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2.
Mo Med ; 119(4): 379-384, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118818

RESUMO

The many health benefits of exercise are well-known. Conversely, the pathologies associated with a sedentary lifestyle are also well-documented. However, science and medicine have only recently begun to explain how exercise does what it does. Here, I discuss recent insight into the biochemical mechanisms underlying the benefits of exercise and the pathologies of inactivity.


Assuntos
Exercício Físico , Comportamento Sedentário , Humanos , Biologia Molecular
3.
Biomol Concepts ; 12(1): 1-7, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33544462

RESUMO

The advent of genome editing technology promises to transform human health, livestock and agriculture, and to eradicate pest species. This transformative power demands urgent scrutiny and resolution of the ethical conflicts attached to the creation and release of engineered genomes. Here, I discuss the ethics surrounding the transformative CRISPR/Cas9-mediated genome editing technology in the contexts of human genome editing to eradicate genetic disease and of gene drive technology to eradicate animal vectors of human disease.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/ética , Animais , Humanos
5.
Mo Med ; 116(3): 217-225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527945

RESUMO

About half a million adverse drug reactions are reported in the US each year that result in disability, hospitalization or death. The efficacy or toxicity of a drug in a patient can be strongly influenced by their genetics as well as environment. Application of genomics to clinical pharmacology, "pharmacogenomics," promises to transform patient care and health resource utilization in the coming decade.


Assuntos
Tratamento Farmacológico/tendências , Farmacogenética , Papel do Médico , Medicina de Precisão , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Genômica , Humanos , Farmacologia
6.
Mo Med ; 116(6): 497-502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31911736

RESUMO

Gene therapy has long been a promise of molecular biology. So far, that promise has largely been unrealized. The advent of gene editing using technology adapted from bacteria may finally usher in the era of gene therapy.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/ética , Terapia Genética/ética , Humanos , Medicina Molecular/tendências
7.
Mo Med ; 115(1): 12-17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228670

RESUMO

Beyond avoiding risky behavior-smoking, substance abuse, obesity-and embracing healthy habits like exercise, a balanced diet, and non-obese body weight, are there things we each do today to significantly extend our lifespan? Caloric restriction is the only behavioral intervention consistently shown to extend both mean and maximal lifespan across a wide range of species. In most cases, the lifespan extension is accompanied by a marked delay in the onset of age-associated disease and infirmity.


Assuntos
Restrição Calórica/métodos , Envelhecimento Saudável , Expectativa de Vida , Longevidade , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino
9.
Mo Med ; 115(4): 337-338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228761
10.
Mo Med ; 114(1): 26-32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-30233096

RESUMO

The price of whole-genome sequencing is now within the budget of the average American consumer. This has resulted in the commercialization of genome sequencing for a variety of applications, including health-related risk assessment. Direct-to-consumer marketing of personal DNA sequence information uncouples the generation of personal health-related data from the physician-patient relationship. Here, I discuss the status of consumer genomics and the current and potential concerns about bypassing physicians in the analysis and interpretation of personal genomic information and subsequent health care decision-making.

12.
Mo Med ; 114(5): 330-334, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-30228624

RESUMO

Tobacco smoking is the largest cause of preventable mortality and morbidity in the United States. Many of the pathological consequences of smoking result from mutations, but gene expression can also be modulated by genomic imprinting mediated by DNA methylation-so-called "epigenetic" regulation. Since genomic imprints, unlike gene mutations, can be reversed, it is of great interest what smoking-related imprints mean for smoking-related pathologies in smokers and their children, and the potential for imprint-targeted diagnostics and therapeutics.


Assuntos
Impressão Genômica/genética , Fumar Tabaco/efeitos adversos , Fumar Tabaco/genética , Criança , Metilação de DNA/genética , Epigenômica/métodos , Feminino , Desenvolvimento Fetal/genética , Humanos , Masculino , Mutação , Fumar Tabaco/epidemiologia , Fumar Tabaco/patologia
14.
Curr Opin Genet Dev ; 37: 109-118, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27010504

RESUMO

On casual inspection, the eukaryotic nucleus is a deceptively simple organelle. Far from being a bag of chromatin, the nucleus is, in some ways, a structural and functional extension of the chromosomes it contains. Recently, interest has intensified in how chromosome compartmentalization and dynamics affect nuclear function. Different studies uncovered functional interactions between chromosomes and the filamentous nuclear meshwork comprised of lamin proteins. Here, we summarize recent research suggesting that telomeres, the capping structures that protect chromosome ends, are stabilized by lamin-binding and that alterations in nuclear lamins lead to defects in telomere compartmentalization, homeostasis and function. Telomere dysfunction contributes to the genomic instability that characterizes aging-related diseases, and might be an important factor in the pathophysiology of lamin-related diseases.


Assuntos
Instabilidade Genômica , Laminas/genética , Telômero/genética , Núcleo Celular/genética , Cromatina/genética , Cromossomos/genética , Dano ao DNA/genética , Reparo do DNA/genética , Humanos
15.
Int Rev Cell Mol Biol ; 320: 75-101, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26614872

RESUMO

Considerable research supports a model in which hydrolytic enzymes of mammalian lysosomes are sorted to their destinations in a receptor-dependent mechanism. The ligand for the mammalian sorting receptors is mannose 6-phosphate (M6P). Two M6P receptors have been defined in mammals. Here, we review the foundational evidence supporting this mechanism and highlight the remaining gaps in our understanding of the mammalian mechanism, including evidence for M6P-independent sorting, and its relevance to lysosomal enzyme sorting in metazoa.


Assuntos
Lisossomos/metabolismo , Sequência de Aminoácidos , Animais , Evolução Molecular , Humanos , Lisossomos/enzimologia , Manosefosfatos/metabolismo , Dados de Sequência Molecular , Transporte Proteico , Receptor IGF Tipo 2/química , Receptor IGF Tipo 2/genética , Receptor IGF Tipo 2/metabolismo
16.
Biol Open ; 4(10): 1316-25, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26405051

RESUMO

The lysosomal enzyme receptor protein (LERP) of Drosophila melanogaster is the ortholog of the mammalian cation-independent mannose 6-phosphate (Man 6-P) receptor, which mediates trafficking of newly synthesized lysosomal acid hydrolases to lysosomes. However, flies lack the enzymes necessary to make the Man 6-P mark, and the amino acids implicated in Man 6-P binding by the mammalian receptor are not conserved in LERP. Thus, the function of LERP in sorting of lysosomal enzymes to lysosomes in Drosophila is unclear. Here, we analyze the consequence of LERP depletion in S2 cells and intact flies. RNAi-mediated knockdown of LERP in S2 cells had little or no effect on the cellular content or secretion of several lysosomal hydrolases. We generated a novel Lerp null mutation, Lerp(F6), which abolishes LERP protein expression. Lerp mutants have normal viability and fertility and display no overt phenotypes other than reduced body weight. Lerp mutant flies exhibit a 30-40% decrease in the level of several lysosomal hydrolases, and are hypersensitive to dietary chloroquine and starvation, consistent with impaired lysosome function. Loss of LERP also enhances an eye phenotype associated with defective autophagy. Our findings implicate Lerp in lysosome function and autophagy.

17.
Mo Med ; 111(5): 428-33, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25438366

RESUMO

The sequence of the human genome represents our genetic blueprint. While it is now possible to draw direct connections between specific DNA sequences and specific physical features and to predict disease risk, the effects of certain genes can be masked by a process called "epigenetics." Here, I summarize our current understanding of epigenetics and it affects gene expression, with impacts on health and aging.


Assuntos
Epigenômica/métodos , Expressão Gênica/genética , Genoma Humano/genética , Envelhecimento/genética , DNA/genética , Humanos , Estresse Fisiológico/genética , Gêmeos
18.
Science ; 345(6200): 1065-70, 2014 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-25170156

RESUMO

Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations. Similarly, an H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various Drosophila tissues. The histone H3K9 demethylase KDM3B/JHDM2 associates with H3K9M-containing nucleosomes, and its misregulation in Drosophila results in changes of H3K9 methylation levels and heterochromatic silencing defects. We have established histone lysine-to-methionine mutants as robust in vivo tools for inhibiting methylation pathways that also function as biochemical reagents for capturing site-specific histone-modifying enzymes, thus providing molecular insight into chromatin signaling pathways.


Assuntos
Cromatina/metabolismo , Histonas/genética , Lisina/genética , Metionina/genética , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster , Inativação Gênica , Glioma/genética , Glioma/metabolismo , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Metilação , Mutação , Transdução de Sinais
19.
Trends Genet ; 30(3): 103-10, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24555990

RESUMO

Heterochromatin protein 1 (HP1a in Drosophila) is a conserved eukaryotic chromosomal protein that is prominently associated with pericentric heterochromatin and mediates the concomitant gene silencing. Mechanistic studies implicate HP1 family proteins as 'hub proteins,' able to interact with a variety of chromosomal proteins through the chromo-shadow domain (CSD), as well as to recognize key histone modification sites [primarily histone H3 di/trimethyl Lys9 (H3K9me2/3)] through the chromodomain (CD). Consequently, HP1 has many important roles in chromatin architecture and impacts both gene expression and gene silencing, utilizing a variety of mechanisms. Clearly, HP1 function is altered by context, and potentially by post-translational modifications (PTMs). Here, we report on recent ideas as to how this versatile protein accomplishes its diverse functions.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cromossomos/metabolismo , Transcrição Gênica , Animais , Homólogo 5 da Proteína Cromobox , Inativação Gênica , Humanos , Processamento de Proteína Pós-Traducional/genética , Ativação Transcricional
20.
Blood ; 123(6): 935-45, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24255918

RESUMO

The extracellular nuclear proteins, histone H4 (H4) and high mobility group box 1 (HMGB1), released by injured cells during the activation of inflammation and coagulation pathways provoke potent inflammatory responses through interaction with pathogen-related pattern recognition receptors (ie, Toll-like receptors [TLRs] and receptor for advanced glycation end products [RAGE]) present on vascular and innate immune cells. Inorganic polyphosphate (polyP) has emerged as a key modulator of coagulation and inflammation. Here, we demonstrate that polyP binds to both H4 and HMGB1 with high affinity, thereby dramatically potentiating their proinflammatory properties in cellular and in vivo models. By using small interfering RNA knockdowns, pharmacologic inhibitors and extracellular domains of the receptors TLR2, TLR4, RAGE, and P2Y1 as competitive inhibitors, we demonstrate that polyP amplifies H4- and HMGB1-mediated inflammatory signaling in human umbilical vein endothelial cells specifically through interaction with the RAGE and P2Y1 receptors, thereby eliciting intracellular Ca(2+) release. Finally, we demonstrate that the natural anticoagulant protease, activated protein C, potently inhibits polyP-mediated proinflammatory effects of both nuclear proteins in cellular and in vivo systems.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Proteína HMGB1/metabolismo , Histonas/metabolismo , Mediadores da Inflamação/metabolismo , Polifosfatos/farmacologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Animais , Cálcio/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína C/metabolismo , RNA Interferente Pequeno/genética , Receptor para Produtos Finais de Glicação Avançada/genética , Receptores Purinérgicos P2Y1/química , Receptores Purinérgicos P2Y1/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
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