RESUMO
Autophagy is an important degradation pathway, which is induced after starvation, where it buffers nutrient deprivation by recycling macromolecules in organisms from yeast to man. While the classical pathway mediating this response is via mTOR inhibition, there are likely to be additional pathways that support the process. Here, we identify Annexin A2 as an autophagy modulator that regulates autophagosome formation by enabling appropriate ATG9A trafficking from endosomes to autophagosomes via actin. This process is dependent on the Annexin A2 effectors ARP2 and Spire1. Annexin A2 expression increases after starvation in cells in an mTOR-independent fashion. This is mediated via Jun N-terminal kinase activation of c-Jun, which, in turn, enhances the trans-activation of the Annexin A2 promoter. Annexin A2 knockdown abrogates starvation-induced autophagy, while its overexpression induces autophagy. Hence, c-Jun-mediated transcriptional responses support starvation-induced autophagy by regulating Annexin A2 expression levels.
Assuntos
Anexina A2/metabolismo , Autofagia/fisiologia , Regulação da Expressão Gênica/fisiologia , Animais , Anexina A2/genética , Proteínas Relacionadas à Autofagia , Fibroblastos , Genes jun , Células HeLa , Humanos , MAP Quinase Quinase 4 , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
Adipocytes are the main constituent of adipose tissue and are considered to be a corner stone in the homeostatic control of whole body metabolism. Their primary function is to control energy balance by storing triacylglycerol in periods of energy excess and mobilizing it during energy deprivation. Besides the classical function of storing fat, adipocytes secrete numerous lipid and protein factors. Collectively they are considered to constitute a major endocrine organ which has a profound impact on the metabolism of other tissues, the regulation of appetite, insulin sensitivity, immunological responses and vascular disease. Adipogenesis is the process during which fibroblast like preadipocytes developed into mature adipocytes. Adipogenesis is a well-orchestrated multistep process that requires the sequential activation of numerous transcription factors, including the CCAAT/enhancer-binding protein (C/EBP) gene family and peroxisome proliferator activated receptor-γ (PPAR-γ). In order to reach maturity, these cells must go through two vital steps: adipocyte determination and adipocyte differentiation. Although many of the molecular details of adipogenesis are still unknown, several factors involved in this processes have been identified. Some stimulators include peroxisome proliferator-activated receptor γ (PPAR γ), insulin-like growth factor I (IGF-l), macrophage colony stimulating factor, fatty acids, prostaglandins and glucocorticoids. Inhibitors include glycoproteins, transforming growth factor-ß (TGF-ß), inflammatory cytokines and growth hormone. Beside these factors, there are others for example age, gender and life style that may affect this process in one way or another. An increase in the number and size of adipocytes causes white adipose tissue (WAT) to expand and this can lead to obesity. Adipogenesis can lead to central obesity if it occurs in the abdominal fat depot and peripheral obesity if it occurs in subcutaneous tissue.
Assuntos
Adipócitos/metabolismo , Adipogenia , Adipócitos/citologia , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
There is accumulating evidence that aggregating, misfolded proteins may have an impact on autophagic function, suggesting that this could be a secondary pathological mechanism in many diseases. In this review, we focus on the role of autophagy in four major neurodegenerative diseases: Alzheimer disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and amyotropic lateral sclerosis.
Assuntos
Autofagia/efeitos dos fármacos , Sistema Nervoso Central/patologia , Terapia de Alvo Molecular/métodos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Progressão da Doença , Humanos , Doenças Neurodegenerativas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Adverse drug reactions and lack of therapeutic efficacy associated with currently prescribed pharmacotherapeutics may be attributed, in part, to inter-individual variability in drug metabolism. Studies on the pharmacogenetics of Cytochrome P450 (CYP) enzymes offer insight into this variability. The objective of this study was to compare the AmpliChip CYP450 Test® (AmpliChip) to alternative genotyping platforms for phenotype prediction of CYP2C19 and CYP2D6 in a representative cohort of the South African population. METHODS: AmpliChip was used to screen for thirty-three CYP2D6 and three CYP2C19 alleles in two different cohorts. As a comparison cohort 2 was then genotyped using a CYP2D6 specific long range PCR with sequencing (CYP2D6 XL-PCR + Sequencing) platform and a PCR-RFLP platform for seven CYP2C19 alleles. RESULTS: Even though there was a low success rate for the AmpliChip, allele frequencies for both CYP2D6 and CYP2C19 were very similar between the two different cohorts. The CYP2D6 XL-PCR + Sequencing platform detected CYP2D6*5 more reliably and could correctly distinguish between CYP2D6*2 and *41 in the Black African individuals. Alleles not covered by the AmpliChip were identified and four novel CYP2D6 alleles were also detected. CYP2C19 PCR-RFLP identified CYP2C19*9,*15, *17 and *27 in the Black African individuals, with *2, *17 and *27 being relatively frequent in the cohort. Eliminating mismatches and identifying additional alleles will contribute to improving phenotype prediction for both enzymes. Phenotype prediction differed between platforms for both genes. CONCLUSION: Comprehensive genotyping of CYP2D6 and CYP2C19 with the platforms used in this study, would be more appropriate than AmpliChip for phenotypic prediction in the South African population. Pharmacogenetically important novel alleles may remain undiscovered when using assays that are designed according to Caucasian specific variation, unless alternate strategies are utilised.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , População Negra/genética , Citocromo P-450 CYP2D6/genética , Técnicas de Genotipagem/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Estudos de Coortes , Citocromo P-450 CYP2C19 , Sistema Enzimático do Citocromo P-450/genética , Frequência do Gene , Humanos , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Estudos ProspectivosRESUMO
The accumulation of misfolded proteins in insoluble aggregates within the neuronal cytoplasm is one of the common pathological hallmarks of most adult-onset human neurodegenerative diseases. The clearance of these misfolded proteins may represent a promising therapeutic strategy in these diseases. The two main routes for intracellular protein degradation are the ubiquitin-proteasome and the autophagy-lysosome pathways. In this review, we will focus on the autophagic pathway, by providing some examples of how impairment at different steps in this degradation pathway is related to different neurodegenerative diseases. We will also consider that upregulating autophagy may be useful in the treatment of some of these diseases. Finally, we discuss how antioxidants, which have been considered to be beneficial in neurodegenerative diseases, can block autophagy, thus potentially compromising their therapeutic potential.
Assuntos
Autofagia/fisiologia , Doenças Neurodegenerativas/patologia , Dobramento de Proteína , Deficiências na Proteostase/patologia , Animais , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Humanos , Lisossomos/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologiaRESUMO
Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (e.g. drug metabolizing enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimizing drug toxicity and optimizing drug efficacy in cardiovascular medicine.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/genética , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Humanos , Polimorfismo GenéticoRESUMO
Autophagy is an intracellular degradation process responsible for the clearance of most long-lived proteins and organelles. Cytoplasmic components are enclosed by double-membrane autophagosomes, which subsequently fuse with lysosomes for degradation. Autophagy dysfunction may contribute to the pathology of various neurodegenerative disorders, which manifest abnormal protein accumulation. As autophagy induction enhances the clearance of aggregate-prone intracytoplasmic proteins that cause neurodegeneration (like mutant huntingtin, tau and ataxin 3) and confers cytoprotective roles in cell and animal models, upregulating autophagy may be a tractable therapeutic strategy for diseases caused by such proteins. Here, we will review the molecular machinery of autophagy and its role in neurodegenerative diseases. Drugs and associated signalling pathways that may be targeted for pharmacological induction of autophagy will also be discussed.
Assuntos
Autofagia , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Animais , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Transdução de SinaisRESUMO
Abundant preclinical and indirect clinical data have for several decades convincingly supported the notion that anti-angiogenesis is an effective strategy for the inhibition of tumor growth. The recent success achieved in patients with metastatic colon carcinoma using a neutralizing antibody directed against vascular endothelial growth factor (VEGF) has translated preclinical optimism into a clinical reality.With this transformation in the field of angiogenesis has come a need for reliable surrogate markers. A surrogate marker by definition serves as a substitute for the underlying process in question, and in the case of angiogenesis, microvessel density (usually in so-called "hot-spots") has until now been the most widely used parameter. However, this parameter is more akin to a static "snap-shot" and does not lend itself either to the dynamic in situ assessment of the status of the tumor microvasculature or to the molecular factors that regulate its growth and involution. This has led to an acute need for developing circulating and imaging markers of angiogenesis that can be monitored in vivo at repeated intervals in large number of patients with a variety of tumors in a non-invasive manner. Such markers of angiogenesis are the subject of this review.