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Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate non-histone proteins involved in non-genomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, non-genomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal HPC (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERß agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Additional experiments indicated that while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect might be independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via non-genomic ER activity. Critically, this novel PCAF-ER interaction might exist as a male-specific mechanism supporting STM.Significance Statement Due to their ability to modulate gene expression, epigenetic mechanisms are necessary for long-term, but not short-term, memory. Recently, the histone acetyltransferase PCAF, has been shown to be necessary in the hippocampus for short-term object memory, but its mechanism of action is unknown. Here, we present evidence for a novel functional interaction between PCAF and estrogen receptors (ERs) in the hippocampus of gonadally-intact male - but not female - rats that enhanced short-term object memory. Further, enhancing PCAF led to rapid activation of downstream ER-related signaling cascades, suggesting that PCAF might activate ERs similar to the effects of estrogens. Indeed, experiments suggested that the PCAF-ER interaction could be estrogen-independent. These results demonstrate a novel mechanism mediating short-term memory enhancement that appears to be specific to males.
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Being the standard solvent for preparing stock solutions of compounds for drug discovery, DMSO is always present in assay buffers in concentrations ranging from 0.1 % to 5 % (v/v). Even at the lowest concentrations, DMSO-containing solutions can have significant effects on individual proteins and possible pitfalls cannot be eliminated. Herein, we used two protein systems, the lysine methyltransferases G9a/KMT1â C and SETD8/KMT5â A, to study the effects of DMSO on protein stability and on the binding of the corresponding inhibitors, using different biophysical methods such as nano Differential Scanning Fluorimetry (nanoDSF), Differential Scanning Fluorimetry (DSF), microscale thermophoresis (MST), and surface plasmon resonance (SPR), all widely used in drug discovery screening campaigns. We demonstrated that the effects of DMSO are protein- and technique-dependent and cannot be predicted or extrapolated on the basis of previous studies using different proteins and/or different assays. Moreover, we showed that the application of orthogonal biophysical methods can lead to different binding affinity data, thus confirming the importance of using at least two different orthogonal assays in screening campaigns. This variability should be taken into account in the selection and characterization of hit compounds, in order to avoid data misinterpretation.
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Dimetil Sulfóxido , Lisina , Metiltransferases , Ligantes , Descoberta de Drogas/métodos , ProteínasRESUMO
Current drugs for Alzheimer's Disease (AD), such as cholinesterase inhibitors (ChEIs), exert only symptomatic activity. Different psychometric tools are needed to assess cognitive and non-cognitive dimensions during pharmacological treatment. In this pilot study, we monitored 33 mild-AD patients treated with ChEIs. Specifically, we evaluated the effects of 6 months (Group 1 = 17 patients) and 9 months (Group 2 = 16 patients) of ChEIs administration on cognition with the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Frontal Assessment Battery (FAB), while depressive symptoms were measured with the Hamilton Depression Rating Scale (HDRS). After 6 months (Group 1), a significant decrease in MoCA performance was detected. After 9 months (Group 2), a significant decrease in MMSE, MoCA, and FAB performance was observed. ChEIs did not modify depressive symptoms. Overall, our data suggest MoCA is a potentially useful tool for evaluating the effectiveness of ChEIs.
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Doença de Alzheimer , Inibidores da Colinesterase , Humanos , Inibidores da Colinesterase/uso terapêutico , Projetos Piloto , Doença de Alzheimer/tratamento farmacológico , Testes de Estado Mental e Demência , Resultado do TratamentoRESUMO
Immunotherapy has emerged as a game-changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest. In an attempt to find novel chemotypes, a virtual screening approach was employed, resulting in the identification of new chemical entities with a certain binding capability, the most versatile of which was the benzimidazole-containing compound 10. Through rational design, a small library of its derivatives was synthesized and evaluated. The homogeneous time-resolved fluorescence (HTRF) assay revealed that compound 17 shows the most potent inhibitory activity (IC50 ) in the submicromolar range and notably, differently from the major part of PD-L1 inhibitors, exhibits satisfactory water solubility properties. These findings highlight the potential of benzimidazole-based compounds as novel promising candidates for PD-L1 inhibition.
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Compostos de Bifenilo , Inibidores de Checkpoint Imunológico , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Ligantes , Relação Estrutura-Atividade , Benzimidazóis/farmacologia , ÁguaRESUMO
INTRODUCTION: The Major Depressive Disorder (MDD) is a mental health disorder that affects millions of people worldwide. It is characterized by persistent feelings of sadness, hopelessness, and a loss of interest in activities that were once enjoyable. MDD is a major public health concern and is the leading cause of disability, morbidity, institutionalization, and excess mortality, conferring high suicide risk. Pharmacological treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) is often the first choice for their efficacy and tolerability profile. However, a significant percentage of depressive individuals do not achieve remission even after an adequate trial of pharmacotherapy, a condition known as treatment-resistant depression (TRD). METHODS: To better understand the complexity of clinical phenotypes in MDD we propose Network Intervention Analysis (NIA) that can help health psychology in the detection of risky behaviors, in the primary and/or secondary prevention, as well as to monitor the treatment and verify its effectiveness. The paper aims to identify the interaction and changes in network nodes and connections of 14 continuous variables with nodes identified as "Treatment" in a cohort of MDD patients recruited for their recent history of partial response to antidepressant drugs. The study analyzed the network of MDD patients at baseline and after 12 weeks of drug treatment. RESULTS: At baseline, the network showed separate dimensions for cognitive and psychosocial-affective symptoms, with cognitive symptoms strongly affecting psychosocial functioning. The MoCA tool was identified as a potential psychometric tool for evaluating cognitive deficits and monitoring treatment response. After drug treatment, the network showed less interconnection between nodes, indicating greater stability, with antidepressants taking a central role in driving the network. Affective symptoms improved at follow-up, with the highest predictability for HDRS and BDI-II nodes being connected to the Antidepressants node. CONCLUSION: NIA allows us to understand not only what symptoms enhance after pharmacological treatment, but especially the role it plays within the network and with which nodes it has stronger connections.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológicoRESUMO
The prevalence of cognitive disorders is growing and evidence suggests the putative role of plant-based foods and beverages containing (poly)phenols. The aim of this study was to explore the association between the consumption of (poly)phenol-rich beverages, including wine and beer, resveratrol intake, and cognitive status in a cohort of older adults. The dietary intakes were assessed using a validated food frequency questionnaire, and cognitive status using the Short Portable Mental Status Questionnaire. Multivariate logistic regression analyses showed that individuals in the second and third tertile of red wine consumption were less likely to have cognitive impairment than those in the first tertile. In contrast, only individuals in the highest tertile of white wine intake were having lower odds of cognitive impairment. No significant results were found for beer intake. Individuals with higher resveratrol intake were less likely to have cognitive impairment. In conclusion, consumption of (poly)phenol-rich beverages may potentially affect cognition among older adults.
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Fenol , Vinho , Humanos , Idoso , Resveratrol , Consumo de Bebidas Alcoólicas/epidemiologia , Cerveja , Bebidas , Fenóis , CogniçãoRESUMO
Histone acetylation, catalyzed by histone acetyltransferases, has emerged as a promising therapeutic strategy in Alzheimer's disease (AD). By longitudinally characterizing spatial memory at 3, 6, and 9 mo of age, we show that acute activation and inhibition of the histone acetyltransferase PCAF remediated memory impairments in 3xTG-AD mice in an age-related bidirectional manner. At 3 and 6 mo of age, PCAF activation ameliorated memory deficits. At 9 mo of age, PCAF activation had no effect on spatial memory, whereas PCAF inhibition improved memory deficits in females. This work reveals a complex potential therapeutic role for PCAF in AD, initially benefitting memory but becoming detrimental as the disease progresses.
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Doença de Alzheimer , Histona Acetiltransferases , Acetilação , Doença de Alzheimer/genética , Animais , Feminino , Histona Acetiltransferases/genética , Transtornos da Memória , Camundongos , Memória Espacial , Fatores de Transcrição de p300-CBPRESUMO
Suicide attempts are a possible consequence of Major Depressive Disorder (MDD), although their prevalence varies across different epidemiological studies. Suicide attempt is a significant predictor of death by suicide, highlighting its importance in understanding and preventing tragic outcomes. Researchers are increasingly recognizing the need to study the differences between males and females, as several distinctions emerge in terms of the characteristics, types and motivations of suicide attempts. These differences emphasize the importance of considering gender-specific factors in the study of suicide attempts and developing tailored prevention strategies. We conducted a network analysis to represent and investigate which among multiple neurocognitive, psychosocial, demographic and affective variables may prove to be a reliable predictor for identifying the 'suicide attempt risk' (SAR) in a sample of 81 adults who met DSM-5 criteria for MDD. Network analysis resulted in differences between males and females regarding the variables that were going to interact and predict the SAR; in particular, for males, there is a stronger link toward psychosocial aspects, while for females, the neurocognitive domain is more relevant in its mnestic subcomponents. Network analysis allowed us to describe otherwise less obvious differences in the risk profiles of males and females that attempted to take their own lives. Different neurocognitive and psychosocial variables and different interactions between them predict the probability of suicide attempt unique to male and female patients.
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The complexity of neurodegenerative diseases, among which Alzheimer's disease plays a pivotal role, poses one of the tough therapeutic challenges of present time. In this perspective, a multitarget approach appears as a promising strategy to simultaneously interfere with different defective pathways. In this paper, a structural simplification plan was performed on our previously reported multipotent polycyclic compounds, in order to obtain a simpler pharmacophoric central core with improved pharmacokinetic properties, while maintaining the modulating activity on neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3ß), as validated targets to combat Alzheimer's disease. The molecular pruning approach applied here led to tetrahydroisoindole-dione (1), tetrahydromethanoisoindole-dione (2) and tetrahydroepoxyisoindole-dione (3) structures, easily affordable by Diels-Alder cycloaddition. Preliminary data indicated structure 3 as the most appropriate, thus a SAR study was performed by introducing different substituents, selected on the basis of the commercial availability of the furan derivatives required for the synthetic procedure. The results indicated compound 10 as a promising, structurally atypical, safe and BBB-penetrating Cav modulator, inhibiting both L- and N-calcium channels, likely responsible for the Ca2+ overload observed in Alzheimer's disease. In a multitarget perspective, compound 11 appeared as an effective prototype, endowed with improved Cav inhibitory activity, with respect to the reference drug nifedipine, and encouraging modulating activity on GSK-3ß.
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Doença de Alzheimer , Humanos , Glicogênio Sintase Quinase 3 beta , Doença de Alzheimer/tratamento farmacológico , Simulação de Acoplamento Molecular , Canais de Cálcio , NeurôniosRESUMO
A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.
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Inibidores da Anidrase Carbônica/farmacologia , Biologia Computacional/métodos , Isoenzimas/antagonistas & inibidores , Quinazolinas/química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
In the last decades, a high increase in life expectancy not adequately balanced by an improvement in the quality of life has been observed, leading possibly to an increase in the prevalence of affective and cognitive disorders related to aging, such as depression, cognitive impairment, dementia and Alzheimer's disease. As mental illnesses have multifactorial aetiologies, many modifiable factors including lifestyle and nutrition play an essential role. Among nutritional factors, intermittent fasting has emerged as an innovative strategy to prevent and treat mental health disorders, sleep disturbances and cognitive impairment. Among all types of intermittent fasting regimens, the time restricted feeding appears to be the most promising protocol as it allows to induce benefits of a total fasting without reducing global calories and nutrients intake. This review summarises the evidence on the effect of time restricted feeding towards brain health, emphasising its role on brain signalling, neurogenesis and synaptic plasticity.
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Transtornos Cognitivos , Jejum , Saúde Mental , Transtornos do Humor , Encéfalo , Cognição , Humanos , Neurogênese , Plasticidade Neuronal , Fatores de TempoRESUMO
Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy. Video Abstract.
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Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Pirimidinonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Melanoma/genética , Melanoma/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Terapia de Alvo Molecular , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.
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Benzamidas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Fosfoproteínas/antagonistas & inibidores , Piperidinas/farmacologia , Análise Serial de Proteínas , Bibliotecas de Moléculas Pequenas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Proteínas de Ciclo Celular/química , Relação Dose-Resposta a Droga , Humanos , Proteínas Associadas aos Microtúbulos/química , Modelos Moleculares , Estrutura Molecular , Fosfoproteínas/química , Piperidinas/síntese química , Piperidinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors.
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Benzimidazóis/química , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/síntese química , Aminas/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Humanos , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bases de Schiff/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
Background: The epidemiological evidence for a relation between dietary polyphenol intake and depression is limited. Therefore, the aim of this study was to assess the association between habitual dietary intake of total polyphenols, their classes, subclasses and individual compounds and depressive symptoms among the participants of the Mediterranean healthy Eating, Lifestyle and Aging (MEAL) study. Methods: Demographic and dietary characteristics of 1572 adults living in southern Italy were analyzed. Food frequency questionnaires and Phenol-Explorer were used to calculate habitual dietary intakes of polyphenols. The Center for Epidemiologic Studies Depression Scale (CES-D-10) was used as screening tool for depressive symptoms. Multivariate logistic regression analyses were used to test associations and were expressed as odds ratio (OR) and 95% confidence intervals (CI). Results: A total of 509 individuals reported having depressive symptoms. Based on multivariate logistic regression analyses, total polyphenol intake was not associated with depressive symptoms. After adjustment for potential confounding factors, dietary intake of phenolic acid (OR = 0.64, 95% CI: 0.44, 0.93), flavanones (OR = 0.54, 95% CI: 0.32, 0.91), and anthocyanins (OR = 0.61, 95% CI: 0.42, 0.89) showed significant inverse association with depressive symptoms, when comparing the highest with the lowest quartile. Moreover, flavanones and anthocyanins, were associated with depressive symptoms in a dose-response manner. Among individual compounds, inverse association was observed for quercetin (OR = 0.53, 95% CI: 0.32, 0.86) and naringenin (OR = 0.51, 95% CI: 0.30, 0.85), for the highest versus lowest quartile of intake. When taking into consideration the major sources of the polyphenols, only citrus fruits and wine consumption was inversely associated with depressive symptoms (Q4 vs. Q1: OR= 0.51, 95% CI: 0.35, 0.75; Q4 vs. Q1: OR = 0.53, 95% CI: 0.38, 0.74, respectively). Conclusions: Higher dietary intake of flavonoid may be inversely associated with depressive symptoms. Further studies are needed to definitively confirm these observed associations.
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Depressão/epidemiologia , Depressão/etiologia , Suplementos Nutricionais , Polifenóis , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dieta Saudável , Dieta Mediterrânea , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polifenóis/administração & dosagem , Vigilância em Saúde Pública , Adulto JovemRESUMO
PURPOSE: Adolescence overweight and obesity have increased considerably, and the misperception of their weight status could reduce the efficiency of intervention programs. The aim of this study was to evaluate the prevalence rate of misperception and to assess the relationship between weight perception and anthropometric parameters, self-perception, physical activity, and adherence to the Mediterranean diet. METHODS: A total of 1643 young adolescents (11-16 years old) were surveyed in a cross-sectional investigation during two scholastic years (period October-May of 2012-2013 and 2013-2014) in 15 secondary schools of Sicily, southern Italy. Data on demographic information, anthropometric characteristics (bioelectrical impedance), physical activity level, The Children and Youth Physical Self-Perception Profile, weight perception, and dietary habits (KIDMED) were collected. RESULTS: Misperception was found in the 27.6 % of the young adolescents, and boys were more likely to underestimate their weight status, while girls had a high percentage of overestimation. The strong association with weight misperception was with socioeconomic status, waist circumference, physical activities, and physical self-worth. Moreover, a good adherence to the Mediterranean diet was inversely associated with both overestimation and underestimation in both boys and girls. CONCLUSION: These findings highlight that almost one-third of the participants had a weight misperception that was associated with several anthropometric, social, and lifestyle factors. Future intervention to prevent overweight and obesity should consider not only gender-specific differences, but also parental SES, perception, and satisfaction of body weight status.
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Imagem Corporal/psicologia , Peso Corporal , Dieta , Autoimagem , Adolescente , Antropometria , Composição Corporal/fisiologia , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Humanos , Estilo de Vida , Masculino , Fatores SocioeconômicosRESUMO
This review illustrates the various studies made to investigate the activity of N-pyrrylarylsulfone containing compounds as potential antiviral, anticancer and SNC drugs. A number of synthetic approaches to obtain tetracyclic, tricyclic and non-cyclic compounds, and their biological activity with regard to structure-activity relationships (SARs) have been reviewed. The literature reviewed here may provide useful information on the potential of N-pyrrylarylsulfone pharmacophore as well as suggest concepts for the design and synthesis of new N-pyrrylarylsulfone based agents.
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Sulfonamidas/química , Sulfonamidas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Técnicas de Química Sintética , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/uso terapêuticoRESUMO
The identification of inhibitors of Hsp90 is currently a primary goal in the development of more effective drugs for the treatment of various types of multidrug resistant malignancies. In an attempt to identify new small molecules modulating the activity of Hsp90, we screened a small library of tetranortriterpenes. A high-affinity interaction with Hsp90 inducible form was uncovered for eight of these compounds, five of which are described here for the first time. By monitoring the ATPase activity and the citrate synthase thermal induced aggregation, compound 1 (cedrelosin A), 3 (7α-limonylacetate), and 5 (cedrelosin B), containing a limonol moiety, were found to be the most effective in compromising the Hsp90α chaperone activity. Consistent with these findings, the three compounds caused a depletion of c-Raf and pAkt Hsp90 client proteins in HeLa and MCF/7 cell lines. Induced fit docking protocol and molecular dynamics were used to rationalize the structural basis of the biological activity of the limonol derivatives. Taken together, these results point to limonol-derivatives as promising scaffolds for the design of novel Hsp90α inhibitors.
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Antineoplásicos/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Extratos Vegetais/química , Triterpenos/química , Adenosina Trifosfatases/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Sobrevivência Celular , Chromolaena/química , Citrato (si)-Sintase/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HeLa , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Folhas de Planta/química , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Triterpenos/farmacologiaRESUMO
INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aß, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aß40 and Aß42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aß correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aß42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aß and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.
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Síndrome de Down/sangue , Síndrome de Down/imunologia , Adolescente , Adulto , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/imunologia , Citocinas/sangue , Progressão da Doença , Síndrome de Down/psicologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Fator de Crescimento Neural/sangue , Neuropeptídeos/sangue , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Precursores de Proteínas/sangue , Serpinas/sangue , Ativador de Plasminogênio Tecidual/sangue , Adulto Jovem , NeuroserpinaRESUMO
EPR spectroscopy was applied to investigate the effects of the treatment of Candida albicans cells with fluconazole (FLC) and two newly synthesized azoles (CPA18 and CPA109), in a concentration not altering yeast morphology, on the lipid organization and dynamics of the plasma membrane. Measurements were performed in the temperature range between 0°C and 40°C using 5-doxyl- (5-DSA) and 16-doxyl- (16-DSA) stearic acids as spin probes. 5-DSA spectra were typical of lipids in a highly ordered environment, whereas 16-DSA spectra consisted of two comparable components, one corresponding to a fluid bulk lipid domain in the membrane and the other to highly ordered and motionally restricted lipids interacting with integral membrane proteins. A line shape analysis allowed the relative proportion and the orientational order and dynamic parameters of the spin probes in the different environments to be determined. Smaller order parameters, corresponding to a looser lipid packing, were found for the treated samples with respect to the control one in the region close to the membrane surface probed by 5-DSA. On the other hand, data on 16-DSA indicated that azole treatments hamper the formation of ordered lipid domains hosting integral proteins and/or lead to a decrease in integral protein content in the membrane. The observed effects are mainly ascribable to the inhibition of ergosterol biosynthesis by the antifungal agents, although a direct interaction of the CPA compounds with the membrane bilayer in the region close to the lipid polar head groups cannot be excluded.