From gestational chronodisruption to noncommunicable diseases: Pathophysiological mechanisms of programming of adult diseases, and the potential therapeutic role of melatonin.

During gestation, the developing fetus relies on precise maternal circadian signals for optimal growth and preparation for extrauterine life. These signals regulate the daily delivery of oxygen, nutrients, hormones, and other biophysical factors while synchronizing fetal rhythms with the external photoperiod. However, modern lifestyle factors such as light pollution and shift work can induce gestational chronodisruption, leading to the desynchronization of maternal and fetal circadian rhythms. Such disruptions have been associated with adverse effects on cardiovascular, neurodevelopmental, metabolic, and endocrine functions in the fetus, increasing the susceptibility to noncommunicable diseases (NCDs) in adult life. This aligns with the Developmental Origins of Health and Disease theory, suggesting that early-life exposures can significantly influence health outcomes later in life. The consequences of gestational chronodisruption also extend into adulthood. Environmental factors like diet and stress can exacerbate the adverse effects of these disruptions, underscoring the importance of maintaining a healthy circadian rhythm across the lifespan to prevent NCDs and mitigate the impact of gestational chronodisruption on aging. Research efforts are currently aimed at identifying potential interventions to prevent or mitigate the effects of gestational chronodisruption. Melatonin supplementation during pregnancy emerges as a promising intervention, although further investigation is required to fully understand the precise mechanisms involved and to develop effective strategies for promoting health and preventing NCDs in individuals affected by gestational chronodisruption.

Maternal melatonin treatment rescues endocrine, inflammatory, and transcriptional deregulation in the adult rat female offspring from gestational chronodisruption.

Introduction: Gestational chronodisruption impact maternal circadian rhythms, inhibiting the nocturnal increase of melatonin, a critical hormone that contributes to maternal changes adaptation, entrains circadian rhythms, and prepares the fetus for birth and successful health in adulthood. In rats, we know that gestational chronodisruption by maternal chronic photoperiod shifting (CPS) impaired maternal melatonin levels and resulted in long-term metabolic and cardiovascular effects in adult male offspring. Here, we investigated the consequences of CPS on mother and adult female offspring and explored the effects of melatonin maternal supplementation. Also, we tested whether maternal melatonin administration during gestational chronodisruption rescues maternal circadian rhythms, pregnancy outcomes, and transcriptional functions in adult female offspring. Methods: Female rats raised and maintained in photoperiod 12:12 light: dark were mated and separated into three groups: (a) Control photoperiod 12:12 (LD); (b) CPS photoperiod; and (c) CPS+Mel mothers supplemented with melatonin in the drinking water throughout gestation. In the mother, we evaluated maternal circadian rhythms by telemetry and pregnancy outcomes, in the long-term, we study adult female offspring by evaluating endocrine and inflammatory markers and the mRNA expression of functional genes involved in adrenal, cardiac, and renal function. Results: In the mothers, CPS disrupted circadian rhythms of locomotor activity, body temperature, and heart rate and increased gestational length by almost 12-h and birth weight by 12%, all of which were rescued by maternal melatonin administration. In the female offspring, we found blunted day/night differences in circulating levels of melatonin and corticosterone, abnormal patterns of pro-inflammatory cytokines Interleukin-1a (IL1a), Interleukin-6 (IL6), and Interleukin-10 (IL10); and differential expression in 18 out of 24 adrenal, cardiac, and renal mRNAs evaluated. Conclusion: Maternal melatonin contributed to maintaining the maternal circadian rhythms in mothers exposed to CPS, and the re-establishing the expression of 60% of the altered mRNAs to control levels in the female offspring. Although we did not analyze the effects on kidney, adrenal, and heart physiology, our results reinforce the idea that altered maternal circadian rhythms, resulting from exposure to light at night, should be a mechanism involved in the programming of Non-Communicable Diseases.

Effect of CYP3A4, CYP3A5, MDR1 and POR Genetic Polymorphisms in Immunosuppressive Treatment in Chilean Kidney Transplanted Patients.

Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs characterized by a narrow therapeutic range and high pharmacokinetic variability. The effect of polymorphisms in genes related to the metabolism and transport of these drugs, namely CYP3A4, CYP3A5, MDR1 and POR genes, has been evaluated in diverse populations. However, the impact of these polymorphisms on drug disposition is not well established in Latin American populations. Using TaqMan® probes, we determined the allelic frequency of seven variants in CYP3A4, CYP3A5, MDR1 and POR in 139 Chilean renal transplant recipients, of which 89 were treated with CsA and 50 with TAC. We tested associations between variants and trough and/or 2-hour concentrations, normalized by dose (C0/D and C2/D) at specific time points post-transplant. We found that CYP3A5*3/*3 carriers required lower doses of TAC. In TAC treated patients, most CYP3A5*3/*3 carriers presented higher C0/D and a high proportion of patients with C0 levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering CYP3A5 genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.

Anestesia general con perfusión de ketamina en cirugía experimental / General anesthesia with ketamine perfusion in experimental surgery

Se evalúa la acción del clorhidrato de ketamina en cirurgía experimental, utilizando en perfusión endovenosa continua en animales caninos, como anestésico general no barbitúrico de acción rápida y sostenida, con marcada analgesia y anestesia quirúrgica. Estas experiencias han sido obtenidas en diferentes sesiones de cirugía experimental, tanto tóraco-abdominales, como microcirugía urológica, cardiovascular, ginecológica y neurológica. Se analizan sus efectos farmacológicos en los parámetros de: tiempo de inducción, sistemas nervioso central y vegetativo, aparato respiratorio y cardiovascular (AU)

Anestesia general con perfusión de ketamina en cirugía experimental / General anesthesia with ketamine perfusion in experimental surgery

Se evalúa la acción del clorhidrato de ketamina en cirurgía experimental, utilizando en perfusión endovenosa continua en animales caninos, como anestésico general no barbitúrico de acción rápida y sostenida, con marcada analgesia y anestesia quirúrgica. Estas experiencias han sido obtenidas en diferentes sesiones de cirugía experimental, tanto tóraco-abdominales, como microcirugía urológica, cardiovascular, ginecológica y neurológica. Se analizan sus efectos farmacológicos en los parámetros de: tiempo de inducción, sistemas nervioso central y vegetativo, aparato respiratorio y cardiovascular

Investigación y estudios experimentales de la protección miocardica en el IAM / Investigation and experimental studies of the myocardial protection in the AMI

En 1977 se inicaron en el Laboratorio de Bioelectrónica, los estudios y experiencias programadas, conducentes a lograr una mejor protección en el infarto agudo de miocardio. Se pudo obtener un modelo experimental adecuado de IAM, que permitió analizar la evolución y las diferentes complicaciones de los primeros estadíos, en particular: arritmias, insuficiencia cardíaca y shock. Prosiguieron las investigaciones destinadas a lograr un sistema de asistencia circulatoria por contrapulsación. Experimentándose el implante de un corazón heterotópico en aorta abdominal. Dicho diseño permitió obtener un correcto efecto de contrapulsación, desde el punto de vista hemodinámico. Del análisis de los métodos más utilizados en la actualidad, y para lograr trasplantes eficaces, fue indispensable experimentar con diferentes técnicas de protección miocárdica. De la evaluación comparativa, se eligió la cardioplejía con sangre entera potásica hipotérmica. La complementación de estas tres etapas ha permitido la integración de este trabajo. Es nuestra intención que ello pueda facilitar investigaciones futuras en este terreno de tan rápidos cambios en la cardiología. (AU)

Investigación y estudios experimentales de la protección miocardica en el IAM / Investigation and experimental studies of the myocardial protection in the AMI

En 1977 se inicaron en el Laboratorio de Bioelectrónica, los estudios y experiencias programadas, conducentes a lograr una mejor protección en el infarto agudo de miocardio. Se pudo obtener un modelo experimental adecuado de IAM, que permitió analizar la evolución y las diferentes complicaciones de los primeros estadíos, en particular: arritmias, insuficiencia cardíaca y shock. Prosiguieron las investigaciones destinadas a lograr un sistema de asistencia circulatoria por contrapulsación. Experimentándose el implante de un corazón heterotópico en aorta abdominal. Dicho diseño permitió obtener un correcto efecto de contrapulsación, desde el punto de vista hemodinámico. Del análisis de los métodos más utilizados en la actualidad, y para lograr trasplantes eficaces, fue indispensable experimentar con diferentes técnicas de protección miocárdica. De la evaluación comparativa, se eligió la cardioplejía con sangre entera potásica hipotérmica. La complementación de estas tres etapas ha permitido la integración de este trabajo. Es nuestra intención que ello pueda facilitar investigaciones futuras en este terreno de tan rápidos cambios en la cardiología.