Research progress of circadian clock genes in hepatocellular carcinoma / 国际外科学杂志

Circadian rhythm is mainly regulated by circadian clock genes, which is the result of biological evolution and plays an important role in maintaining the normal structure and function of organisms. When the circadian rhythm is disturbed or out of balance, it will have adverse health consequences. In addition to studies on diseases of nervous system, endocrine system or cardiovascular system, it has been found that circadian rhythm disorder mediated by circadian clock gene also plays a key regulatory role in the occurrence and development of hepatocellular carcinoma, which is a potential diagnostic marker and therapeutic target. In this paper, the research on the role of circadian clock gene in hepatocellular carcinoma in recent years is reviewed, and the research progresis and existing problems of targeting circadian clock gene in the treatment of hepatocellular carcinoma are discussed.

Research progress of circadian rhythm and circadian rhythm sleep-wake disorders / 中华神经科杂志

Circadian rhythm is driven by the suprachiasmatic nucleus biological clock, and many life activities and physiological functions are regulated by circadian rhythm, such as central nervous system activity, autonomic nervous system activity, endocrine function, metabolism and immune function. At the molecular level, circadian rhythm is regulated by molecular mechanisms generated by clock genes′ oscillations. Endogenous circadian rhythm is one of the main processes controlling sleep. Circadian rhythm disorder is the most common cause of abnormal sleep-wake cycle, and can also lead to a series of diseases and adverse consequences such as other sleep disorders, abnormal cognitive function, hypertension, diabetes and tumors. Recently, the relationship between circadian rhythm and sleeping awakening has become a hot topic for researchers. In this paper, the research progress of circadian rhythm and circadian rhythm sleep-wake disorders was reviewed.

Restricted feeding modulates peripheral clocks and nutrient sensing pathways in rats

ABSTRACT Objective: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes ( Clock, Bmal1 ) and genes involved in lipid metabolism ( Pgc1a, Pparg, Ucp2 ) through nutrient-sensing pathways ( Sirt1, Ampk, Nampt ) in peripheral tissues. Materials and methods: Rats were grouped according to food access: Control group (CG, food ad libitum ), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. Results: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a , Pparg , and Ucp2 but not Ampk and Nampt . Conclusion: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.

El nodo sinusal normal: Lo que ahora sabemos / The normal sinus node: What we know now

RESUMEN El nodo sinusal constituye el marcapasos fisiológico del corazón. Diferentes estados fisiopatológicos conducen a una reducción de su función, lo que es llamado en la clínica, disfunción sinusal. Sin embargo, para la mejor comprensión de su estado de enfermedad se requiere dilucidar cómo opera en condiciones normales. Las nuevas evidencias señalan que el automatismo del nodo sinusal se produce por la interacción del reloj de membrana y el reloj de calcio, lo que le confiere un fuerte carácter que lo protege contra fallas de funcionamiento. Se presentan las evidencias actuales sobre la sincronía celular dentro del nodo sinusal, así como la forma de propagación eléctrica y el acoplamiento fuente-sumidero. Además, se describen recientes hallazgos anatómicos e histológicos.

ABSTRACT The sinus node is the physiological pacemaker of the heart. Different pathophysiological conditions lead to a reduction of its function, which is clinically called sinus dysfunction. However, for a better understanding of its disease state, it is necessary to elucidate how it works under normal conditions. New evidences indicate that the automatism of the sinus node is produced by the interaction of the membrane clock and the calcium clock, which gives it a strong character that protects it against malfunctions. Current evidences on cell synchrony within the sinus node are presented, as well as the form of electrical propagation and the source-sink coupling. In addition, recent anatomical and histological findings are described.

Role of circadian clock genes in the development and progression of nonalcoholic fatty liver disease / 临床肝胆病杂志

Circadian clock is an inherent biological rhythm of organism which forms in the long process of evolution to adapt to the changes in light and temperature due to day-night alternation. Circadian clock in humans is accurately regulated by various circadian clock genes at the molecular level and are hierarchically regulated by the central clock and the peripheral clock at the anatomical level. Recent studies have found that circadian clock genes can participate in intracellular lipid metabolism by regulating downstream clock-controlled genes, and the disorder of circadian clock genes can result in abnormal lipid metabolism, oxidative stress, insulin resistance, and abnormal secretion of glucocorticoids and inflammatory factors, which are closely associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The disorder of circadian clock genes can also increase the susceptibility to fatty liver disease and thus acts as a bridge that connects circadian clock genes and NAFLD. The pathogenesis of NAFLD remains unclear at present, and therefore, this article summarizes the recent studies on the association between circadian clock genes and NAFLD, so as to provide a theoretical basis for further clarifying the pathogenesis of NAFLD.

DA-JC1 improves circadian rhythm disorder induced by amyloid β-protein 31-35 / 中华神经科杂志

Objective To observe the effect of DA-JC1 on the circadian rhythm disorder in C57BL/6 mice and the abnormal expression of period1 in HT22 cells induced by amyloid β-protein 31-35 (Aβ31-35).Methods (1) The six-eight weeks old C57BL/6 male mice were selected for wheelrunning behavior experiment.Then we analyzed the effect of DA-JC1 on the circadian rhythm disorder induced by Aβ31-35.(2) HT22 mouse hippocampal cells were adopted as the research objects.Cells were divided into vehicle group,Aβ31-35 group,pre-DA-JC1 group and DA-JC1 group (n =4 respectively) by random number table method.Cell viability was assessed by methylthiazolyldiphenyl-tetrazolium bromide cytotoxicity assay.Real-time quantitative PCR was used to detect the expression of clock gene period1,and Western blotting was applied to examine the expression of period1 protein at circadian time (CT) 12.Results (1) Compared with the vehicle group ((23.54 ± 0.07) h),the circadian rhythm of mice in the Aβ31-35 group was disturbed which exhibited significantly longer free running period ((23.80 ± 0.06) h,t=0.265,P=0.010),whereas the disruption was significantly relieved with pre-treatment of DA-JC1 ((23.61 ± 0.06) h,t =0.193,P =0.047).(2) Compared with the vehicle group (100.0％ ± 3.6％),5 μmol/L Aβ31-35 decreased the cell viability significantly (78.7％ ± 3.4％,t =12.393,P =0.005),and DA-JC1 can reduce the toxicity of Aβ31-35 in HT22 cells (89.2％ ± 2.3％,t =9.748,P =0.048).(3) Compared with the vehicle group (period1 gene:1.00 ± 0.09;period1 protein:1.01 ± 0.07),abnormal rhythmic expression of period1 was induced by Aβ31-35 in HT22 cells which significantly decreased at CT12 (period1 gene:0.58 ± 0.04,t =0.419,P =0.001;period1 protein:0.74 ± 0.07,t =0.221,P =0.007) while DA-JC1 pre-treatment can reverse the abnormal expression (period1 gene:0.79 ±0.11,t =0.279,P=0.024;period1 protein:0.99 ±0.05,t=0.226,P=0.009).Conclusion DA-JC1 improves the circadian rhythm disorder induced by Aβ31-35 in C57BL/6 mice and improves the abnormal expression of period1 induced by Aβ31-35 in HT22 cells.

Disturbances of circadian rhythm of blood pressure and local cardiac clock genes in nephrotic rats / 中华肾脏病杂志

Objective To observe the circadian blood pressure (BP) rhythms and the phase of heart circadian gene expression in adriamycin (ADR)-induced nephropathy rats,thus exploring the effect of circadian systems on circadian BP variation in nephrotic rats.Methods Sprague-Dawley (SD) male rats (8 weeks) were housed in a 12∶12 hour light/dark cycle in two weeks,and randomly divided into ADR group and control group.ADR rats were injected 6.5 mg/kg adriamycin via vein to establish nephrotic rats model two weeks later,while control rats were injected the equal volume of saline.Five rats in each group were implanted with the radio-telemetry into abdominal aortic.After seven days,systolic blood pressure (SBP),diastolic blood pressure (DBP),mean arterial pressure (MAP) and heart rate (HR) were recorded every one minute during 72 hours via radio-telemetry.Three rats in each group were sacrificed in six time points (zeitgeber time=02:00,06:00,10:00,14:00,18:00,22:00) to get the blood sample and heart tissue,respectively.The mRNA expressions of core clock gene CLOCK,BMAL1,Per1,Per2,Cry1 and Cry2 in heart issue were evaluated by the real-time quantitative PCR.The plasma levels of renin activity angiotensin Ⅱ and aldosterone were measured by radioimmunoassay.All the data were analyzed by a partial Fourier analysis and stepwise regression.Results (1) There was no significant difference in 24 h average of SBP,DBP and MAP between two groups.In control group,there was higher SBP (3.22 mmHg),DBP (1.16 mmHg) and MAP (3.19 mmHg) in dark period than those in light period,only SBP and MAP showing statistical difference (all P ＜ 0.05).However,SBP,DBP and MAP had no significant difference between dark and light in ADR group (all P ＞ 0.05).(2) Control rats had (8.0+24.0) h rhythm of SBP,and their DBP,MAP and HR appeared 24.0-hour normal circadian pattern (all P ＜ 0.05).In ADR group,the rhythm of SBP completely disappeared.And their DBP and MAP remained 24.0 h circadian rhythm,but the peak time advanced 1.5 h to 3.0 h compared with SD rats.(3) In SD controls,daily rhythms period of the core clock genes (CLOCK,BMAL1,Cry1,Cry2,Per1 and Per2) mRNA expression in the heart were (4.8+ 12.0) h,24.0 h,12.0 h,(12.0+24.0) h,(4.8+12.0) h and 12.0 h (all P ＜ 0.05),respectively.In ADR rats,the rhythm of CLOCK,BMAL1,Cry2,Per1 and Per2 mRNA completely disappeared (all P ＞ 0.05).The circadian rhythm of Cry1 mRNA remained,but the period was changed from 12.0 h to (4.8+6.0) h.(4) The plasma renin and aldosterone concentration presented 12.0 h and 24.0 h daily rhythms in SD rats (all P ＜ 0.05).These diurnal changes however completely disappeared in ADR rats (all P ＞ 0.05).Conclusions ADR nephrotic rats lose the circadian rhythm of BP with the disturbances of cardiac circadian clock system.The disrupted diurnal rhythm of the core clock genes (CLOCK,BMAL1,Cry2,Per1 and Per2) mRNA expression in the heart may regulate the pathological circadian rhythms of heart tissue,which is involved with disturbances of circadian rhythm of BP.

Marcapasos permanente: a propósito del diagnóstico tardío del desplazamiento del electrodo / Permanent pacemaker: report of a late diagnosis of displacement of the electrode

Fundamento: en los últimos años el implante de marcapasos permanente se ha convertido en un procedimiento seguro con bajo índice de complicaciones pero cuando estas se presentan, pueden ocasionar un desenlace fatal en la vida del paciente debido a la disfunción del dispositivo. Objetivo: analizar el diagnóstico tardío del desplazamiento del electrodo de marcapasos permanente en una paciente. Caso clínico: paciente de 68 años de edad, con historia de hipertensión arterial de alrededor de 25 años de evolución, con tratamiento diario de amlodipino e hidroclorotiazida de 10 y 25 mg, respectivamente. Hacía cinco años se le había implantado un marcapasos permanente, por bloqueo auriculoventricular de tercer grado y síncope, con buena evolución y sin complicaciones al alta hospitalaria. A los cuatro meses de operada presentó otro síncope y acudió a consulta de programación de marcapasos, sin problemas con la estimulación del dispositivo. Continuó con mareos y pérdida del conocimiento, por lo que recurrió a las consultas programadas de seguimiento especializado. Finalmente se le diagnostica el desplazamiento del electrodo, se reinterviene y se coloca un nuevo cable. En el seguimiento posterior no presento más síncope ni mareos. Conclusiones: el método clínico constituye el elemento principal para el diagnóstico de complicaciones en el seguimiento de pacientes con marcapasos permanentes, aun así un solo medio diagnóstico no es suficiente para descartar la misma, por lo que se deben utilizar otros medios diagnósticos.

Background: in the last years, the placement of permanent pacemakers has become a safe procedure with low rates of complications; however, when these complications present they can cause a fatal end for patients due to the dysfunction of the device. Objective: to analyze the late diagnosis of displacement of the electrode in the permanent pacemaker of a patient. Clinical case: a sixty-six-year-old female patient with a history of high blood pressure of 25 years of evolution. The patient was under a daily treatment with amlodipine and hydrochlorothiazide, 10 and 25 mg respectively. Five years ago, because of third-degree atrioventricular block and syncope, she underwent the implantation of a permanent pacemaker. The patient had a good progress and no complications when discharged from the hospital. Four months after the operation she presented syncope and went to the pacemaker program consultation; there were no problems with the stimulation of the device. She continued presenting dizziness and loss of consciousness so she went to the specialized programmed follow-up consultations. Finally, the patient is diagnosed with displacement of the electrode. She underwent another procedure to place a new lead. She did not present dizziness or syncope in the follow-up. Conclusions: the clinical method is the main element for the diagnosis of complications in the follow-up of patients with permanent pacemakers; still, only one diagnosis element is not enough to discard the problem so is necessary to use other diagnostic means.

Changes in expression of hepatic circadian clock gene in different types of circadian rhythm and effect of isoflurane anesthesia on expression of hepatic circadian clock gene in mice / 中华麻醉学杂志

Objective To investigate the changes in the expression of hepatic circadian clock gene in different types of circadian rhythm and the effect of isoflurane anesthesia on the expression of hepatic circadian clwk gene in mice.Methods Seventy-two male C57/B6 mice,aged 2 months,weighing 20-25 g,were randomly divided into 3 groups (n =24 each):normal light/dark (LD) cycle group,reversal LD cycle group and anesthesia group.Normal LD cycle group and anesthesia groupwere maintained in a regular 12 h LD cycle with lights on at 8:00 am and off at 8:00 pm for 3 weeks,and in addition anesthesia was then performed with isoflurane in anesthesia group.Reversal LD cycle group was kept in an inverted12 h LD cycle with lights on at 8:00 pm and off at 8:00 am for 3 weeks.The natural time was converted to circadian time (CT) and the initial time was set at CT0.Isoflurane anesthesia group was exposed to 2％ isoflurane for 6 h during the wakening period from CT14 to CT20.The liver and suprachiasmatic nucleus (SCN) were removed from mice at CT2,CT8,CT14 and CT20 for determination of Clock and Cry1 mRNA expression by real-time quantitative PCR.Results Clock and Cry1 mRNA expression in the liver and SCN showed rhythm in the two different types of circadian rhythm.Compared with that in SCN,the peak phase of Clock and Cry1 mRNA expression in livers was delayed in two different types of circadian rhythm.Isoflurane anesthesia caused a peak phase delay of Cry1 and Clock mRNA expression in livers as compared with normal LD cycle group.Conclusion Circadian clock gene in livers shows rhythmic expression in different types of circadian rhythm,and isoflurane anesthesia can cause a large peak phase delay of circadian clock gene expression in livers of mice.

Uso de la dexmedetomidina (DXM) en implantación de resincronizador cardiaco: ¿es realmente seguro? / The use of dexmedetomidine (DXM) for implanting a cardiac resynchronization device: is it really safe?

La dexmedetomidina (DXM) es un agonista selectivo de los receptores alfa 2 preganglionares, que actúa tanto en el sistema nervioso central como en el periférico. Desde su incursión en la práctica médica, ha sido utilizada satisfactoriamente en un amplio espectro de procedimientos anestésicos, que van desde sedación hasta intervenciones bajo anestesia general. Dentro de sus principales ventajas se encuentran la estabilidad hemodinámica y la mínima depresión respiratoria. Este artículo describe una terapia de resincronización cardiaca exitosa a través de la implantación deun marcapasos biventricular en un paciente hemodinámicamenteinestable, bajo sedación con DXM y midazolam a bajas dosis.

Dexmedetomidine (DXM) is a selective 2-adrenoreceptor agonist acting over both the central and peripheral nervous system. Since it became available for medical application, DXM has been satisfactorily used for a broad spectrum of anesthetic procedures, ranging from sedation to interventions under general anesthesia. Its key advantages include its hemodynamic stability and minimal respiratory depression. This articleprovides a description of a successful cardiac resynchronization therapy implanting a biventricular pacemaker in a hemodynamically unstable patient under DXM and low-dose midazolamsedation.

Clinical Study on Treatment of Biliary Colic with Midnight-Noon Ebb-Flow Day-Prescription of Acupoints / 针灸推拿医学（英文版）

Objective: To observe the clinical effect of midnight-noon ebb-flow day-prescription of acupoints on biliary colic. Methods: 60 cases with biliary colic were randomized into two groups, 30 cases in each group. Day-prescription of five transport points was employed in the treatment group, while point selection based on pattern identification was employed in the control group. Results: The pain-killing rates between the two groups had no statistical differences (P>0.05). Conclusion: Day-prescription of acupoints can obtain similar pain-killing effect with point selection based on pattern identification, but with less points and treatments.

Exfoliated epithelial cells: potentials to explore gastrointestinal maturation of preterm infants / Células epiteliais exfoliadas: potencial para investigar a maturação gastrointestinal em crianças pré-termo

Exfoliated epithelial cells represent valuable source of information on the physiopathological state of the mucosa. However, the interpretation of data obtained from exfoliated cells is complicated by the conditions of isolation as well as the health of the subject. Exfoliation is either: a) a natural loss of body cells implying a molecular signal related to the turnover of terminally differentiated cells and to the progressive mobilization of proliferative as well as stem cells or b) the result of manual exfoliation by applying mechanical constraints like scraping. Depending on the methodology of isolation, exfoliated epithelial cells are believed to be either in apoptosis or in anoïkis. Most studies are using microscopic examination to demonstrate the presence of typical cells along with measurements on a limited number of biomarkers. Only few studies using proteomics or transcriptomics are available and they open discussion about tissue references and normalization. The main advantage of measures realized on exfoliated epithelial cells is that they are strictly non-invasive and open the possibility to evaluate maturation of gastric and intestinal tissues in long-term experiments performed on the same animal or in translational research on samples recovered from preterm infants.

Células epiteliais exfoliadas são uma fonte de informação valiosa sobre o estado fisiológico da mucosa. Contudo, a interpretação dos dados obtidos de células exfoliadas é complicado pelas condições de isolamento e da saúde do sujeito. A exfoliação é: a) uma perda natural de células implicando um sinal molecular relacionado ao turnover terminal de células diferenciadas e à progressiva mobilização de células proliferativas e de células tronco ou b) o resultado de aplicação de fatores mecânicos como raspagem. Dependendo do método de islolamento, acredita-se que podem estar em apoptose ou em anoikis. A maior parte dos estudos tem utilizado exame microscópico para demonstrar a presença de células típicas com medições sobre um número limitado de biomarcadores. Apenas uns poucos estudos usando proteômica ou transcriptômica estão disponíveis e discutem sobre referenciais de tecidos e normalização. A principal vantagem de medidas realizadas em células epiteliais exfoliadas é que elas são estritamente não invasivas e abertas à possibilidade de avaliar a maturação de tecidos gástricos e intestinais em experimentos de longo prazo feitos no mesmo animal ou em pesquisas translacionais com amostras obtidas de crianças pré-termo.

Telómeros y telomerasa: breve recuento de una historia iniciada por Hermann Müller y Bárbara McClintock / Telomere and telomerase: brief review of a history initiated by Hermann Müller and Barbara McClintock

¿Cuál es la naturaleza del reloj biológico que determina el envejecimiento de las células? ¿De qué manera se explica la génesis de las enfermedades asociadas con el envejecimiento? Las anteriores son sólo algunas de las preguntas cuya respuesta puede ser hallada en el marco del modus operandi de la dupla telómeros-telomerasa, convertida en objeto de estudio para un sinnúmero de hombres y mujeres de ciencia, desde los pioneros Hermann Müller y Bárbara McClintock hasta los más recientes Jack Szostak, Elizabeth Blackburn y Carol Greider, entre otros.

What is the nature of the biological clock that determines the cells aging? What is the way to explain the genesis of diseases associated in aging? The above are only some of the questions whose answer could be found within the modus operandi frame of the telomere-telomerase pair, which had become in objective of study for a number of science men and women since the pioneers Hermann Müller and Barbara McClintock, until the most recent Jack Szostak, Elizabeth Blackburn and Carol Greider, among others.

Progress in the Studies of Biological Clocks Genes / 生物化学与生物物理进展

Circadian rhythms describe biological phenomena that oscillate with an 24 hour cycle. These rhythms include blood pressure, body temperature, hormone level, the number of immune cells in blood, and the sleep-wake cycle. The aim is to introduce common genes between species that are responsible for determining the circadian behavior, especially some transcription factor s that serve to regulate many circadian rhythm genes. And the common molecular mechanism of biological clocks between fly and human will be in troduced.