Research progress of m6A methylation in prostate cancer / 亚洲男科学杂志(英文版)

N6-methyladenosine (m6A) is a ubiquitous RNA modification in mammals. This modification is "written" by methyltransferases and then "read" by m6A-binding proteins, followed by a series of regulation, such as alternative splicing, translation, RNA stability, and RNA translocation. At last, the modification is "erased" by demethylases. m6A modification is essential for normal physiological processes in mammals and is also a very important epigenetic modification in the development of cancer. In recent years, cancer-related m6A regulation has been widely studied, and various mechanisms of m6A regulation in cancer have also been recognized. In this review, we summarize the changes of m6A modification in prostate cancer and discuss the effect of m6A regulation on prostate cancer progression, aiming to profile the potential relevance between m6A regulation and prostate cancer development. Intensive studies on m6A regulation in prostate cancer may uncover the potential role of m6A methylation in the cancer diagnosis and cancer therapy.

Roles of m6A modification in neurological diseases / 中南大学学报(医学版)

N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications for eukaryotic mRNA. Under the catalytic regulation of relevant enzymes, m6A participates in the body's pathophysiological processes via mediating RNA transcription, splicing, translation, and decay. In the past, we mainly focused on the regulation of m6A in tumors such as hematological tumors, cervical cancer, breast cancer. In recent years, it has been found that m6A is enriched in mRNAs of neurogenesis, cell cycle, and neuron differentiation. Its regulation in the nervous system is gradually being recognized. When the level of m6A modification and the expression levels of relevant enzyme proteins are changed, it will cause neurological dysfunction and participate in the occurrence and conversion of neurological diseases. Recent studies have found that the m6A modification and its associated enzymes were involved in major depressive disorder, Parkinson's disease, Alzheimer's disease, Fragile X syndrome, amyotrophic lateral sclerosis, and traumatic brain injury, and they also play a key role in the development of neurological diseases and many other neurological diseases. This paper mainly reviewed the recent progress of m6A modification-related enzymes, focusing on the impact of m6A modification and related enzyme-mediated regulation of gene expression on the central nervous system diseases, so as to provide potential targets for the prevention of neurological diseases.

Comprehensive Analysis of the Relationship between m6A Methylation Patterns and Immune Microenvironment in Lung Adenocarcinoma / 中国肺癌杂志

BACKGROUND@#m6A RNA methylation modification plays an important role in the occurrence and progression of lung cancer and regulates tumor immunity. Current studies mostly focus on the differential expression of some specific m6A effectors and infiltrating immune cell. m6A methylation modification is the result of mutual adjustment and balance between effectors, and changes in the expression of one or two effectors are far from enough to reflect the panorama of m6A methylation. The role of m6A in the immune microenvironment of lung adenocarcinoma (LUAD) is still poorly understood. The aim of this study is to investigate the effect of different m6A modification patterns in immune microenvironment of LUAD.@*METHODS@#LUAD data was obtained from The Cancer Genome Atlas (TCGA), University of California Santa Cruz Xena (UCSC Xena) and Gene Expression Omnibus (GEO) databases. Gene mutation, differential expression and survival analysis were performed for 24 m6A effectors. The m6A modification pattern was constructed by unsupervised clustering method, and the m6A clusters survival analysis, gene set variation analysis, immune score and immune cell infiltration analysis were performed. The association between LRPPRC protein expression levels and infiltration of CD8+ cytotoxic T lymphocytes and CD68+ macrophages in the tumor microenvironment was validated by immunohistochemistry in LUAD tissue microarray with 68 cases.@*RESULTS@#The mutations of m6A effector were found in 150 of 567 LUAD cases with a frequency of 26.46%. 6 readers and 3 writers were significantly up regulated in LUAD tissues compared with normal tissues. IGF2BP1 and HNRNPC are the independent risk factors for prognosis of LUAD. Abundant cross-talks among writers, erasers and readers were demonstrated. Three m6A modification patterns with different immune cell infiltration characteristics and clinical prognosis were established. Among m6A effectors, LRPPRC was found to be inversely associated with the infiltration of CD8+ cytotoxic T lymphocytes and CD68+ macrophages, and was validated in 68 LUAD tissues.@*CONCLUSIONS@#m6A modification patterns play non-negligible roles in regulating the immune microenvironment. LRPPRC has potential to be a new biomarker for checkpoint inhibitor immunotherapy.

Rendesivir para tratamento de pacientes com COVID-19 hospitalizados com pneumonia e necessidade de suplementação de oxigênio / Rendesivir for the treatment of patients with COVID-19 hospitalized with pneumonia and need for oxygen supplementation

INTRODUÇÃO: No dia 12 de março de 2021 a ANVISA concedeu o registro para comercialização de rendesivir no Brasil como primeiro e único medicamento com indicação aprovada em bula, para tratamento de pacientes com COVID-19 com pneumonia e necessidade de suplementação de oxigênio (baixo ou alto fluxo e ventilação mecânica não invasiva). A autorização fornecida pela ANVISA para uso do medicamento no Brasil, diverge da recomendação da OMS que desaconselha o uso do rendesivir para tratamento de pacientes hospitalizados por COVID-19, independente de sua gravidade usando como base os resultados interinos do estudo Solidarity (14). Este estudo revelou que o uso do rendesivir, assim como outros antivirais analisados, não foi capaz de reduzir de forma significativa a mortalidade geral ou de nenhum subgrupo estudado, nem retardar o início da ventilação mecânica ou reduzir o tempo de hospitalização. A redução do tempo de internação para a ANVISA foi um critério importante para o contexto brasileiro devido a constante falta de leitos disponíveis para o tratamento dos pacientes acometidos pela COVID-19. TECNOLOGIA: Remdesivir (Veklury®). PERGUNTA: O uso do rendesivir é eficaz e seguro para tratamento de pacientes hospitalizados com COVID-19 e que necessitam de suplementação de oxigênio (de baixo ou alto fluxo e ventilação mecânica não invasiva)? EVIDÊNCIAS CLÍNICAS: As evidências avaliadas baseiam-se em quatro ensaios clínicos randomizados, onde dois compararam rendesivir com placebo e outros dois comparando rendesivir com cuidado padrão. Foram obtidos resultados favoráveis ao rendesivir com maior probabilidade de recuperação no 29º dia (Hazard Ratio [HR] 1,29, 95%IC 1,12-1,49, p<0,001) em um dos estudos. Para o desfecho mortalidade no 29º dia, os resultados do mesmo ensaio foram significativos apenas para o subgrupo de pacientes que necessitavam de suplementação de oxigênio de baixo ou alto fluxo (HR = 0,30, 95%IC 0,14- 0,64). Ao sumarizar os dados dos quatro estudos observou-se que em pacientes hospitalizados com COVID-19, o uso do rendesivir comparado com o grupo controle não resultou em diferenças estatisticamente significativas tanto quanto os desfechos de mortalidade (Risco Relativo [RR]: 0,98, 95%IC 0,84-1,14); necessidade de ventilação mecânica (RR: 0,77, 95%IC 0,48-1,22) e recuperação (RR: 1,09, 95%IC 1,03-1,15), segundo três estudos. O rendesivir comparado com placebo e cuidado padrão pode reduzir em 25% o risco da ocorrência de eventos adversos sérios (RR: 0,75, 95%IC 0,63-0,90). AVALIAÇÃO ECONÔMICA: Os resultados do modelo econômico apresentado pelo demandante têm limitações que tornam incertos os resultados do modelo econômico apresentado, de forma que a sua utilização para tomada de decisão sobre a tecnologia é duvidosa. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário incremental após a proposta de redução de preço pelo demandante foi estimado em aproximadamente 28 bilhões de reais, como melhor cenário. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas oito tecnologias potenciais para a indicação clínica. O opaganib consiste no primeiro agente de uma nova classe farmacológica, a dos inibidores de esfingosina-quinases. Outro potencial medicamento para a indicação a ser administrado por via oral e em combinação ao cuidado padrão (não especificado no protocolo do estudo), é o fostamatinib. O reparixin é um análogo do ibuprofeno e sua eficácia para o tratamento de pacientes com pneumonia grave acometidos por COVID-19 está sendo avaliada. O BDB-001 e o ravulizumab têm como alvo farmacológico o fator C5a do sistema complemento. Os anticorpos monoclonais canaquinumab, mavrilimumab e tocilizumabe também estão em desenvolvimento. Além disso, foram identificados três depósitos de patentes relacionados ao rendesivir no Instituto Nacional da Propriedade Intelectual. CONSIDERAÇÕES FINAIS: O balanço entre os aspectos positivos e negativos do rendesivir foi desfavorável ao seu uso no tratamento de pacientes com COVID-19. Apesar do baixo risco de eventos adversos, houve uma baixa confiança na eficácia do medicamento, uma vez que os resultados dos estudos são discrepantes e baseados em uma análise de subgrupo de apenas um estudo. O impacto orçamentário estimado foi considerado elevado. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, a Conitec, em sua 98ª Reunião Ordinária, realizada no dia 10 de junho de 2021, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação no SUS do rendesivir para o tratamento da doença causada pelo coronavírus 2019 (COVID19), em pacientes adultos com pneumonia que requerem suplementação de oxigênio de baixo ou alto fluxo. Foi discutido, emplenária, que a evidência disponívelsobre a tecnologia emavaliação foi baseada emestudos adaptativos heterogêneos, com importantes limitações metodológicas, que podem se traduzir em resultados devidos apenas ao acaso. Além disso, o perfil de segurança do rendesivir, quando comparado aos medicamentos de cuidado padrão, mostrou que o medicamento está associado a um risco aumentado de bradicardia em pacientes diagnosticados com COVID-19. CONSULTA PÚBLICA: Foram recebidas 90 contribuições, sendo 34 contribuições técnico-científicas e 56 de experiência e opinião. Diante das argumentações apresentadas, o plenário da Conitec entendeu que não houve argumentação suficiente para mudança de entendimento acerca de sua recomendação preliminar, com base nas evidências científicas apresentadas, tampouco na redução de preço proposta pelo fabricante. Desse modo, a Comissão, diante das incertezas quanto à eficácia do medicamento, manteve a posição desfavorável à incorporação do rendesivir para o tratamento dos pacientes hospitalizados com pneumonia provocada pelo COVID-19 com necessidade de suplementação de oxigênio. DELIBERAÇÃO FINAL: O Plenário da Conitec, em sua 100ª Reunião Ordinária, no dia 05 de agosto de 2021, deliberou por unanimidade recomendar a não incorporação do rendesivir para o tratamento de pacientes com COVID-19 com necessidade de suplementação de oxigênio (baixo ou alto fluxo, ventilação não invasiva) no âmbito do SUS, com base nas incertezas quanto à eficácia do medicamento. Foi assinado o Registro de Deliberaçã nº 651/2021. DECISÃO: Não incorporar o rendesivir para tratamento de pacientes com Covid-19 hospitalizados com pneumonia e necessidade de suplementação de oxigênio, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 60, publicada no Diário Oficial da União nº 171, seção 1, página 77, em 9 de setembro de 2021.

RNA methylation and neurovascular unit remodeling / 中南大学学报(医学版)

RNA methylation is of great significance in the regulation of gene expression, among which the more important methylation modifiers are N6-methyladenosine (m6A) and 5-methylcytosine (m5C). The methylation process is mainly regulated by 3 kinds of proteins: methyltransferase, demethylase, and reader. m6A, m5C, and their related proteins have high abundance in the brain, and they have important roles in the development of the nervous system and the repair and remodeling of the vascular system. The neurovascular unit (NVU) is a unit of brain structure and function composed of neurons, capillaries, astrocytes, supporting cells, and extracellular matrix. The local microenvironment for NVU has an important role in nerve cell function repair, and the remodeling of NVU is of great significance in the prognosis of various neurological diseases.

Research Advance of the Roles of N6-methyladenosine in the Regulation of Hematopoiesis--Review / 中国实验血液学杂志

There are more than 150 types of chemical modifications in RNA, mainly methylation, which are widely distributed in all kinds of RNA, including messenger RNA, transfer RNA, ribosomal RNA, non-coding small RNA and long non-coding RNA. In recent years, the identification of RNA methylation modification enzymes and the development of high-throughput sequencing technology at transcriptome level laid a foundation for revealing the expression and function of genes regulated by chemical modification of RNA. In this review, the most recent advances of RNA methylation, especially N6-methyladenosine (m

Adenosine: an endogenous mediator in the pathogenesis of psoriasis

Abstract: It is known that inflammatory and immune responses protect us from the invasion of micro-organisms and eliminate "wastes" from the injured sites, but they may also be responsible for significant tissue damage. Adenosine, as a purine nucleoside, which is produced in inflamed or injured sites, fulfills its role in limiting tissue damage. Although, it may have a pleiotropic effect, which signals it with a proinflammatory state in certain situations, it can be considered a potent anti-inflammatory mediator. The effects of adenosine, which acts through its receptors on T cell, on mast cell and macrophages, on endothelial cells, on neutrophils and dendritic cells, as they indicate TNF-alpha and cytokines, show that this mediator has a central role in the pathogenesis of psoriasis. The way it acts in psoriasis will be reviewed in this study.

Adenosin deaminasa en la tripanosomiasis experimental: futuras implicaciones / Adenosine deaminase in experimental trypanosomiasis: future implications

La adenosin deaminasa representa un punto de control en la regulación de los niveles extracelulares de adenosina, desempeñando así un papel fundamental en la modulación de las respuestas purinérgicas a ciertos eventos patofisiológicos. Diversos estudios señalan que los niveles séricos y plasmáticos de la enzima se elevan en algunas enfermedades causadas por microorganismos, lo cual podría representar un mecanismo compensatorio como consecuencia de la elevación de las concentraciones de adenosina y la liberación de mediadores inflamatorios. Recientes investigaciones indican que la actividad de la adenosin deaminasa disminuye e influye en los parámetros hematológicos de animales infectados con Trypanosoma evansi, de manera que tales alteraciones podrían tener implicaciones en la patogénesis de la enfermedad. Adicionalmente, la enzima ha sido detectada en este parásito; lo que permite inferir que podría estar asociada a las funciones vitales del mismo, de manera similar a lo que ocurre en los mamíferos. Este conocimiento puede ser útil al asociar la quimioterapia con inhibidores específicos de la enzima en futuros estudios.

The adenosine deaminase represents a control point in the regulation of extracellular adenosine levels, thus playing a critical role in the modulation of purinergic responses to certain pathophysiological events. Several studies have shown that serum and plasma enzyme levels are elevated in some diseases caused by microorganisms, which may represent a compensatory mechanism due to the elevated levels of adenosine and the release of inflammatory mediators. Recent research indicates that adenosine deaminase activity decreases and affects hematological parameters of infected animals with Trypanosoma evansi, so that such alterations could have implications in the pathogenesis of the disease. In addition, the enzyme has been detected in this parasite; allowing the inference that it could be associated with the vital functions of the same, similar to what occurs in mammals. This knowledge may be useful in the association of chemotherapy with specific inhibitors of the enzyme in future studies.

In vivo and in vitro anti-natriuretic activity of twigs fraction from Dorstenia picta: a possible mechanism

The present study examine the in vivo effects of Dorstenia Picta [D. picta] on urinary volume and sodium excretion in streptozotocin-induced diabetic rats, and determine a possible mechanism by which the extract increased sodium transport in A6 cells monolayers. Administration of the plant extract at the dose of 150 mg/kg during two weeks decreased urinary volume and sodium excretion. In vitro study showed that, apical application of the plant extract at the dose of 100 micro g/mL does not significantly increase sodium transport, whereas basolateral administration provoked a significant [P<0.05] increase of sodium transport in a concentration-dependent manner. The plant extract increases the sodium transport by 69.93% versus 55.41% for insulin and 78.44% for adenosine after 30 min. Preincubation of A6 cells monolayers with inhibitor of all adenosine receptors completely suppressed adenosine and plant extract stimulated sodium transport. Interesting is that, the A1 inhibitor receptor [DPCPX], at 100 nM completely abolished the effect of plant extract. The plant extract increased sodium transport by increase PI3-kinase activity and this effect is strongly inhibited by LY-294002. These data also suggest that, the twigs methanol fraction from Dorstenia picta increase sodium transport via PI 3-kinase pathway and requires A1 adenosine receptor

Treinamento físico de natação promove remodelamento cardíaco e melhora a perfusão sanguínea no músculo cardíaco de SHR via mecanismo dependente de adenosina / Swimming physical training promotes cardiac remodeling and improves

INTRODUÇÃO: Exercícios físicos são utilizados como terapia não farmacológica para o tratamento da hipertensão arterial, e o treinamento físico (TF) por natação é reconhecido por produzir remodelamento cardíaco em animais experimentais. Entretanto, a ação vasodilatadora da adenosina (ado) resultante do exercício físico como prevenção e tratamento da hipertensão é pouco explorada. OBJETIVO: Avaliar o remodelamento cardíaco e o papel da adenosina na distribuição do fluxo sanguíneo para o miocárdio após treinamento físico em SHR. Método: 28 SHR machos babies e adultos foram submetidos ao TF aeróbio de natação, durante 10 semanas (5x/sem -1h/dia). Foram utilizados protocolos de microesferas coloridas para avaliar fluxo sanguíneo, técnicas de morfologia para avaliar hipertrofia cardíaca e análises bioquímicas para verificar atividade de enzimas envolvidas na formação de adenosina. RESULTADOS: TF por natação atenuou a evolução da HA em SHR babies (S: 145 ± 2; T: 140 ± 2mmHg), promoveu bradicardia de repouso em SHR adultos (S: 340 ± 4; T: 321 ± 6bpm) e desenvolveu HC nos dois grupos (TB: 12 por cento; TA: 10 por cento). Na condição basal, o TF aumentou o FS coronário em SHR babies (S: 4.745 ± 2.145; T: 6.970 ± 2.374mi/coração) e maior resposta vasodilatadora à infusão de adenosina foi observada (S: 18.946 ± 6.685; T: 25.045 ± 7.031mi/coração). Neste grupo, o TF promoveu maior atividade da enzima 5'-nucleotidase, levando à maior formação de adenosina (S: 0,45 ± 0,09; T: 1,01 ± 0,05). CONCLUSÃO: O TF de natação, além de desenvolver HC e apresentar maior hidrólise de AMP, promoveu aumento no FS coronário, sendo mostrado que desempenha um importante papel na regulação da hipertensão.

Exercise training (ET) has been used as non-pharmacological therapy for hypertension treatment and swimming physical training is recognized for yielding cardiac remodeling in experiments. However, little is known on the effects of adenosine (Ado) resulting from ET as hypertension prevention and treatment. OBJECTIVE: To evaluate cardiac remodeling and the role of adenosine in cardiac blood flow distribution (BF) to the myocardium after aerobic ET on SHR. METHODS: 28 male SHR, babies and adults, were submitted to swimming training protocol during 10 weeks (5 times a week - 1 h a day). Colored micro spheres protocols were used to evaluate blood flow, morphological techniques were used to evaluate cardiac hypertrophy and biochemical analysis were performed to verify enzyme activity in the adenosine formation. RESULTS: ET attenuated the evolution of hypertension in the SHR babies group (S: 145 2; T: 140 2mmHg), HR was lower in adult SHR (S: 340 4; T: 321 6bpm) and CH increased in both groups (TB: 12 percent; TA: 10 percent). At basal condition, BF was increased in trained babies (S: 4.745 ± 2.145; T: 6.970 ± 2.374mi/heart) and higher vasodilatation response was observed due to adenosine infusion (S: 18.946 ± 6.685; T: 25.045 ± 7.031mi/heart). In this group, the ET promoted a higher 5'-nucleotidase enzyme activity leading to a higher adenosine formation (S: 0.45 ± 0.09; T: 1.01 ± 0.05). CONCLUSION: The swimming training developed CH as well as increased adenosine formation, leading to higher coronary blood flow, and its important role in hypertension regulation was demonstrated.

Roles of Adenosine and Serotonin Receptors on the Antinociception of Sildenafil in the Spinal Cord of Rats

PURPOSE: The phosphodiesterase 5 inhibitor sildenafil has antinociceptive effects, mediated by an increase in cGMP. This study examined the role of spinal adenosine and serotonin receptors played in the antinociceptive effects of intrathecal sildenafil. MATERIALS AND METHODS: Intrathecal catheters were inserted into the subarachnoid space of Sprague-Dawley male rats as a drug delivery device. Pain was induced by injecting formalin into the plantar surface of rats and observing nociceptive behavior (flinching response) for 60 mininutes. Then, the effects of intrathecal adenosine and serotonin receptor antagonists on the antinociceptive activity of intrathecal sildenafil were examined. RESULTS: Intrathecal sildenafil suppressed the flinching response in a dose-dependent manner during phases 1 and 2 in the formalin test. Both CGS 15943 and dihydroergocristine decreased the antinociceptive effects of sildenafil during phases 1 and 2 in the formalin test. CONCLUSION: Intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Both adenosine and serotonin receptors may be involved in the antinociceptive action of sildenafil at the spinal level.

Kinetics of oxidation of adenosine by tert-butoxyl radicals: Protection and repair by chlorogenic acid.

The rates of oxidation of adenosine and chlorogenic acid by tert-butoxyl radicals (t-BuO-) were studied by measuring the absorbance of adenosine at 260 nm and chlorogenic acid at 328 nm spectrophotometrically. t-BuO- radicals were generated by the photolysis of tert-butyl hydroperoxide (t-BuOOH) in presence of tert-butyl alcohol to scavenge OH. radicals. The rates and the quantum yields() of oxidation of chlorogenic acid by t-BuO-radicals were determined in the absence and presence of varying concentrations of adenosine. An increase in the concentration of adenosine was found to decrease the rate of oxidation of chlorogenic acid, suggesting that adenosine and chlorogenic acid competed for t-BuO. radicals. From competition kinetics, the rate constant of chlorogenic acid reaction with t-BuO- was calculated to be 3.20 109 dm3 mol-1 s-1. The quantum yields (expt) were calculated from the experimentally determined rates of oxidation of chlorogenic acid under different experimental conditions. Assuming that chlorogenic acid acts as a scavenger of t-BuO- radicals only, the quantum yields (cal) were theoretically calculated. expt and cal values suggested that chlorogenic acid not only protected adenosine from t-BuO- radicals, but also repaired adenosine radicals, formed by the reaction of adenosine with t-BuO- radicals.

Anti-nociceptive effect of duloxetine in mouse model of diabetic neuropathic pain.

The involvement of adenosinergic pathway in the anti-nociceptive effect of duloxetine, a balanced 5-HT/NE reuptake inhibitor, was evaluated in streptozotocin induced diabetic male albino mice of Laca strain. After four weeks of single injection of streptozotocin (200 mg/kg, ip), mice were tested in the tail immersion and hot-plate assays. Cerebral adenosine levels were measured by high-performance liquid chromatography (HPLC/PDA detector). Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose, decreased body weights and reduced cerebral adenosine levels. Administration of duloxetine (5, 10 and 20 mg/kg, ip) to diabetic mice produced dose-dependent anti-nociceptive effect in both tail-immersion and hot-plate assays. Adenosine levels were also significantly and dose-dependently increased by different doses of duloxetine. The results demonstrated the involvement of adenosinergic pathway in duloxetine mediated anti-hyperalgesia in diabetic neuropathic pain.

Changes in Serum Adenosine Deaminase Activity during Normal Pregnancy

Adenosine deaminase (ADA), an enzyme essential for the differentiation of lymphoid cells, has been used for monitoring diseases with altered immunity. The purpose of this study was to investigate the changes in serum ADA activity throughout normal pregnancy. We measured the catalytic values of serum ADA from 202 normal pregnant women using a commercial kit. Subjects were divided into four groups according to the gestational age in weeks (Gwks) (Group I: 5-9 Gwks [n=58]; Group II: 15-20 Gwks [n= 63]; Group III: 24-30 Gwks [n=34]; Group IV: 30-39 Gwks [n=47]). The serum ADA levels for the Groups I, II, III, and IV were as follows: 20.1+/-6.9 IU/L, 20.0+/-7.6 IU/L, 37.9+/-19.9 IU/L, and 24.5+/-8.6 IU/L, respectively. The serum ADA activity of group III was significantly higher than the other groups (p<0.05). However, there was no significant correlation between the Gwks and the serum ADA activity. Furthermore, other parameters, such as maternal age (p=0.29), gestational age at delivery (p=0.07), delivery mode (p=0.39), and birth weight (p=0.59) had no correlation with ADA activity. Reference values of serum ADA in normal pregnancy may provide important database for making clinical decisions in pregnancies complicated by conditions where cellular immunity has been altered.

Influência do pré-condicionamento isquêmico na proteçäo miocárdica em revascularizaçäo do miocárdio com pinçamento intermitente da aorta / Influence of the ischemic preconditioning in the myocardial protection in myocardial revascularization with intermittent aortic cross-clamping

Objetivo: Este estudo testa a hipótese de que curtos períodos de isquemia podem aumentar a proteçäo obtida pelo pinçamento intermitente da aorta. Métodos: No grupo controle (18), a operaçäo foi realizada com hipotermia sistêmica a 32 ºC com pinçamento intermitente da aorta e uso de circulaçäo extracorpórea (CEC). No segundo grupo, denominado de pré-condicionamento (17), foram acrescidos dois pinçamentos de 3 minutos da aorta com intervalo de 2 minutos de reperfusäo entre eles, previamente ao pinçamento intermitente da forma convencional. CK-MB, troponina I, adenosina e lactato foram obtidos do seio ocoronário no início da circulaçäo extracorpórea (1), ao final da segunda anastomose (2) e ao final da CEC (3). Resultados: Os níveis de CK-MB e troponina I apresentaram uma leve tendência a aumentar ao final da CEC no grupo controle, enquanto os de adenosina e lactato näo apresentaram diferença. (Ver tabela). Conclusäo: Concluímos que o pré-condicionamento isquêmico näo promoveu melhora significante na proteçäo miocárdica

Induction of apoptosis in human leukemia cells by 3-deazaadenosine is mediated by caspase-3-like activity

3-Deazaadenosine (DZA), one of the potent inhibitors of S-adenosylhomocysteine hydrolase, is known to possess several biological properties including an induction of apoptosis. To evaluate a possibility that DZA may be utilized for the treatment of human leukemia, we studied molecular events of cell death induced by DZA in human leukemia HL-60 and U-937 cells. DZA induced a specific cleavage of poly ADP-ribose polymerase (PARP) and an activation of the cysteine protease caspase-3/CPP32 which is known to cleave PARP. DZA-mediated nuclear DNA-fragmentation was completely blocked in the presence of a universal inhibitor of caspases (z-VAD-fmk) or the specific inhibitor of caspase-3 (z-DEVD-fmk) unlike of cycloheximide (CHX). DNA fragmentation was preceded by the lowering of c-myc mRNA in the DZA treated cells. In addition, DZA-induced apoptosis was blocked by pretreatment with adenosine transporter inhibitors such as nitrobenzylthioinosine (NBTI) and dipyridamole (DPD). Taken together, these results demonstrate that DZA-induced apoptosis initiated through an active transport of DZA into human leukemia cells, is dependent on the caspase-3-like activity without de novo synthesis of proteins and possibly involves c-myc down-regulation.

El corazón como organo endocrino / Heart as an endocrine organ

La adenosina es un metabolito del nucléotido adenina. Su mecanísmo de acción está relacionado a la interacción de dos tipos de receptores. Su principal efecto biológico es la vasodilatación, el cual es consecuencia de la interacción productiva de la adenosina con el receptor A. La adenosina es producida por las células cardíacas durante cualquier situación en la cual el suministro de oxígeno es inadecuado. Sus vías de formación son dos: desfosforilación del 5' - AMP y la hidrólisis del S-adenosil-homocisteína. Las acciones de la ademosina están dirigidas a mantener el equilibrio entre el suministro y la demanda de oxígeno. En situaciones de isquemia, la adenosina puede aumentar el flujo coronario en forma directa (vasodilatación) ó en forma indirecta, inhibiéndo el crecimiento endotelial y previniéndo la obstrucción mecánica de los vasos por neutrófilos y plaquetas

Does adenosine functions as a retaliatory metabolite in the heart?

Adenosine formation is augmented when the O2 supply is inadequate. Cardiac actions of adenosine can increase O2 supply [vasodilation] and decrease O2 consumption. We suggest that adenosine serves as a negative-feedback signal to correct an imbalance betweenO2 supply and consumption, thus acting as a cardioprotective metabolite

Effect of adenosine on melatonin and morepinephrine release in rat pineal explants

Con el objeto de estudiar el efecto de la adenosina sobre la producción de melatonina, se incubaron durante 6 h explantos de pineales de rata con adenosina o 2-cloroadenosina 10**-4 M en presencia y ausencia de noradrenalina (NE) (5 x 10**-5 M). El contenido de melatonina en las glándulas pineales y en los medios se determinó por RIA. Tanto adenosina como 2-cloroadenosina estimularon la producción de melatonina entre 3 y 4 veces e incrementaron aquella inducida por NE en un 30-40%. El agregado de adenosina deaminasa previo a NE redujo el incremento en la liberación de melatonina inducido por NE en un 40-46%. El tratamiento con 2-cloroadenosina contrarrestó dicho efecto de la enzima. La adenosina y su agonista Al, ciclohexiladenosina (CHA), disminuyeron en un 20-22% la liberación del neurotransmisor-3H inducida por estímulo despolarizante de K+ en pineales de rata preincubadas con 3H-NE. Estos resultados sugieren que la adenosina modula mecanismos pineales pre- y post-sinápticos

Efecto de la adenosina sobre la P50 y su relación con el 2, 3-difosfoglicerato / The efect of adenosin on the P50 and its relationship with the 2, 3 diphosphoglyceric acid

En 17 perros anestesiados mantenidos en condiciones estables de ventilación, temperatura y equilibrio ácido base, estudiamos los efectos de dosis crecientes de adenosina administrada por infusión continua, sobre la posición de la curva de disociación de la hemoglobina (CDH) y su relación con los niveles intraeritrocíticos de 2,3 difosfo glicerato (2,3 DPG). en todos los perros la CDH (en sangre arterial y venosa) se desplazó a la izquierda en forma significativa, excepto a la dosis de 120 ug/kg/min, en que la CDH se desplazó a la derecha, y a partir de 240 ug/kg/minla CDH se estabilizó en un nivel inferior al control. Estos cambios fueron paralelos con los experimentos, la frecuencia cardiaca y la presión arterial disminuyeron significativamente. Concluimos que la adenosina modifica la CDH desplazándola en general hacia la izquierda, y que ésto parece estar en relación con un cambio en los niveles intraeritrocíticos de 2,3-DPG