Evolutionary cardiology and experimental research / Cardiología evolutiva e investigación experimental

Abstract Evolutionary medicine studies the role of evolution in health problems. Diseases are considered as phenotypes generated by the expression of sets of genes and a complex interplay with the environment. The main mechanisms involved in evolutionary medicine are antagonistic pleiotropy, ecological antagonistic pleiotropy, atavisms and heterochrony. Antagonistic pleiotropism refers to genes that are beneficial during certain stages of development but become detrimental in others. Ecological antagonistic pleiotropy refers to the misadaptation to current lifestyle conditions which are different from those in which humans evolved. These mechanisms participate in the development of congestive heart failure, hypertension and atherosclerosis. Atavistic conditions or genes are expressed in our ancestors but have remained silent during evolution being suddenly expressed without an apparent cause during the appearance of a disease is another mechanism in evolutionary cardiology. The change in the heart metabolism from fatty acid to glucose dependent can be considered as an atavistic condition that appears in the heart after a stroke and may underlie impaired cardiomyocyte regeneration. Heterochrony is the expression of genes that cause the appearance of traits at a different timing during development and is therefore related to atavisms. Evolutionary medicine explains the interactions of pathogens and the host in infectious diseases where the cardiac tissue becomes a target. Mechanisms involved in evolutionary medicine participate in the generation of diseases and may be approached experimentally. Therefore, to better understand health problems and therapeutical approaches, an evolutionary medicine approach in experimental medicine may prove useful.

Resumen La medicina evolutiva estudia el papel de la evolución en los problemas de salud. Las enfermedades son fenotipos generados por la expresión de genes y una interacción compleja con el medio ambiente. Los principales mecanismos implicados son la pleiotropía antagonista, la pleiotropía antagonista ecológica, los atavismos y la heterocronía. El pleiotropismo antagonista se refiere a situaciones donde los genes que son beneficiosos durante ciertas etapas del desarrollo resultan perjudiciales en otras. La pleiotropía antagonista ecológica se refiere a la mala adaptación a las condiciones de vida actuales, que difieren de aquellas en las que los humanos evolucionaron. Estos mecanismos participan en el desarrollo de insuficiencia cardiaca congestiva, hipertensión y aterosclerosis. Las condiciones o genes atávicos fueron características que se expresaron en nuestros antepasados pero han permanecido silenciadas durante la evolución, expresándose repentinamente durante una enfermedad; un ejemplo es el cambio metabólico en el corazón de dependiente de ácidos grasos a dependiente de glucosa en condiciones de hipoxia que aparece después de un infarto y puede subyacer a la dificultad de la regeneración de los cardiomiocitos. La heterocronía es la expresión de genes que provocan la aparición de rasgos en un momento diferente durante el desarrollo. La medicina evolutiva también explica las interacciones entre los patógenos y el huésped en enfermedades infecciosas. Los mecanismos implicados en la medicina evolutiva participan en la generación de enfermedades y pueden abordarse experimentalmente. Por tanto, la medicina experimental puede enriquecer la medicina evolutiva y el origen de muchos problemas de salud.

Review on correction methods related to the pleiotropic effect in Mendelian randomization / 中华流行病学杂志

Mendelian randomization is an approach using the genetic variants as instrumental variable to estimate and assess the casual relationship between exposure of interest and outcomes. As a valid instrument, genetic variants have to meet the assumptions of strong correlation with exposure but without pleiotropic effect with the outcomes. However, pleiotropy of the variants is usually inevitable, owing to the existence of complex biological effects. Thus, correction methods related to pleiotropic bias are introduced in this paper regarding the selection of instrumental variables, testing of invalid instrumental variables, construction of pleiotropic effect correction models and sensitivity analysis of the robust results. For practical application, investigators should take consideration on the following areas including the types of data, sample size and other relative aspects, thereby selecting the suitable method for the inference of consistent and robust casual estimation.

Pathophysiological and pharmacological modulation of melatonergic system.

Pineal gland once considered as rudimentary or vestigial, has become a principal endocrine gland that regulates the body’s internal environment, after the discovery of melatonin - a hormone produced by it. Melatonin is also synthesized from extrapineal sites such as retina, skin, platelets, bone marrow, and gastrointestinal tract. The chronobiological property of this hormone in maintaining the circadian rhythm by synchronizing with the dark-light cycle is well-established. Melatonin also possesses anti-inflammatory, anti-depressant, anti-oxidant, oncostatic, immunomodulatory, antiepileptic, and glucose-regulating properties. These pleiotropic effects of melatonin on diverse organ systems either through a receptor or non-receptor mediated pathways are under investigation. This review highlights the pathophysiological and pharmacological actions of melatonin along with melatonergic agonists in “real life” clinical practice.

Severe Darier's disease in a psychiatric patient

Darier’s disease is characterized by dense keratotic lesions in the seborrheic areas of the body such as scalp, forehead, nasolabial folds, trunk and inguinal region. It is a rare genodermatosis, an autosomal dominant inherited disease that may be associated with neuropsichiatric disorders. It is caused by ATPA2 gene mutation, presenting cutaneous and dermatologic expressions. Psychiatric symptoms are depression, suicidal attempts, and bipolar affective disorder. We report a case of Darier’s disease in a 48-year-old female patient presenting severe cutaneous and psychiatric manifestations.

Association of vascular endothelial growth factor gene polymorphism with diabetic retinopathy in different population: a meta-analysis / 中华眼底病杂志

Objective To assess the association of vascular endothelial growth factor (VEGF) gene-460C/T and-634C/G polymorphism with diabetic retinopathy (DR) among patients in Asia and European by meta-analysis.Methods A systematic search of electronic databases (PubMed,Cochrane Library,EMBASE,VIP,Wanfang technological,CNKI,etc.) was carried out until Jun,2014.Case-control studies on the relationship between genetic polymorphism of VEGF-460C/T and VEGF-634C/G with diabetic retinopathy were included in this analysis.The data were quantitatively analyzed by RevMan 5.0 software after assessing the quality of included studies.The pooled odds ratios (OR) and their corresponding 95％ confidence intervals (CI) were used to assess the strength of the association.Results VEGF-460C/T (7 studies:899 cases and 786 controls) and VEGF-634C/G (10 studies:1615 cases and 1861 controls) were inclued in this meta-analysis.Significant association was found for-460C/T polymorphism in Aisa (C versus T:OR=1.52,95％CI was [1.22,1.90],Z=3.72,P=0.0002;CC versus CT+TT:OR=1.61,95％CI was [1.19,2.19],Z=3.05,P=0.002;TT versus CT+CC:OR=0.64,95％CI was [0.41,0.98],Z=2.07,P=0.04),and VEGF-634CC gene type was associated with DR in European (OR=1.56,95％CI [1.08,2.25],Z=2.37,P=0.02).No significant publication bias was found.Conclusions The metaanalysis demonstrated that DR was associated with VEGF-460C/T polymorphism in Asia,and C alleles and CC gene type was the risk polymorphism;VEGF-634C/G polymorphism was not associated with DR,but its CC genotype maybe the risk factor in European.Further case-control studies based on larger sample size are still needed,especially for-634C/G polymorphism.

Relationship between hOGG1 and XPD gene polymorphism and genetic susceptibility of gastric cancer / 中国基层医药

Objective To investigate the relationship between hOGG1 and XPD gene polymorphism and genetic susceptibility of gastric cancer.Methods This study was carried out in Dongying Shengli Petroleum Administration Bureau Hospital.Under the narrow band imaging(NBI) mode,the blood samples of a total of 98 gastric cancers and 80 controls without cancers were collected.Genetic polymorphisms of DNA repair genes were identified by polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP),then its relationship with cancers was analyzed.Results Carrying 326Cys allele with the wine increased the risk of gastric cancer; Lys 751Gln genotype increased the susceptibility of the gastric cancers (OR =1.486,0.73 ～ 3.025).Conclusion Lys751 Gln genotype increases the risk of gastric cancer.

Análise genética de fenótipos cardiometabólicos complexos em população urbana e rural de Minas Gerais / The cardiometabolic phenotypes with different strategies of genetic analyses using the estimate of heritability in an urban area, in Minas Gerais

Fenótipos cardiometabólicos como doenças cardiovasculares, obesidade, resistência à insulina, diabetes, alteração nos níveis lipídicos são responsáveis por elevada mortalidade e outras complicações. A predisposição genética influencia diversos aspectos do metabolismo que elevam o risco, e, consequentemente, contribui para o aumento da prevalência desses fenótipos, sendo uma das áreas promissoras na descoberta da etiogênese das doenças crônicas. Portanto, o objetivo do estudo foi investigar potenciais associações genéticas - utilizando diferentes estratégias de análise - com fenótipos cardiometabólicos por meio da estimativa da herdabilidade em população rural e da estimativa de ocorrência do polimorfismo do receptor de leptina (LEPR) Gln223Arg em população urbana, ambas em Minas Gerais. Para tal, foram utilizados dois estudos transversais. O primeiro foi realizado nas áreas rurais de Virgem das Graças, Caju e São Pedro do Jequitinhonha, no qual 931 indivíduos pertencentes a 89 pedigrees foram fenotipados. Nesse estudo foi utilizada a estratégia de estimativa de herdabilidade (h2), correlações genéticas e ambientais e sua associação com níveis lipídicos, índice de massa corporal, circunferência abdominal e pressão arterial. No segundo estudo foi utilizada a avaliação da frequência do polimorfismo do LEPR Gln223Arg e potenciais associações com sobrepeso, obesidade, obesidade abdominal e gordura corporal. As estimativas de h2 para os fenótipos avaliados variaram de 28 a 60%, e correlações genéticas (ρg) significativas foram encontradas para a maioria dos pares de fenótipos avaliados (considerando os modelos ajustados): triglicérides - VLDL (ρg=0,99), colesterol total - LDL (ρg=0,90), pressão arterial diastólica - triglicérides (ρg=0,63), pressão arterial diastólica - VLDL (ρg=0,59), além do triglicérides-colesterol total (ρg=0,58). De forma geral, as correlações genéticas foram superiores às correlações ambientais. Foram encontrados efeito household...

Cardiometabolic phenotypes such as cardiovascular diseases, obesity, insulin resistance, diabetes, high level of lipids were responsible for high mortality and its complications. Genetics could influence metabolism in many aspects and it could contribute to the high prevalence of these phenotypes. Therefore, the objective of this study was to research the cardiometabolic phenotypes with different strategies of genetic analyses using the estimate of heritability in a rural area, in Vale do Jequitinhonha and to associate the leptin receptor polymorphism (LEPR) Gln223Arg in an urban area, in Minas Gerais. Both studies were cross-sectional. The first study was conducted in the rural area of Virgem das Graças, Caju and São Pedro do Jequitinhonha, in which 931 individuals of 89 pedigrees were phenotyped. In the first study, the strategy of estimating heritability (h2), pleiotropy and its association with lipid levels, body mass index, waist circumference and blood pressure was evaluated. In the second study, the frequency of the LEPR Gln223Arg and the potentials associations with overweight, obesity, abdominal obesity and higher body fat was evaluated. The h2 estimates for the phenotypes evaluated ranged 28 to 60% and significant genetic correlations (ρg) were found for most pairs of phenotypes evaluated mainly among triglycerides - VLDL (ρg = 0.99), total cholesterol - LDL (ρg = 0.90), diastolic blood pressure - triglycerides (ρg = 0.63) and diastolic blood pressure - VLDL (ρg = 0.59), total cholesterol - triglycerides (ρg = 0.58). In general, genetic correlations were higher than the environmental correlations. Household effects have been found for HDL (c2 = 0.21, P < 0.001) and VLDL (c2 = 0.10, P = 0.010) and hypertension (c2 = 0.14, P = 0.015). Finally, to complete pleiotropy found between VLDL - triglycerides, it means that these phenotypes are controlled by a single gene or by a set of genes. Moreover, in the urban area, high levels of...

Estatinas nas síndromes coronarianas agudas / Statins in acute coronary syndromes / Estatinas en los síndromes coronarios agudos

As estatinas são o principal recurso disponível para redução do LDL-colesterol. Seu uso contínuo reduz a morbidade e a mortalidade cardiovascular decorrente da doença aterosclerótica. A administração das estatinas demonstrou ser efetiva em estudos clínicos de prevenção primária e secundária em pacientes de baixo e alto risco. O mecanismo presumido de benefício da terapia hipolipemiante na prevenção das complicações da doença aterosclerótica age na redução da deposição de lipoproteínas aterogênicas em áreas vulneráveis da vasculatura. Estudos experimentais com estatinas demonstraram grande variedade de outros efeitos que poderiam estender o benefício clínico além da modificação do perfil lipídico por si só. A terapia com estatinas altera beneficamente componentes importantes do processo aterotrombótico: inflamação, oxidação, coagulação, parâmetros fibrinolíticos, função endotelial, vasorreatividade e função plaquetária. A demonstração dos efeitos não dependentes da redução do colesterol ou pleiotrópicos das estatinas fornece a base teórica para seu possível papel como terapia adjunta das síndromes coronarianas agudas. Análises retrospectivas de uma variedade de estudos indicam potencial benefício das estatinas durante os eventos coronarianos agudos. Estudos clínicos recentes têm abordado essa importante questão em ensaios prospectivos controlados, demonstrando fortes evidências a favor da administração das estatinas como terapia adjunta nas síndromes coronarianas agudas.

Statins are the main resource available to reduce LDL-cholesterol levels. Their continuous use decreases cardiovascular morbidity and mortality due to atherosclerosis. The administration of these medications demonstrated to be effective in primary and secondary prevention clinical trials in low and high risk patients. Specialists believe that a possible benefit of hypolipidemic therapy in preventing complications of atherosclerotic diseases is in the reduction of deposition of atherogenic lipoproteins in vulnerable areas of the vasculature. Experimental studies with statins have shown an enormous variety of other effects that could extend the clinical benefit beyond the lipid profile modification itself. Statinbased therapies benefit other important components of the atherothrombotic process: inflammation, oxidation, coagulation, fibrinolysis, endothelial function, vasoreactivity and platelet function. The demonstration of the effects that do not depend on cholesterol lowering or the pleiotropic effects of statins provides the theoretical basis for their potential role as adjunctive therapy in acute coronary syndromes. Retrospective analyses of a variety of studies indicate the potential benefit of statins during acute coronary events. Recent clinical studies have addressed this important issue in prospective controlled trials showing strong evidence for the administration of statins as adjunctive therapy in acute coronary syndromes.

Las estatinas son el principal recurso disponible para la reducción del LDL-colesterol. Su uso continuo reduce la morbilidad y la mortalidad cardiovascular proveniente de la enfermedad arterioesclerótica. La administración de las estatinas demostró ser efectiva en los estudios clínicos de prevención primaria y secundaria en pacientes de bajo y alto riesgo. El mecanismo entendido como beneficioso de la terapia hipolipemiante en la prevención de las complicaciones de la enfermedad arterosclerótica, actúa en la reducción de la deposición de lipoproteínas aterogénicas en áreas vulnerables de la vasculatura. Estudios experimentales con estatinas han venido demostrando una gran variedad de otros efectos que podrían extender el beneficio clínico más allá de la modificación del perfil lipídico por sí mismo. La terapia con estatinas altera benéficamente los componentes importantes del proceso aterotrombótico: inflamación, oxidación, coagulación, parámetros fibrinolíticos, función endotelial, vasorreactividad y una función plaquetaria. La demostración de los efectos no dependientes de la reducción del colesterol o pleiotrópicos de las estatinas, suministra una base teórica para su posible papel como terapia coadyuvante de los síndromes coronarios agudos. Los análisis retrospectivos de una variedad de estudios indican un potencial beneficioso de las estatinas durante los eventos coronarios agudos. Recientes estudios clínicos han abordado esa importante problemática en ensayos prospectivos controlados, demostrando fuertes evidencias en favor de la administración de las estatinas como una terapia coadyuvante en los síndromes coronarios agudos.

Significance of Cellular Senescence in Aging and Cancer / Journal of the Korean Cancer Association, 대한암학회지

Cellular senescence is a mechanism that induces an irreversible growth arrest in all somatic cells. Senescent cells are metabolically active but lack the capacity to replicate. Evolutionary theories suggest that cellular senescence is related to the organismal decline occurring in aging organisms. Also, such theories describe senescence as an antagonistically pleiotropic process that can have beneficial or detrimental effect on the organism. Cellular senescence is believed to be involved in the cellular changes observed as aging progresses. Accumulation of senescent cells appears to occur widely as the organism ages. Furthermore, senescence is a key element of the tumor suppressor pathways. Therefore, it is part of the natural barrier against the uncontrolled proliferation observed in cellular development of malignancies in multicellular organisms. Activation of the senescence process guarantees a limited number of cellular replications. The genetic network led by p53 is responsible for activation of senescence in response to DNA damage and genomic instability that could lead to cancer. A better comprehension of the genetic networks that control the cell cycle and induce senescence is important to analyze the association of senescence to longevity and diseases related to aging. For these reasons, experimental research both in vitro and in vivo aims to develop anticancer therapies based on senescence activation. The last decade of research on role and function of senescence in aging and cancer are discussed in this paper.

Family based analysis of quantitative changes of erythrocyte membrane proteins in essential hypertension.

Our previous studies have found significant quantitative changes in the erythrocyte membrane proteins in essential hypertension (EH). The purpose of the present study was to quantify genetic and environmental contributions to quantitative variability of erythrocyte membrane proteins in EH. We studied 115 hypertensive patients, 126 normotensive subjects, 235 of their first-degree relatives and 24 twin pairs by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. The decomposition of total phenotypic variance of erythrocyte membrane proteins to genetic and environmental components was performed by the least squares method. We found that genetic factors play a significant role in the control of quantitative changes in erythrocyte membrane proteins in EH. The genetic contribution to anion exchanger variation was stronger in hypertensives (88%) than in normotensives (36%), and was attributed exclusively to additive polygenic effects. Variation in glucose transporter was under marked control of major gene effect (74%). Importantly, variations in anion and glucose transporters in EH but not in healthy controls were strongly affected by common underlying genes with strong pleiotropic effects (r=0.921, P<0.05). These data provide evidence to support the genetic source of quantitative changes in membrane proteins in EH. Furthermore, the pleiotropic effects of common underlying genes seem to be responsible for variations in the transport proteins likely associated with genetic susceptibility to essential hypertension.