Melatonin and cardiovascular disease: from mechanisms of action to potential clinical use (literature review)

Cardiovascular disease remains the most relevant public health problem. Most cardiovascular diseases are associated with an atherosclerosis, the development of which is associated with inflammation and endothelial dysfunction. Melatonin is a neurohormone that is synthesized mainly in the pineal gland and plays a central role in the regulation of sleep and some other body cyclic processes. For a long time, melatonin was perceived as a substance that is effective in the treatment of circadian cycle impairments. At the same time, a large number of studies have accumulated recently that demonstrate a wider range of its biological effects, including anti-inflammatory, antioxidant, antihypertensive and, possibly, hypolipidemic. The review includes current data from experimental and clinical studies demonstrating the cardioprotective effects of melatonin in atherosclerosis, myocardial ischemia, and heart failure.

Circadian patterns of energy metabolism are only partially reconstituted in gnotobiotic mice

SUMMARYMicrobiota composition correlates with host metabolic health in both humans and mice. Here we investigated the extent to which a gnotobiotic microbiota can mimic the influence of a complete microbiota on mouse metabolism using an isolator-housed TSE-PhenoMaster® system. We found that energy expenditure was equivalent between germ-free (GF) and specific-opportunistic-pathogen free line (SPF) mice, and we extend this observation to the OligoMM12 microbiota (12 species across 5 phyla that are naturally abundant in a murine gut microbiota). Moreover, microbiota-released calories were well compensated by food intake in all groups. However, each group of mice have a distinctive circadian metabolic profile. OligoMM12 clustered with GF during the light phase, but with SPF during the dark phase for both RER and metabolome. Therefore, interactions between the host and a reductionist microbiota are non-uniform over the circadian cycle, revealing a promising tool to identify key microbiota species/functions that modify host metabolism.

The endogenous circadian system worsens asthma at night independent of sleep and other daily behavioral or environmental cycles

Asthma often worsens at night. To determine if the endogenous circadian system contributes to the nocturnal worsening of asthma, independent of sleep and other behavioral and environmental day/night cycles, we studied patients with asthma (without steroid use) over 3 wk in an ambulatory setting (with combined circadian, environmental, and behavioral effects) and across the circadian cycle in two complementary laboratory protocols performed in dim light, which separated circadian from environmental and behavioral effects: 1) a 38-h “constant routine,” with continuous wakefulness, constant posture, 2-hourly isocaloric snacks, and 2) a 196-h “forced desynchrony” incorporating seven identical recurring 28-h sleep/wake cycles with all behaviors evenly scheduled across the circadian cycle. Indices of pulmonary function varied across the day in the ambulatory setting, and both laboratory protocols revealed significant circadian rhythms, with lowest function during the biological night, around 4:00 AM, uncovering a nocturnal exacerbation of asthma usually unnoticed or hidden by the presence of sleep. We also discovered a circadian rhythm in symptom-based rescue bronchodilator use (β2-adrenergic agonist inhaler) whereby inhaler use was four times more likely during the circadian night than day. There were additive influences on asthma from the circadian system plus sleep and other behavioral or environmental effects. Individuals with the lowest average pulmonary function tended to have the largest daily circadian variations and the largest behavioral cycle effects on asthma. When sleep was modeled to occur at night, the summed circadian, behavioral/environmental cycle effects almost perfectly matched the ambulatory data. Thus, the circadian system contributes to the common nocturnal worsening of asthma, implying that internal biological time should be considered for optimal therapy.

Abstract MP21: Circadian Cycle Exaggerates Sympathoexcitatory Responses To Activation Of Chemosensitive Renal Sensory Nerves

Renal sensory nerves contribute to hypertension and renal dysfunction in chronic kidney disease. Selective chemokines (e.g., bradykinin or capsaicin) activate renal sensory nerves and produce reflexive efferent sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses. SNA, ABP, and renal function exhibit circadian patterns; yet the impact of circadian cycle on chemosensitive responses is unknown. We hypothesized that SNA and hemodynamic responses would be greater during the active phrase or nighttime versus the inactive phase or daytime. In Inactin anesthetized rats, simultaneous renal and splanchnic SNA and ABP were measured during intrarenal arterial infusion of capsaicin or bradykinin (0.1 μM - 30.0 μM; 50 μl over 15 s) at nighttime (N; 20:00-04:00; n= 12M, 10F) versus daytime (D; 09:00-16:00; n= 8M, 8F). Baseline mean ABP was significantly elevated during nighttime (N: 104±2 mmHg; D: 97±2 mmHg, p=0.04). Intrarenal capsaicin infusion produced concentration-dependent increases in renal and splanchnic SNA. Renal SNA increased more at nighttime versus daytime at 10 μM (N: 723±136 vs D: 409±79 %; p=0.03) and 30 μM (N: 826±181 vs D: 509±80 %; p=0.03). Similarly, splanchnic SNA was greater during nighttime versus daytime at 10 μM (N: 501±117 vs D: 204±53 %, p=0.03) and 30 μM (N: 537±101 vs D: 295±68 %; p=0.03). However, ABP responses were similar between nighttime versus daytime (30uM: 7±1 vs 6±1 mmHg, respectively). Intrarenal infusion of bradykinin produced concentration-dependent increases in renal and splanchnic SNA. Renal SNA increased more at nighttime versus daytime at 10 μM (N: 1773±216 vs D: 1249±112 %; p=0.01) and 30 μM (N: 2605±263 vs D: 1783±163 %; p=0.001). Similarly, splanchnic SNA was exaggerated at nighttime versus daytime at 0.1 μM (N: 163±65 vs D: 0±0 %; p=0.02), 1.0 μM (N: 566±114 vs D: 184±52 %; p=0.005), 10 μM (N: 1110±193 vs D: 583±87 %; p=0.006) and 30 μM (N: 2008±193 vs D: 1044±162 %; p<0.001). ABP response were similar between nighttime versus daytime at 30 μM (10±2 vs 6±1 mmHg, respectively). Circadian cycle exaggerates sympathoexcitatory responses produced by chemosensitive renal sensory nerve activation.

Modification of the Daily Activity Pattern of the Diurnal Triatomine Mepraia spinolai (Hemiptera: Reduviidae) Induced by Trypanosoma cruzi (Trypanosomatida: Trypanosomatidae) Infection

Mepraia spinolai, (Porter) 1934, is a diurnal triatomine endemic to Chile and a wild vector of the protozoan Trypanosoma cruzi, (Chagas) 1909, which causes Chagas disease. Behavioral changes in M. spinolai induced by this parasite have been reported previously, which include detection of a potential host, defecation latency, and some life history traits. In this study we assessed changes in locomotor and daily activity due to infection with T. cruzi. No difference was detected in distance traveled between infected and uninfected individuals. However, the groups differed in their daily activity patterns; infected individuals showed significant reduction of movements during the light phase and concentrated their activity in the dark phase. Uninfected individuals showed no differences in locomotor activity between the phases. The results suggest that T. cruzi induces a displacement in the activity of M. spinolai toward the dark phase of the circadian cycle, which may improve its vector competence.

CGRP induces migraine-like symptoms in mice during both the active and inactive phases

Background Circadian patterns of migraine attacks have been reported by patients but remain understudied. In animal models, circadian phases are generally not taken into consideration. In particular, rodents are nocturnal animals, yet they are most often tested during their inactive phase during the day. This study aims to test the validity of CGRP-induced behavioral changes in mice by comparing responses during the active and inactive phases. Methods Male and female mice of the outbred CD1 strain were administered vehicle (PBS) or CGRP (0.1 mg/kg, i.p.) to induce migraine-like symptoms. Animals were tested for activity (homecage movement and voluntary wheel running), light aversive behavior, and spontaneous pain at different times of the day and night. Results Peripheral administration of CGRP decreased the activity of mice during the first hour after administration, induced light aversive behavior, and spontaneous pain during that same period of time. Both phenotypes were observed no matter what time of the day or night they were assessed. Conclusions A decrease in wheel activity is an additional clinically relevant phenotype observed in this model, which is reminiscent of the reduction in normal physical activity observed in migraine patients. The ability of peripheral CGRP to induce migraine-like symptoms in mice is independent of the phase of the circadian cycle. Therefore, preclinical assessment of migraine-like phenotypes can likely be done during the more convenient inactive phase of mice.

Complexity and Variability Analyses of Motor Activity Distinguish Mood States in Bipolar Disorder

Aims Changes in motor activity are core symptoms of mood episodes in bipolar disorder. The manic state is characterized by increased variance, augmented complexity and irregular circadian rhythmicity when compared to healthy controls. The aim was to characterize differences in motor activity when comparing manic patients to their euthymic selves. Methods Motor activity was collected from 14 bipolar inpatients in mania and remission. 24-h recordings and 2-h time series in the morning and evening were analyzed for mean activity, variability and complexity. Lastly, the recordings were analyzed with the similarity graph algorithm and graph theory concepts such as edges, bridges, connected components and cliques. Results When compared to euthymia, over the duration of approximately one circadian cycle, the manic state presented reduced variability, displayed by decreased standard deviation (p = 0.013) and augmented complexity shown by increased sample entropy (p = 0.025). During mania there were also fewer edges (p = 0.039) and more bridges (p = 0.026). Similar changes in variability and complexity were observed in the 2-h morning and evening sequences, mainly in the estimates of the similarity graph algorithm. A comparison of morning and evening sequences within states revealed no significant change in estimates for mania. Contrarily, the euthymic state showed significant evening differences in variance and complexity, displayed by fewer edges (p = 0.010) and an increased number of connected components (p = 0.009). Conclusion The motor activity of mania is characterized by altered complexity, variability, and circadian rhythms when compared within-subject to euthymia.

Humidity Sensing by Chitosan-Coated Fibre Bragg Gratings (FBG)

In this work, we report novel relative humidity sensors realized by functionalising fibre Bragg gratings with chitosan, a moisture-sensitive biopolymer never used before for this kind of fibre optic sensor. The swelling capacity of chitosan is fundamental to the sensing mechanism. Different samples were fabricated, testing the influence of coating design and deposition procedure on sensor performance. The sensitivity of the sensors was measured in an airtight humidity-controlled chamber using saturated chemical salt solutions. The best result in terms of sensitivity was obtained for a sensor produced on filter paper substrate. Tests for each design were performed in the environment, lasted several days, and all designs were independently re-tested at different seasons of the year. The produced sensors closely followed the ambient humidity variation common to the 24-h circadian cycle.

Frog vocalization is influenced by moon phases: Brazilian frogs tend to prefer low-albedo phases

Lunar phases remarkably influence the circadian cycle of living beings. Early amphibian studies date back to the 1960s, but only recently has more research been conducted in this field. Much still needs to be understood to establish the behavioral pattern of this group according to the synodic cycle. In the present study, we sought to determine (i) whether the vocalization activity was influenced by the lunar phases and (ii) whether the influence was species-specific or affects the community with equal intensity. We expected a great diversity of behaviors and adaptations. Rayleigh's test was used to verify whether the sample differs significantly from the null hypothesis; Rao's test was used to check sample size sufficiency; and the Kiviat diagram was used to evaluate the activity of the species in relation to the complete synodic cycle. We have observed 1691 individuals of 37 species over 882 d. The lunar cycle influenced 78 % of the species, with 32 % preferring the lower-albedo phases. The activity pattern of each species was established. These results suggest that the lunar phases influence the vocalization activity of most species. Therefore, there is a general pattern of activity related to the synodic cycles; however, the specificities still need to be better understood.

Circadian rhythms disorders in athletes and possibilities for their correction

Transmeridional movement and the corresponding change in the time zone are accompanied by a syndrome complex, which is called acute desynchronosis. Acute desynchronosis is manifested in athletes by pronounced disturbances of the sleep-wake rhythm and vegetative-vascular shifts. This can lead to a significant decrease in functional readiness of athletes and their temporary inability to fully work in the new environment. Similarly, moving to an area with an unusual climate also leads to the development of adaptive responses that reduce functionality. There are several therapeutic strategies to counteract the detrimental effects of jet lag on the normal circadian cycle. More research is needed to develop specific treatment recommendations for athletes.