The Angiotensin-melatonin axis

Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies

Melatonin supplementation in the management of obesity and obesity-associated disorders: a review of physiological mechanisms and clinical applications

Despite the evolving advances in clinical approaches to obesity and its inherent comorbidities, the therapeutic challenge persists. Among several pharmacological tools already investigated, recent studies suggest that melatonin supplementation could be an efficient therapeutic approach in the context of obesity. In the present review, we have amalgamated the evidence so far available on physiological effects of melatonin supplementation in obesity therapies, addressing its effects upon neuroendocrine systems, cardiometabolic biomarkers and body composition. Most studies herein appraised employed melatonin supplementation at dosages ranging from 1 to 20 mg/day, and most studies followed up participants for periods from 3 weeks to 12 months. Overall, it was observed that melatonin plays an important role in glycaemic homeostasis, in addition to modulation of white adipose tissue activity and lipid metabolism, and mitochondrial activity. Additionally, melatonin increases brown adipose tissue volume and activity, and its antioxidant and anti-inflammatory properties have also been demonstrated. There appears to be a role for melatonin in adiposity reduction; however, several questions remain unanswered, for example melatonin baseline levels in obesity, and whether any seeming hypomelatonaemia or melatonin irresponsiveness could be clarifying factors. Supplementation dosage studies and more thorough clinical trials are needed to ascertain not only the relevance of such findings but also the efficacy of melatonin supplementation

Melanopsin System Dysfunction in Smith-Magenis Syndrome Patients

PURPOSE: Smith-Magenis syndrome (SMS) causes sleep disturbance that is related to an abnormal melatonin profile. It is not clear how the genomic disorder leads to a disturbed synchronization of the sleep/wake rhythm in SMS patients. To evaluate the integrity of the intrinsically photosensitive retinal ganglion cell (ipRGC)/melanopsin system, the transducers of the light-inhibitory effect on pineal melatonin synthesis, we recorded pupillary light responses (PLR) in SMS patients. METHODS: Subjects were SMS patients (n = 5), with molecular diagnosis and melatonin levels measured for 24 hours and healthy controls (n = 4). Visual stimuli were 1-second red light flashes (640 nminsignificant direct ipRGC activation), followed by a 470-nm blue light, near the melanopsin peak absorption region (direct ipRGC activation). Blue flashes produce a sustained pupillary constriction (ipRGC driven) followed by baseline return, while red flashes produce faster recovery. RESULTS: Pupillary light responses to 640-nm red flash were normal in SMS patients. In response to 470-nm blue flash, SMS patients had altered sustained responses shown by faster recovery to baseline. SMS patients showed impairment in the expected melatonin production suppression during the day, confirming previous reports. CONCLUSIONS: SMS patients show dysfunction in the sustained component of the PLR to blue light. It could explain their well-known abnormal melatonin profile and elevated circulating melatonin levels during the day. Synchronization of daily melatonin profile and its photoinhibition are dependent on the activation of melanopsin. This retinal dysfunction might be related to a deficit in melanopsin-based photoreception, but a deficit in rod function is also possible.Sao Paulo Research Foundation (FAPESP) [2014/26818-2, 2014/50457-0, 2016/04538-3, 2014/06457-5, 2015/22227-2, 2016/22007-5]National Council for Scientific and Technological Development (CNPq) [480428/2013-4, 470785/2014-4, 404239/2016-1]CAPES [3263/2013]Janos Bolyai Scholarship of the Hungarian Academy of SciencesUniv Sao Paulo, Dept Expt Psychol, Inst Psychol, Sao Paulo, BrazilSemmelweis Univ, Dept Ophthalmol, Budapest, HungaryUniv Sao Paulo, Dept Neurol, Fac Med, Sao Paulo, BrazilBudapest Univ Technol & Econ, Dept Mechatron Opt & Engn Informat, Budapest, HungaryUniv Texas San Antonio, Dept Cellular & Struct Biol, San Antonio, TX USAUniv Fed Sao Paulo, Dept Physiol, Sao Paulo, BrazilUniv Sao Paulo, Dept Physiol & Biophys, Inst Biomed Sci, Av Lineu Prestes 1524, BR-05508000 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Physiol, Sao Paulo, BrazilFAPESP [2014/26818-2, 2014/50457-0, 2016/04538-3, 2014/06457-5, 2015/22227-2, 2016/22007-5]CNPq [480428/2013-4, 470785/2014-4, 404239/2016-1]CAPES [3263/2013]Web of Scienc

Poor sleep quality is associated with cardiac autonomic dysfunction in treated hypertensive men

Hypertensives present cardiac autonomic dysfunction. Reduction in sleep quality increases blood pressure (BP) and favors hypertension development. Previous studies suggested a relationship between cardiovascular autonomic dysfunction and sleep quality, but it is unclear whether this association is present in hypertensives. Thus, this study evaluated the relationship between sleep quality and cardiac autonomic modulation in hypertensives. Forty-seven middle-aged hypertensive men under consistent anti-hypertensive treatment were assessed for sleep quality by the Pittsburgh Sleep Quality Index (PSQI—higher score means worse sleep quality). Additionally, their beat-by-beat BP and heart rate (HR) were recorded, and cardiac autonomic modulation was assessed by their variabilities. Mann-Whitney and t tests were used to compare different sleep quality groups: poor (PSQI > 5, n = 24) vs good (PSQI ≤ 5, n = 23), and Spearman’s correlations to investigate associations between sleep quality and autonomic markers. Patients with poor sleep quality presented lower cardiac parasympathetic modulation (HR high-frequency band = 26 ± 13 vs 36 ± 15 nu, P =.03; HR total variance = 951 ± 1373 vs 1608 ± 2272 ms2, P =.05) and cardiac baroreflex sensitivity (4.5 ± 2.3 vs 7.1 ± 3.7 ms/mm Hg, P =.01). Additionally, sleep quality score presented significant positive correlation with HR (r = +0.34, P =.02) and negative correlations with HR high-frequency band (r = −0.34, P =.03), HR total variance (r = −0.35, P =.02), and cardiac baroreflex sensitivity (r = −0.42, P =.01), showing that poor sleep quality is associated with higher HR and lower cardiac parasympathetic modulation and baroreflex sensitivity. In conclusion, in treated hypertensive men, poor sleep quality is associated with cardiac autonomic dysfunction

From Antenna to Antenna: Lateral Shift of Olfactory Memory Recall by Honeybees

Honeybees, Apis mellifera, readily learn to associate odours with sugar rewards and we show here that recall of the olfactory memory, as demonstrated by the bee extending its proboscis when presented with the trained odour, involves first the right and then the left antenna. At 1–2 hour after training using both antennae, recall is possible mainly when the bee uses its right antenna but by 6 hours after training a lateral shift has occurred and the memory can now be recalled mainly when the left antenna is in use. Long-term memory one day after training is also accessed mainly via the left antenna. This time-dependent shift from right to left antenna is also seen as side biases in responding to odour presented to the bee's left or right side. Hence, not only are the cellular events of memory formation similar in bees and vertebrate species but also the lateralized networks involved may be similar. These findings therefore seem to call for remarkable parallel evolution and suggest that the proper functioning of memory formation in a bilateral animal, either vertebrate or invertebrate, requires lateralization of processing

Food-anticipatory activity in Syrian hamsters: behavioral and molecular responses in the hypothalamus according to photoperiodic conditions.

When food availability is restricted, animals adjust their behavior according to the timing of food access. Most rodents, such as rats and mice, and a wide number of other animals express before timed food access a bout of activity, defined as food-anticipatory activity (FAA). One notable exception amongst rodents is the Syrian hamster, a photoperiodic species that is not prone to express FAA. The present study was designed to understand the reasons for the low FAA in that species. First, we used both wheel-running activity and general cage activity to assess locomotor behavior. Second, the possible effects of photoperiod was tested by challenging hamsters with restricted feeding under long (LP) or short (SP) photoperiods. Third, because daytime light may inhibit voluntary activity, hamsters were also exposed to successive steps of full and skeleton photoperiods (two 1-h light pulses simulating dawn and dusk). When hamsters were exposed to skeleton photoperiods, not full photoperiod, they expressed FAA in the wheel independently of daylength, indicating that FAA in the wheel is masked by daytime light under full photoperiods. During FAA under skeleton photoperiods, c-Fos expression was increased in the arcuate nuclei independently of the photoperiod, but differentially increased in the ventromedial and dorsomedial hypothalamic nuclei according to the photoperiod. FAA in general activity was hardly modulated by daytime light, but was reduced under SP. Together, these findings show that food-restricted Syrian hamsters are not prone to display FAA under common laboratory conditions, because of the presence of light during daytime that suppresses FAA expression in the wheel.journal articleresearch support, non-u.s. gov't20152015 05 13importedFunding: This work was supported by doctoral scholarship from Fundação de Amparo à Pesquisa do Estado do São Paulo (São Paulo State, Brazil) to RFDF, and by Centre National de la Recherche Scientifique and University of Strasbourg (France) to EC, VS and PP

Rat retina shows robust circadian expression of clock and clock output genes in explant culture.

PURPOSE: Circadian rhythms are central to vision and retinal physiology. A circadian clock located within the retina controls various rhythmic processes including melatonin synthesis in photoreceptors. In the present study, we evaluated the rhythmic expression of clock genes and clock output genes in retinal explants maintained for several days in darkness. METHODS: Retinas were dissected from Wistar rats, either wild-type or from the Per1-luciferase transgenic line housed under a daily 12 h:12 h light-dark cycle (LD12/12), and put in culture at zeitgeber time (ZT) 12 on semipermeable membranes. Explants from wild-type rats were collected every 4 h over 3 days, and total RNA was extracted, quantified, and reverse transcribed. Gene expression was assessed with quantitative PCR, and the periodicity of the relative mRNA amounts was assessed with nonlinear least squares fitting to sine wave functions. Bioluminescence in explants from Per1-luciferase rats was monitored for several days under three different culture protocols. RESULTS: Rhythmic expression was found for all studied clock genes and for clock downstream targets such as c-fos and arylalkylamine N-acetyltransferase (Aanat) genes. Clock and output genes cycled with relatively similar periods and acrophases (peaks of expression during subjective night, except c-fos, which peaked around the end of the subjective day). Data for Per1 were confirmed with bioluminescence monitoring, which also permitted culture conditions to be optimized to study the retina clock. CONCLUSIONS: Our work shows the free-running expression profile of multiple clock genes and potential clock targets in mammalian retinal explants. This research further strengthens the notion that the retina contains a self-sustained oscillator that can be functionally characterized in organotypic culture.journal articleresearch support, non-u.s. gov't20142014 06 02importe