Significado biológico y utilidad clínica del lactato en la sepsis / Biological significance and clinical utility of lactate in sepsis

La sepsis es un problema global de salud y la progresión hacia el shock séptico se asocia con un incremento marcado de la morbimortalidad. En este escenario, el aumento del lactato plasmático demostró ser un indicador de gravedad y un predictor de mortalidad, y suele interpretarse casi exclusivamente como marcador de baja perfusión tisular. Sin embargo, últimamente se produjo un cambio de paradigma en la exégesis del metabolismo y propiedades biológicas del lactato. En efecto, la adaptación metabólica al estrés, aun con adecuado aporte de oxígeno, puede justificar la elevación del lactato circulante. Asimismo, otras consecuencias fisiopatológicas de la sepsis, como la disfunción mitocondrial, se asocian con el desarrollo de hiperlactatemia sin que necesariamente se acompañen de baja perfusión tisular. Interpretar el origen y la función del lactato puede resultar de suma utilidad clínica en la sepsis, especialmente cuando sus niveles circulantes fundamentan las medidas de reanimación.

Sepsis is a global health problem; progression to septic shock is associated with a marked increase in morbidity and mortality. In this setting, increased plasma lactate levels demonstrated to be an indicator of severity and a predictor of mortality, and are usually interpreted almost exclusively as a marker of low tissue perfusion. However, a recent paradigm shift has occurred in the exegesis of lactate metabolism and its biological properties. Indeed, metabolic adaptation to stress, even with an adequate oxygen supply, may account for high circulating lactate levels. Likewise, other pathophysiological consequences of sepsis, such as mitochondrial dysfunction, are associated with the development of hyperlactatemia, which is not necessarily accompanied by low tissue perfusion. Interpreting the origin and function of lactate may be of great clinical utility in sepsis, especially when circulating lactate levels are the basis for resuscitative measures.

Plant-based diets and their effects on the metabolism and survival of chronic renal patients undergoing conservative treatment

Diet therapy in conservative treatment of chronic kidney disease involves protein restriction, but there is not enough evidence to recommend a particular type of protein, whether animal or plant based. However, studies suggest that plant-based diets help reduce the consumption of total and animal protein, reduce the need for nephroprotective drugs, improve complications and bring advantages in terms of disease progression and patient survival. The article considers up-to-date data on the effects of this diet and observed that when low in protein, primarily vegetable and in some cases supplemented with ketoanalogues, it can result in positive clinical outcomes, such as: delay in the decrease in the glomerular filtration rate, lower concentrations of urea, reduction of serum creatinine and phosphorus concentrations, lower metabolic acidosis, higher insulin sensitivity and lower systemic inflammation. As a whole, this dietary pattern may be able to postpone the start of dialysis with less progression of renal insufficiency. Additional research is needed to better characterize this dietary pattern.

La dietoterapia en el tratamiento conservador de la enfermedad renal crónica implica la restricción de proteínas, pero aún no hay pruebas suficientes para recomendar un tipo concreto de proteínas, ya sean animales o vegetales. Sin embargo, los estudios sugieren que las dietas basadas en plantas ayudan a reducir la ingesta de proteínas totales y animales, disminuyen la necesidad de fármacos nefroprotectores, mejoran las complicaciones y presentan ventajas con respecto a la progresión de la enfermedad y la supervivencia de los pacientes. En este artículo se consideran datos actualizados sobre los efectos de esta dieta y se observa que, cuando es hipoproteica, principalmente vegetal y en algunos casos se complementa con cetoanálogos, puede dar lugar a resultados clínicos positivos, como una disminución retardada de la tasa de filtración glomerular, concentraciones más bajas de urea, concentraciones reducidas de creatinina y fósforo séricos, menor acidosis metabólica, mayor sensibilidad a la insulina y menor inflamación sistémica. En conjunto, este patrón dietético tiene el potencial de retrasar el inicio de la diálisis con una menor progresión de la insuficiencia renal. Es necesario seguir investigando para caracterizar mejor este patrón dietético.

Critical speed, thresholds for vo2max and boundaries of the severe exercise intensity domain / Velocidad crítica, vo2máx y límites de el dominio de la intensidad del ejercicio severo / Velocidade crítica, vo2max e limites de o domínio de intensidade de exercício severo

ABSTRACT Introduction: The severe exercise intensity domain can be defined as the range of work rates or speeds over which VO2max can be elicited. Objectives: Our purpose was to determine if critical speed (running analog of critical power) identifies the lower boundary of the severe domain and to identify the upper boundary of the domain. Methods: Twenty-five individuals performed five running tests to exhaustion, each lasting > 2.5 min and < 16 min. The two-parameter speed vs time-to-exhaustion relationship generated values for critical speed and the three-parameter speed vs time-to-reach-VO2max relationship generated values for the threshold speed above which VO2max can be elicited. The relationships were solved to calculate the minimum time needed to elicit VO2max. Results: Critical speed (3.00 ± 0.38 m·s−1) and the threshold speed above which VO2max can be elicited (2.99 ± 0.37 m·s−1) were correlated (r = 0.83, p < 0.01) and did not differ (p = 0.70), confirming critical speed as the lower boundary of the severe domain. The minimum time needed to elicit VO2max (103 ± 7 s) and the associated highest speed at which VO2max can be elicited (4.98 ± 0.52 m·s−1) identified the upper boundary of the severe domain for these participants. Conclusion: The critical power concept, which requires no metabolic measurements, can be used to identify the lowest speed at which VO2max can be elicited. With addition of metabolic measurements, mathematical modeling can also identify the highest speed and shortest exercise duration at which VO2max can be elicited. Evidence Level I; Validating cohort study with good reference standards.

RESUMEN Introducción: El dominio de la intensidad del ejercicio severo se puede definir como el rango de ritmos o velocidades de trabajo sobre las que se puede obtener el VO2max. Objetivos: Nuestro propósito fue determinar si la velocidad crítica (funcionamiento analógico de potencia crítica) identifica el límite inferior del dominio severo e identificar el límite superior del dominio. Métodos: Veinticinco personas realizaron cinco pruebas de carrera hasta el agotamiento, cada una con una duración de > 2,5 min y <16 min. La relación de dos parámetros de velocidad frente a tiempo de agotamiento generó valores para la velocidad crítica y la relación de tres parámetros de velocidad frente a tiempo de alcance de VO2max generó valores para la velocidad umbral por encima del cual se puede obtener el VO2max. Las relaciones se resolvieron para calcular el tiempo mínimo necesario para obtener el VO2max. Resultados: La velocidad crítica (3,00 ± 0,38 m·s−1) y la velocidad umbral por encima de la cual se puede obtener el VO2max (2,99 ± 0,37 m·s−1) se correlacionaron (r = 0,83, p < 0,01) y no difirieron (p = 0,70), lo que confirma la velocidad crítica como el límite inferior del dominio severo. El tiempo mínimo necesario para obtener el VO2max (103 ± 7 s) y la velocidad más alta asociada a la que se puede obtener el VO2max (4,98 ± 0,52 m·s−1) identificaron el límite superior del dominio severo para estos participantes. Conclusión: El concepto de potencia crítica, que no requiere mediciones metabólicas, se puede utilizar para identificar la velocidad más baja a la que se puede obtener el VO2max. Con la adición de mediciones metabólicas, el modelado matemático también puede identificar la velocidad más alta y la duración más corta del ejercicio a la que se puede obtener VO2max. Nivel de Evidencia I; Estudio de cohortes con alto estándar de referencia.

RESUMO Introdução: O domínio de intensidade de exercício severo pode ser definido como a faixa de taxas de trabalho ou velocidades sobre as quais o VO2max pode ser obtido. Objetivos: Nosso propósito foi determinar se a velocidade crítica (execução analógica da potência crítica) identifica o limite inferior do domínio severo e identificar o limite superior do domínio. Métodos: Vinte e cinco indivíduos realizaram cinco testes de corrida até a exaustão, cada um com duração > 2,5 min e < 16 min. A relação velocidade de dois parâmetros contra tempo até a exaustão gerou valores para a velocidade crítica e a relação velocidade de três parâmetros contra tempo para alcançar o VO2max valores gerados para a velocidade limite acima da qual o VO2max pode ser obtido. As relações foram resolvidas para calcular o tempo mínimo necessário para eliciar o VO2max. Resultados: A velocidade crítica (3,00 ± 0,38 m·s−1) e a velocidade limite acima da qual o VO2max pode ser eliciado (2,99 ± 0,37 m·s−1) foram correlacionadas (r = 0,83, p < 0,01) e não diferiram (p = 0,70), confirmando a velocidade crítica como o limite inferior do domínio grave. O tempo mínimo necessário para eliciar o VO2max (103 ± 7 s) e a maior velocidade associada na qual o VO2max pode ser eliciado (4,98 ± 0,52 m·s−1) identificou o limite superior do domínio severo para esses participantes. Conclusão: O conceito de potência crítica, que não requer medidas metabólicas, pode ser usado para identificar a velocidade mais baixa em que o VO2max pode ser eliciado. Com a adição de medidas metabólicas, a modelagem matemática também pode identificar a velocidade mais alta e a duração mais curta do exercício em que o VO2max pode ser obtido. Nível de Evidência I; Estudo de coorte com alto padrão de referência.

High-intensity interval training in people with spinal cord injury: a systematic review / Entrenamiento por intervalos de alta intensidad en personas con lesiones medulares: una revisión sistemática / Treinamento intervalado de alta intensidade em pessoas com lesão da medula espinhal: revisão sistemática

ABSTRACT Objective: Analyze the effects of high-intensity interval training (HIIT) on cardiometabolic parameters, and cardiorespiratory fitness to compile the most used HIIT training types in adults with spinal cord injury (SCI). Methods: This is a systematic review of searches performed in the electronic databases PubMed / Medline, Science Direct, and Google Scholar. Studies included I) needed to apply HIIT training II) adults with SCI to analyze III) cardiometabolic aspects and cardiorespiratory fitness. Two independent reviewers selected the articles for inclusion, extracted their data, and assessed their methodological quality. Results: 654 studies were found. Thus, 12 studies, 11 pre- and post-intervention, and one control group (CG) with 106 participants were analyzed. Pre- and post-HIITT intervention results revealed significant improvement in cardiorespiratory fitness and cardiometabolic aspects (VO2peak, LDH, HDL, insulin resistance). In addition, GC results revealed significant improvement in cardiorespiratory fitness observed in the intervention group (HIIT) compared to the moderate-low intensity (GC) group. Seven studies used the arm ergometer as the primary exercise modality. Two studies described functional electrical stimulation (FES) performed with the arm ergometer plus electrical stimulation in the lower limbs. None reported heart rate dynamics during the study period. Conclusion: High-intensity interval training improves physical fitness and cardiometabolic health in adults with SCI. Evidence level II; Systematic Review of level II studies.

RESUMEN Objetivo: Analizar los efectos del entrenamiento interválico de alta intensidad (HIIT) sobre los parámetros cardiometabólicos, fitness cardiorrespiratorio y recopilar los tipos de HIIT más utilizados en el entrenamiento en adultos con lesión medular (LME). Métodos: Se trata de una revisión sistemática, para lo cual se realizaron búsquedas en bases de datos electrónicas PubMed/Medline, Science Direct y Google Scholar. Se incluyeron estudios que I) necesitaban aplicar entrenamiento HIIT en II) adultos con SCI y analizar III) aspectos cardiometabólicos y aptitud cardiorrespiratoria. Dos revisores independientes seleccionaron los artículos para su inclusión, extrajeron sus datos y evaluaron su calidad metodológica. Resultados: De los 654 estudios encontrados, se analizaron 12 estudios, 11 pre y post intervención y 1 grupo control (GC) con un total de 106 participantes. Los resultados previos y posteriores a la intervención HIIT revelaron una mejora significativa en la aptitud cardiorrespiratoria y los aspectos cardiometabólicos (VO2pico, LDH, HDL, resistencia a la insulina). Los resultados de GC revelaron una mejora significativa en la aptitud cardiorrespiratoria observada del grupo de intervención (HIIT) en comparación con el grupo de intensidad moderada-baja (GC). Siete estudios utilizaron el ergómetro de brazo como la modalidad principal de ejercicio. Dos estudios describieron la estimulación eléctrica funcional (EEF) realizada con el ergómetro de brazo más la estimulación eléctrica en los miembros inferiores. Ninguno informó la dinámica de la frecuencia cardíaca durante el período de estudio. Conclusiones: El entrenamiento intervalos de alta intensidad mejora la condición física y la salud cardiometabólica en adultos con LME. Evidencia de nivel II; Revisión sistemática de estudios de nivel II.

RESUMO Objetivo: Analisar os efeitos do treinamento intervalado de alta intensidade (HIIT) nos parâmetros cardiometabólicos, aptidão cardiorrespiratória e compilar os tipos de HIIT mais utilizados no treinamento em adultos com lesão da medula espinhal (LME). Métodos: Trata-se de revisão sistemática, para a qual foram realizadas pesquisas nas bases de dados eletrônicas PubMed / Medline, Science Direct e Google Scholar. Foram incluídos estudos em que I) o treinamento HIIT era aplicado em II) adultos com LME e analisaram III) os aspectos cardiometabólicos e aptidão cardiorrespiratória. Dois revisores independentes selecionaram os artigos para a inclusão, extraindo seus dados e avaliarando a sua qualidade metodológica. Resultados: 654 estudos foram encontrados. Desses, 12 estudos, 11 pré e pós intervenção e 1 grupo controle (GC) com um total de 106 participantes foram analisados. Resultados pré e pós intervenção de HIIT revelaram significante melhora na aptidão cardiorrespiratória e aspectos cardiometabólicos (VO2pico, LDH, HDL, resistência à insulina). Resultados do GC revelaram uma significativa melhoria na aptidão cardiorrespiratória observada no grupo de intervenção (HIIT) em relação ao grupo de intensidade moderada-baixa (GC). Sete estudos usaram o ergômetro de braço como modalidade de exercício primária. Dois estudos descreveram a estimulação elétrica funcional (EEF) realizada com o ergômetro de braço adicionando estimulação elétrica nos membros inferiores. Nenhum relatou a dinâmica da frequência cardíaca durante o período do estudo. Conclusão: O treinamento intervalado de alta intensidade melhora a aptidão física e a saúde cardiometabólica em adultos com LME. Nível de evidência II; Revisão sistemática de Estudos de Nível II.

Evaluation of newborn screening in the state of Mato Grosso from 2005 to 2019 / Avaliação da triagem neonatal no Estado de Mato Grosso no período de 2005 a 2019

ABSTRACT Objective: To evaluate quality indicators of the Neonatal Screening Referral Service of the state of Mato Grosso (NSRS-MT) from 2005 to 2019. Methods: Cross-sectional, retrospective, exploratory, descriptive, and observational study from 2005 to 2019. The following parameters were analyzed: age of newborns at the first collection, time between sample collection and arrival at the laboratory, time between the arrival and release of results and time between requesting the second sample and arrival at the NSRS. The population coverage of the program and the incidence of each clinical situation screened were also analyzed. Results: NSRS-MT coverage was analyzed and recorded as 76%. The incidence was analyzed for congenital hypothyroidism (CH) 1:1867, phenylketonuria (PKU) 1:33,311, sickle cell disease (SCD) 1:2004, cystic fibrosis (CF) 1:12,663, congenital adrenal hyperplasia (CAH) 1:15,843, and biotinidase deficiency (DB) 1:25,349. The median age (days) at the first consultation was: 44 for HC, 22 for PKU, 60 for DF, 52 for FC, 79 for HAC and 79 for DB. The mean time between exam collection and delivery to the NSRS was 8.4 days; between the arrival and release of results, 9 days; and for the return of recalls, 59 days. Conclusions: Regarding the coverage of the target population and collection at the ideal age, the NSRS-MT presents values below the national average. However, regarding the mean age at the time of the first consultation, the state's performance is better than the national.

RESUMO Objetivo: Avaliar indicadores de qualidade do Serviço de Referência em Triagem Neonatal do Estado de Mato Grosso (SRTN/MT) no período de 2005 a 2019. Métodos: Estudo transversal, retrospectivo, exploratório, descritivo e observacional, que utilizou dados do formulário FormSUS nos anos de 2005 a 2019. Foram analisados os seguintes parâmetros: idade dos recém-nascidos na primeira coleta, tempo entre coleta da amostra e chegada ao laboratório, tempo entre a chegada e a liberação dos resultados e tempo entre a solicitação da segunda amostra até a chegada ao SRTN. Foram analisadas, também, a cobertura populacional do programa e a incidência de cada situação clínica triada. Resultados: Cobertura do SRTN-MT: 76%. Incidências: hipotireoidismo congênito (HC) 1:1.867, fenilcetonúria (PKU) 1:33.311, doença falciforme (DF) 1:2.004, fibrose cística (FC) 1:12.663, hiperplasia adrenal congênita (HAC) 1:15.843 e deficiência de biotinidase (DB) 1:25.349. A mediana da idade (dias) na primeira consulta foi: 44 para HC, 22 para PKU, 60 para DF, 52 para FC, 79 para HAC e 79 para DB. A média entre a coleta do exame e a entrega no SRTN foi de 8,4 dias; entre a chegada e liberação dos resultados, de 9 dias; e para o retorno de reconvocados, de 59 dias. Conclusões: Com relação à cobertura da população alvo e a coleta na idade ideal, o SRTN apresenta valores abaixo da média nacional. Contudo, quanto à idade média no momento da primeira consulta, o desempenho de MT é melhor que a média nacional.

Analysis of the effectiveness coefficient in greco-roman fighting athletes at different levels of competition / Análisis del coeficiente de eficacia en atletas de lucha griego-romana en distintos niveles de competición / Análise do coeficiente de efetividade em atletas de luta greco-romana em diferentes níveis de competição

ABSTRACT Introduction: Wrestling is an ancient combat sport, individual and of complex performance, which integrates high technical and tactical complexity, associated with a bioenergetic interaction and a high coordinative pattern. In Brazil, the number of competitors at different levels has increased significantly in the last years, evidencing the need to search for answers that can help coaches in the different situations of the competitive calendar. The prescription of the means and methods of training in Greco-Roman wrestling aims at the development of the technical effectiveness. However, there is no evidence of indicators of technical effectiveness, in Brazilian elite athletes of Greco-Roman wrestling, in national and international competitions. Objectives: The objective of the study was to verify and to compare the technical effectiveness of the wrestlers of Greco-Roman fight of the Brazilian selection, in two competitions: one in the national level and the other international. Methods: Seven athletes of the Brazilian wrestling team participated of the investigation (age: 25±5 years; stature: 175±12 cm; corporal mass: 80± 21kg). Analysis of the effective, not effective and total technique were accomplished. After identifying the normality of the data (SHAPIRO WILKS), the Student's t test was used to compare the variables, according to the moment evaluated, considering the significance level of 5%. Results: The results showed a significant decrease (p = 0.03) in the standing effective technique and in the total effective technique (p = 0.01), comparing the national competition with the international competition. Conclusion: Technical effectiveness of Brazilian wrestlers was found to be below the indices presented in studies with competitors from countries considered to have high world performance. In international competition, it presents a negative impact compared to national events. Level of Evidence IV; Therapeutic Studies - Investigation of Treatment Results.

RESUMEN Introducción: El Wrestling es una modalidad de combate milenaria, individual y de rendimiento complejo, que integra elevada complejidad técnico-táctica, asociada a una interacción bioenergética y un alto patrón coordinativo. En Brasil, el número de competidores en diferentes niveles aumentó significativamente en los últimos años, evidenciando la necesidad en la búsqueda de respuestas que auxilien a los entrenadores en las diferentes situaciones del calendario competitivo. La prescripción de los medios y métodos de entrenamiento en la lucha greco-romana tiene como objetivo el desarrollo de la efectividad técnica. Entre tanto, no hay evidencias de indicadores de efectividad técnica, en atletas de alto rendimiento brasileño en la lucha greco-romana, en competencias nacionales e internacionales. Objetivos: El objetivo de este estudio fue verificar y comparar la efectividad técnica de los atletas de lucha greco-romana de la selección brasileña, en dos competencias: una a nivel nacional y otra internacional. Métodos: Participaron de la investigación siete atletas de la selección brasileña de lucha greco-romana (edad: 25±5 años; estatura: 175±12 cm; masa corporal: 80± 21kg). Fueron realizados análisis de la técnica efectiva, no efectiva y total. Después de identificar la normalidad de los datos (SHAPIRO WILKS), fue utilizado el test de t de Student para la comparación de las variables, según el momento evaluado, considerando el nivel de significación de 5%. Resultados: Los resultados mostraron una disminución significativa (p = 0,03) en la técnica efectiva en pie y en la técnica efectiva total (p = 0,01), comparándose la competencia nacional con la internacional. Conclusión: Se concluyó que la eficacia técnica de los luchadores brasileños está por debajo de los índices presentados en estudios con competidores de países considerados de alto rendimiento mundial. En la competición internacional, presenta un impacto negativo en comparación con los eventos nacionales. Nivel de Evidencia IV; Estudios Terapéuticos - Investigación de Los Resultados Del Tratamiento.

RESUMO Introdução: O Wrestling é uma modalidade de combate milenar, individual e de rendimento complexo, que integra elevada complexidade técnico-táctica, associada a uma interação bioenergética e um alto padrão coordenativo. No Brasil, o número de competidores em diferentes níveis aumentou significativamente nos últimos anos, evidenciando a necessidade da busca de respostas que auxiliem os treinadores nas diferentes situações do calendário competitivo. A prescrição dos meios e métodos de treinamento na luta greco-romana visa o desenvolvimento da efetividade técnica. Entretanto, não há evidências de indicadores de efetividade técnica, em atletas de elite brasileira de luta greco-romana, em competições nacionais e internacionais. Objetivo: o objetivo do estudo foi verificar e comparar a efetividade técnica dos lutadores de luta greco-romana da seleção brasileira, em duas competições: uma no nível nacional e a outra internacional. Métodos: Participaram da investigação sete atletas da seleção brasileira de luta greco-romana (idade: 25±5 anos; estatura: 175±12 cm; massa corporal: 80± 21kg). Foram realizadas análises da técnica efetiva, não efetiva e total. Após identificar a normalidade dos dados (SHAPIRO WILKS), foi utilizado o teste t de Student para a comparação das variáveis, segundo o momento avaliado, considerando nível de significância de 5%. Resultados: Os resultados mostraram uma diminuição significativa (p = 0,03) na técnica efetiva em pé e na técnica efetiva total (p = 0,01), comparando-se a competição nacional com a internacional. Conclusão: Concluiu-se que a efetividade técnica dos lutadores brasileiros está abaixo dos índices apresentados em estudos com competidores de países considerados de alto desempenho mundial. Em competição internacional, apresenta um impacto negativo comparativamente a eventos nacionais. Nível de Evidência IV; Estudos Terapêuticos - Investigação dos Resultados do Tratamento.

Design and development of 6-hydrazinonicotinyl-fatty acid-mimetic 99mTc-complex as a potential myocardial imaging agent

Abstract The goal of this work is to identify new fatty acid-mimetic 99mTc-complexes to be used as myocardial imaging agents that allow studying heart abnormalities in high-risk patients. In this sense, we designed a fatty acid-mimetic substructure including an amide moiety that, among other properties, could improve myocardial residence time. A diamide with a chain length of 15 atoms and porting a 6-hydrazinonicotinyl (HYNIC) chelator, and an analog with a short carbon-chain, were prepared with convergent organic synthetic procedures and radiolabeled with 99mTc using tricine as the sole coligand. The in vivo proofs of concept were performed using healthy mice. The new 99mTc-complexes were obtained with adequate radiochemical purity. The lipophilicities were in agreement with the length of the chains. While both 99mTc-complexes showed uptake in the myocardial muscle, the designed radiopharmaceutical with the longest chain length had preferential target-uptake and target-retention compared to other complexes described in the bibliography. Further studies, involving imaging assays, synthetic modifications, and assay of new coligands for 99mTc-HYNIC complexes, are currently ongoing.

Embryo development is impaired by sperm mitochondrial-derived ROS

BACKGROUND: Basal energetic metabolism in sperm, particularly oxidative phosphorylation, is known to condition not only their oocyte fertilising ability, but also the subsequent embryo development. While the molecular pathways underlying these events still need to be elucidated, reactive oxygen species (ROS) could have a relevant role. We, therefore, aimed to describe the mechanisms through which mitochondrial activity can influence the first stages of embryo development. RESULTS: We first show that embryo development is tightly influenced by both intracellular ROS and mitochondrial activity. In addition, we depict that the inhibition of mitochondrial activity dramatically decreases intracellular ROS levels. Finally, we also demonstrate that the inhibition of mitochondrial respiration positively influences sperm DNA integrity, most likely because of the depletion of intracellular ROS formation. CONCLUSION: Collectively, the data presented in this work reveals that impairment of early embryo development may result from the accumulation of sperm DNA damage caused by mitochondrial-derived ROS.

Research progress on mitochondria regulating anti-tumor immunity / 浙江大学学报·医学版

Tumor cells adaptively reforge their metabolism to meet the demands of energy and biosynthesis. Mitochondria, pivotal organelles in the metabolic reprogramming of tumor cells, contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells. Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation, proliferation, and differentiation of immune cells. The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics, thereby facilitating the establishment of a tumor immunosuppressive microenvironment. Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals, including cGAS-STING, TLR9, and NLRP3. Moreover, mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy. Additionally, mtROS, a crucial factor in tumorigenesis, drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment. This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles. We expect to explore the core role of mitochondria in the dynamic interplay between the tumor and the host, in order to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.

Preliminary study on the mechanism of halofuginone inhibiting the activity of HepG2 cells / 药学学报

This study aimed to investigate halofuginone's inhibitory effect and mechanism on the activity of hepatocellular carcinoma cells. HepG2 cells were used to detect the effects of halofuginone. After treatment, cell activity, cell migration, cell cycle, and cell apoptosis were detected by CCK-8, transwell, and flow cytometry, respectively. The expression levels of growth and metabolism-related factors such as citrate synthase (CS), ketoglutarate dehydrogenase (OGDH), and isocitrate deoxygenase (IDH) were detected by real-time quantitative PCR and Western blot. Compared with the control group, the activity of HepG2 cells was significantly inhibited by halofuginone (P < 0.01), the migration rate of HepG2 cells was decreased (P < 0.01), the apoptosis of HepG2 cells was induced (P < 0.01), and the cell cycle was arrested in S phase (P < 0.01). The expression levels of tricarboxylic acid key enzymes CS, IDH3, and OGDH were up-regulated, the expression level of isocitrate dehydrogenase isoenzymes IDH1 and IDH2 were down-regulation. In conclusion, halofuginone can inhibit the proliferation and migration of HepG2 cells and promote apoptosis in a dose-dependent manner, which may be due to the promotion of the aerobic metabolism of cells.

The characteristics of bone disseminated cells of 4T1 / 药学学报

Based on bone metastasis potential of mouse breast cancer 4T1 cells, the bone disseminated breast tumor cells 4T1 (B-4T1) were acquired through the screening of 6-mercaptopurine. The characteristics of B-4T1 were studied by morphological observation, proliferation assay, expression of epithelial and mesenchymal cell markers detection, transcriptome sequencing, and tumor formation experiments. The results showed that B-4T1 was round and spindle-shaped than primary 4T1 cells, and its proliferation rate was reduced, as well as epithelial cell adhesion molecule (EpCAM) and E-cadherin expression. The transcript level of N-cadherin was increased in the B-4T1, but not vimentin, indicating that B-4T1 had partial epithelial mesenchymal transition. Besides, B-4T1 had higher fatty acid metabolism and better tumor formation capacity. This study lays the experimental foundation for the basic study of metastasis in breast cancer. All animal experiments in this paper were conducted in accordance with the standards of the Animal Ethics Committee of China Pharmaceutical University.

The role of glucose metabolism reprogramming and its targeted therapeutic agents in inflammation-related diseases / 药学学报

Cells undergo glucose metabolism reprogramming under the influence of the inflammatory microenvironment, changing their primary mode of energy supply from oxidative phosphorylation to aerobic glycolysis. This process is involved in all stages of inflammation-related diseases development. Glucose metabolism reprogramming not only changes the metabolic pattern of individual cells, but also disrupts the metabolic homeostasis of the body microenvironment, which further promotes aerobic glycolysis and provides favourable conditions for the malignant progression of inflammation-related diseases. The metabolic enzymes, transporter proteins, and metabolites of aerobic glycolysis are all key signalling molecules, and drugs can inhibit aerobic glycolysis by targeting these specific key molecules to exert therapeutic effects. This paper reviews the impact of glucose metabolism reprogramming on the development of inflammation-related diseases such as inflammation-related tumours, rheumatoid arthritis and Alzheimer's disease, and the therapeutic effects of drugs targeting glucose metabolism reprogramming on these diseases.

Effect of Precocious Puberty on Glucose and Lipid Metabolism in Female Rats / 中山大学学报(医学科学版)

ObjectiveTo explore the effect of precocious puberty on glucose metabolism and lipid metabolism in female rats. MethodsSixty two-day-old female rats were randomly divided into 2 groups. When aged 5 days， the precocious puberty group and normal group were given a single subcutaneous injection of danazol and solvent soybean oil respectively. The vaginal opening of rats was monitored from their 21 days of age. After 12 hours of fasting， all successful modeling rats were randomly executed within 3 days after vaginal opening， when aged 7 and 12 weeks. Then we measured the rats’ body weight and length， determined the concentrations of glucose， insulin， blood lipids， estradiol， leptin and adiponectin with enzyme-linked immunosorbent assay and observed the pathological changes of perirenal fat， uterus and ovary. ResultsFor body weight and length， rats in the precocious puberty group were smaller than those in the normal group within 3 days after vaginal opening， but which did not affect their subsequent growth and development， and there was no significant difference between the two groups at 7 and 12 weeks of age. Within 3 days after vaginal opening， insulin levels had significant difference between the two groups （P = 0.001）， the precocious group showed hyperinsulinemia and increased number of perirenal adipocytes. At three execution times， no significant difference was noted in estradiol， leptin and adiponectin levels between the two groups. The same was true in the ratios of ovary or uterus to body weight between the two groups. ConclusionsPrecocious puberty makes earlier onset of pubertal development and allows body maladaptation to the sudden changes of the internal environment. However， the changes due to precocious puberty are temporary and reversible， and they may become normal in adulthood.

Blumea balsamifera （L.） DC Oil Alleviates LPS-Induced Inflammatory Response in Macrophages by Affecting Arachidonic Acid Metabolism Via NF-κB Nonclassical Pathway / 中山大学学报(医学科学版)

ObjectiveTo study the anti-inflammatory effects of Blumea balsamifera （L.） DC oil （BBO） based on nuclear factor kappa-B （NF-κB） nonclassical and arachidonic acid （AA） pathway. MethodsEffects of BBO on the production of slow reacting substance of anaphylaxis （SRS-A） were detected by the ileal smooth muscle method. The contents of prostaglandin E2 （PGE2） and leukotriene B4 （LTB4） in lipopolysaccharides （LPS） -induced macrophages were detected by ELISA kit. The expression of COX-2， 5-LOX， FLAP and RelB were detected by qRT-PCR. Western blot was performed to detect the effects of BBO on the level of NF-κB nonclassical pathway proteins TNF receptor associated factor 3 （TRAF3）， TNF receptor associated factor 2 （TRAF2）， NF-κB-inducing kinase （NIK）， p100 and RelB. ResultsThe contractile tension of guinea pig ileum was reduced （P<0.001）， and the SRS-A production inhibition rate reached 65.34% at 1mg·mL-1 BBO concentration. Compared with LPS group， BBO reduced the concentrations of PGE2 （P<0.05） and LTB4 （P<0.05）， and decreased the expressions of COX-2 （P<0.05）， 5-LOX （P<0.05） and FLAP （P<0.05） in AA pathway at concentrations of 40-80 μg·mL-1. Moreover， 40-80 μg·mL-1 BBO decreased the concentrations of TRAF3 （P<0.05）， TRAF2 （P<0.05）， and NIK （P<0.05）， and further inhibited the phosphorylation of p100 （P<0.05）， as well as the level of the transcription factor RelB in genes （P<0.05） and proteins （P<0.05） in nonclassical NF-κB pathway， whereas BBO did not cause such changes. ConclusionBBO may potentially exert its anti-inflammatory effects by suppressing the regulatory proteins TRAF3 and TRAF2 and the transcription factor RelB in NF-κB nonclassical pathway. The inhibitory action extending to the induction kinase function of NIK， further hindering the phosphorylation of p100 and its binding with the transcription factor RelB. Consequently， downstream elements in the AA pathway， including the pivotal rate-limiting enzymes COX-2， 5-LOX and FLAP， were altered. This modulation influences the levels of inflammatory mediators such as PGE2 and LTB4.

Research progress on metabolic function in patients with polycystic ovary syndrome / 公共卫生与预防医学

The incidence of infertility disorders is increasing year by year, affecting about 12-15% of women of reproductive age worldwide. Polycystic ovary syndrome (PCOS) is one of the common causes of infertility. In recent years, the incidence rate of PCOS has increased year by year, but the improvement of endocrine and metabolic dysfunction and pregnancy outcomes in patients with PCOS are not satisfactory. There is a consensus both domestically and internationally that improving metabolic function and endocrine abnormalities in PCOS patients can increase their pregnancy rate. Therefore, it is important to explore the improvement of metabolic function in patients with PCOS. This article reviews the progress of basic research on improving metabolic function in patients with PCOS.

Clinical value of genetic polymorphism analysis of hypertension drugs for individualized treatment of hypertension patients in the southern Anhui region / 中国临床药理学与治疗学

AIM: To analyze the distribution frequency of gene polymorphisms of β receptor blockers, angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, calcium antagonists, and diuretics in hypertensive patients from southern Anhui province, and provide a theoretical basis for gene detection of hypertension drugs and personalized medication. METHODS: Drug gene testing information from 839 hospitalized patients with hypertension at Yijishan Hospital of Wannan Medical College from July 2021 to April 2023 were collected, and the distribution frequency of each gene locus were analyzed. RESULTS: The genotype frequencies of ACE (I/D) I/I, I/D, and D/D were 42.1%, 46.0%, and 11.9%, respectively. the genotype frequencies of ADRB1 (1165G>C) G/G, G/C, and C/C were 8.3%, 40.0%, and 51.6%, respectively. The genotype frequencies of AGTR1 (1166A>C) A/A, A/C, and C/C were 90.2%, 9.8%, and 0.0%. The genotype frequencies of CYP2C9*3 (1075A>C) *1/*1, *1/*3, and *3/*3 were 91.3%, 8.7%, and 0.0%, respectively; the genotype frequencies of CYP2D6* 10 (100C > T) *1/*1, *1/*10, and *10/*10 were 25.0%, 36.6%, and 38.4%, respectively. The genotype frequencies of CYP3A5*3 (6986A>G) *1/*1, *1/*3, and *3/*3 were 7.0%, 39.0%, and 54.0%, respectively. The frequencies of NPPA (2238T>C) T/T, T / C, and C / C genotypes were 97.9%, 2.1%, and 0.0%, respectively. In addition, there was a significant difference in the genotype distribution frequency of multiple drug related gene loci in southern Anhui compared to other regions in China (P< 0.05). CONCLUSION: The genotype distribution frequency of hypertensive drug related gene loci had certain bias in southern Anhui, and were significant different from other regions in China, indicating that conducting genetic polymorphism testing of hypertensive drugs had certain guiding significance for the individualized application of hypertensive drugs in southern Anhui.

Role of sirtuin 5 in cardiovascular diseases / 中国药理学通报

Cardiovascular diseases ( CVDs ) are the leading cause of death worldwide and pose a serious threat to human health. Silent information regulator 5 ( SIRT5 ) , which is widely distributed in cardiac myocytes, vascular smooth muscle cells and endothelial cells,as a novel deacylation-modifying enzyme,plays an important role in CVDs through deacetylation, desuccinylation and demalonylation. This review summarizes the pathophysiolog-ical mechanism of SIRT5 from the aspects of energy metabolism, regulation of inflammatory response and oxidative stress, apart from the role of SIRT5 in CVDs such as myocardial infarction, myocardial hypertrophy, arrhythmia, atherosclerosis and heart failure. This review also figures out the current research progress of SIRT5 -related inhibitors and agonists, so as to provide strategies for targeting SIRT5 to prevent and treat CVDs.

Expression, purification, and functional verification of recombinant human glycoprotein hormone beta 5/alpha 2 fusion protein in CHO-S cells / 中国药理学通报

Aim To express and purify recombinant hCGH-CTP fusion protein in high-density suspension culture of Chinese hamster ovary cells (CHO-S), and to verify the lipid accumulation effect of rhCGH-CTP on 3T3-L1 mature adipocytes. Methods The recombinant protein expression vector (pcDNA3. 1-rhCGH-CTP) was constructed, achieved by fusing the human glycoprotein hormone beta 5/alpha 2 cDNA with CTP Linker. The expression plasmid was transiently transfected into the suspended CHO-S to express rhCGH-CTP protein and then purified, and the protein biological activity was verified. Intervention with 3T3-L1 mature adipocyte cells for 24 h was performed to detect the changes of intracellular triglyceride (TG) level. Results Western blot results showed that rhCGH-CTP protein was successfully expressed in CHO-S cells, and the yield was up to 715. 4 mg • L~ . The secreted protein was purified by AKTA pure system with higher purity that was up to 90% as identified by SDS-PAGE. In addition, the intracellular cAMP content of mature adipocytes with high expression of TSHR gene significantly increased after intervention with different concentrations of rhCGH-CTP protein by ELISA kit, indicating that rhCGH-CTP protein had biological activity. Oil red 0 staining showed that compared with the control group, the lipid content of mature adipocytes in the intervention groups with different concentrations of rhCGH-CTP protein significantly decreased (P < 0. 05) . Conclusions The rhCGH-CTP protein has been successfully expressed and purified with biological activity, and effectively reduce TG. This research provides an important theoretical basis for further revealing the physiological role of CGH protein and its potential application in clinical practice.

Research progress on bone metabolism and molecular mechanisms in accelerated aging SAMP6 mice / 中国药理学通报

Senile osteoporosis (SOP) is a systemic bone disease characterized by increased susceptibility to fractures. The pathogenesis of SOP is complex and not well understood. Currently, the rapid aging model mouse, senescence accelerated mouse prone 6 (SAMP6), is an ideal model for studying the mechanisms of SOP development and exploring its prevention and treatment. This model exhibits characteristics including increased bone fragility, degradation of bone microstructure, loss of bone matrix, and abnormal metabolism and dysfunction of bone cells, faithfully replicating the process of SOP occurrence and progression at both macroscopic and microscopic levels.

Research progress in ferroptosis pathways and ubiquitination modification of ferroptosis-related molecules / 中国药理学通报

Ferroptosis is an iron-dependent cell death caused by phospholipid peroxidation damage of polyunsaturated fatty acids on cell membranes and involves several pathways, including the iron homeostasis regulatory pathway, the cystine glutamate reverse transporter (system Xc) pathway and the voltage-dependent anion channel (VDAC) pathway. Ferroptosis is involved in the development of several diseases (e. g. myocardial infarction, stroke, cancer and degenerative diseases). The ubiquitination is an important post-translational modification of various protein molecules in the organism. Studies have shown that regulating the ubiquitination of ferroptosis pathway-related molecules can control cellular ferroptosis. Targeting the ubiquitination of ferroptosis pathway-related molecules can effectively promote or inhibit ferroptosis, which is expected to be a new strategy for the treatment of cancer or cardiovascular diseases. In this paper we review the progress of the ferroptosis pathways and the ubiquitination modification of ferroptosis-related molecules.