/metabolismo , Microglia/patologia , Doença de Niemann-Pick Tipo A/patologia , Esfingomielina Fosfodiesterase/genética , Animais , Linhagem Celular , Pré-Escolar , Modelos Animais de Doenças , Progressão da Doença , Humanos , Recém-Nascido , Lisossomos/metabolismo , Lisossomos/patologia , Camundongos , Camundongos Knockout , Microglia/metabolismo , Doença de Niemann-Pick Tipo A/genética , Fenótipo , Esfingomielinas/metabolismo
14.
Am J Pathol ; 189(3): 665-676, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30553833

RESUMO

Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the transforming growth factor-ß superfamily. In the adult brain, they modulate neurogenesis, favor astrogliogenesis, and inhibit oligodendrogenesis. Because BMPs may be involved in the failure of remyelination in multiple sclerosis (MS), we characterized the expression of BMP-2, BMP-4, BMP-5, and BMP-7; BMP type II receptor (BMPRII); and phosphorylated SMAD (pSMAD) 1/5/8 in lesions of MS and other demyelinating diseases. A total of 42 MS lesions, 12 acute ischemic lesions, 8 progressive multifocal leukoencephalopathy lesions, and 10 central nervous system areas from four nonneuropathological patients were included. Lesions were histologically classified according to the inflammatory activity. The expression of BMP-2, BMP-4, BMP-5, BMP-7, BMPRII, and pSMAD1/5/8 was quantified by immunostaining, and colocalization studies were performed. In MS lesions, astrocytes, microglia/macrophages, and neurons expressed BMP-2, BMP-4, BMP-5, and BMP-7; BMPRII; and pSMAD1/5/8. Oligodendrocytes expressed BMP-2 and BMP-7 and pSMAD1/5/8. The percentage of cells that expressed BMPs, BMPRII, and pSMAD1/5/8 correlated with the inflammatory activity of MS lesions, and changes in the percentage of positive cells were more relevant in MS than in other white matter-damaging diseases. These data indicate that BMPs are increased in active MS lesions, suggesting a possible role in MS pathogenesis.


Assuntos
Astrócitos/metabolismo , Proteínas Morfogenéticas Ósseas/biossíntese , Regulação da Expressão Gênica , Esclerose Múltipla/metabolismo , Oligodendroglia/metabolismo , Substância Branca/metabolismo , Astrócitos/patologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/metabolismo , Leucoencefalopatia Multifocal Progressiva/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Oligodendroglia/patologia , Proteínas Smad/metabolismo , Substância Branca/fisiologia
15.
ACS Chem Neurosci ; 10(3): 1765-1782, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30525452

RESUMO

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).

16.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 29(5): 250-254, sept.-oct. 2018. ilus
Artigo em Espanhol | IBECS | ID: ibc-180318

RESUMO

Se presenta un caso de aneurisma gigante no traumático de la arteria meníngea media en un paciente de 59años con antecedentes de trasplante hepático, cirrosis hepática y hepatocarcinoma, enfermedad renal crónica, HTA y bronquitis crónica que ingresó por presentar crisis tónico-clónica. La TC y la RM mostraron una lesión sugestiva de metástasis sin descartar un tumor de tipo glial. Fue intervenido mediante una craneotomía FT izquierda. Durante la cirugía se produjo una hemorragia arterial. La muestra histológica orientó hacia un origen aneurismático que se confirmó con ARM y angiografía. Una segunda intervención permitió la extirpación de un aneurisma gigante de la arteria meníngea media parcialmente trombosado. Los aneurismas de la arteria meníngea media son raros y en general presentan un antecedente traumático. No se ha encontrado en la literatura médica ningún caso de aneurisma gigante


A case of a non-traumatic giant aneurysm of the middle meningeal artery is presented in a 59-year-old patient with a history of liver transplantation, liver cirrhosis and hepatocarcinoma, chronic renal disease, hypertension and chronic bronchitis who presented with tonic-clonic seizures. CT and MRI showed a lesion suggestive of metastasis without ruling out a glial type tumor. He was operated through a left FT craniotomy. During the surgery there was an arterial hemorrhage. The histological sample oriented toward an aneurysmal origin that was confirmed with ARM and angiography. A second intervention allowed the removal of a giant middle meningeal aneurysm partially thrombosed. Aneurysms of the middle meningeal artery are rare and generally present a traumatic history. No case of giant aneurysm has been found in the medical literature


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Aneurisma/diagnóstico por imagem , Aneurisma/cirurgia , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/cirurgia , Angiografia Cerebral
17.
Nat Med ; 24(7): 1024-1035, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29892069

RESUMO

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/secundário , Fator de Transcrição STAT3/metabolismo , Animais , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Sobrevivência Celular , Marcação de Genes , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imunidade Inata , Camundongos , Fosforilação , Microambiente Tumoral
18.
J Med Chem ; 61(15): 6546-6573, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29890830

RESUMO

Epigenetic regulators that exhibit aberrant enzymatic activities or expression profiles are potential therapeutic targets for cancers. Specifically, enzymes responsible for methylation at histone-3 lysine-9 (like G9a) and aberrant DNA hypermethylation (DNMTs) have been implicated in a number of cancers. Recently, molecules bearing a 4-aminoquinoline scaffold were reported as dual inhibitors of these targets and showed a significant in vivo efficacy in animal models of hematological malignancies. Here, we report a detailed exploration around three growing vectors born by this chemotype. Exploring this chemical space led to the identification of features to navigate G9a and DNMT1 biological spaces: not only their corresponding exclusive areas, selective compounds, but also common spaces. Thus, we identified from selective G9a and first-in-class DNMT1 inhibitors, >1 log unit between their IC50 values, with IC50 < 25 nM (e.g., 43 and 26, respectively) to equipotent inhibitors with IC50 < 50 nM for both targets (e.g., 13). Their ADME/Tox profiling and antiproliferative efficacies, versus some cancer cell lines, are also reported.


Assuntos
Aminoquinolinas/química , Aminoquinolinas/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Desenho de Drogas , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Aminoquinolinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/metabolismo , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Conformação Proteica
19.
J Med Chem ; 61(15): 6518-6545, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29953809

RESUMO

Using knowledge- and structure-based approaches, we designed and synthesized reversible chemical probes that simultaneously inhibit the activity of two epigenetic targets, histone 3 lysine 9 methyltransferase (G9a) and DNA methyltransferases (DNMT), at nanomolar ranges. Enzymatic competition assays confirmed our design strategy: substrate competitive inhibitors. Next, an initial exploration around our hit 11 was pursued to identify an adequate tool compound for in vivo testing. In vitro treatment of different hematological neoplasia cell lines led to the identification of molecules with clear antiproliferative efficacies (GI50 values in the nanomolar range). On the basis of epigenetic functional cellular responses (levels of lysine 9 methylation and 5-methylcytosine), an acceptable therapeutic window (around 1 log unit) and a suitable pharmacokinetic profile, 12 was selected for in vivo proof-of-concept ( Nat. Commun. 2017 , 8 , 15424 ). Herein, 12 achieved a significant in vivo efficacy: 70% overall tumor growth inhibition of a human acute myeloid leukemia (AML) xenograft in a mouse model.


Assuntos
Antineoplásicos/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nat Med ; 24(9): 1481, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29921958

RESUMO

In the version of this article originally published, the names of three authors were incorrect. The authors were listed as "Coral Fustero-Torres", "Elena Pineiro" and "Melchor Sánchez-Martínez". Their respective names are "Coral Fustero-Torre", "Elena Piñeiro-Yáñez" and "Melchor Sanchez-Martinez". The errors have been corrected in the print, HTML and PDF versions of this article.

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