Interactions of renin-angiotensin system and COVID-19: the importance of daily rhythms in ACE2, ADAM17 and TMPRSS2 expression.

Angiotensin-converting enzyme 2 (ACE2) was identified as a molecule that mediates the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several membrane molecules of the host cell must cooperate in this process. While ACE2 serves in a membrane receptor-mediating interaction with the surface spike (S) glycoprotein of SARS-CoV-2 located on the virus envelope, enzyme A disintegrin and metalloproteinase 17 (ADAM17) regulates ACE2 availability on the membrane and transmembrane protease serine 2 (TMPRSS2) facilitates virus-cell membrane fusion. Interestingly, ACE2, ADAM17 and TMPRSS2 show a daily rhythm of expression in at least some mammalian tissue. The circadian system can also modulate COVID-19 progression via circadian control of the immune system (direct, as well as melatonin-mediated) and blood coagulation. Virus/ACE2 interaction causes ACE2 internalization into the cell, which is associated with suppressed activity of ACE2. As a major role of ACE2 is to form vasodilatory angiotensin 1-7 from angiotensin II (Ang II), suppressed ACE2 levels in the lung can contribute to secondary COVID-19 complications caused by up-regulated, pro-inflammatory vasoconstrictor Ang II. This is supported by the positive association of hypertension and negative COVID-19 prognosis although this relationship is dependent on numerous comorbidities. Hypertension treatment with inhibitors of renin-angiotensin system does not negatively influence prognosis of COVID-19 patients. It seems that tissue susceptibility to SARS-CoV-2 shows negative correlation to ACE2 expression. However, in lungs of infected patient, a high ACE2 expression is associated with better outcome, compared to low ACE2 expression. Manipulation of soluble ACE2 levels is a promising COVID-19 therapeutic strategy.

Urinary levels of 6-sulphatoxymelatonin and their associations with sleep disorders and behavioural impairments in children with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with sleep disturbances that may result from abnormalities in melatonin production. The correlations of melatonin levels with the severity of sleep disorder and/or severity of ASD were reported. OBJECTIVES: To evaluate urinary levels of the melatonin metabolite, 6-sulphatoxymelatonin (aMT6s), in children with ASD, and their associations with sleep abnormalities and behavioural impairments. METHODS: Study involved 77 children with ASD and 84 controls aged 2.5‒15.5 years. Sleep disorders were assessed by Children's Sleep Habits Questionnaire. Morning and afternoon levels of aMT6s were determined by radioimmunoassay method. Urinary creatinine levels were assessed by an enzymatic method. RESULTS: The urinary aMT6s/creatinine values indicate that the night-time melatonin levels are significantly lower in ASD than in controls, but there are no significant differences in the daytime levels. In the ASD group, on average, a 6.8-fold difference between night-time and daytime values of urinary aMT6s/creatinine was found, whereas for the controls a 12.5-fold difference was observed, indicating a lower night-time increase in melatonin levels. In ASD group, the difference in night-time-daytime aMT6s/creatinine value correlated with some types of sleep problems, but not with the severity of ASD. CONCLUSION: The results indicate that in ASD there are differences in the patterns of melatonin secretion that may be associated with sleep impairment (Tab. 4, Fig. 2, Ref. 28).

Intense blue light therapy during the night-time does not suppress the rhythmic melatonin biosynthesis in a young boy.

OBJECTIVE: Melatonin is a hormone predominantly synthesized and secreted during the night by the pineal gland. Artificial light at night, especially its blue part, acutely suppresses the melatonin production. Th e aim of the present study was to find out, whether an intense blue light phototherapy of severe hyperbilirubinemia, may suppress the melatonin production during the night when the eyes will be properly protected by a sleep mask. METHODS: The main melatonin metabolite, 6-sulphatoxymelatonin was measured in urine in a nine-year old boy suffering from the Crigler-Najjar syndrome type I. The boy was treated during the sleep period with an intense blue light (to 1800 lx) 10 h/day, since his birth. During the phototherapy, his eyes were protected with a sleep mask. The concentration of 6-sulphatoxymelatonin was determined in the first morning urine and urine collected afternoon during the six days. The patient was exposed to phototherapy for three nights, two nights without and the last one with the treatment. The control urine samples were obtained from 8 healthy nine-year old boys. The level of 6-sulphatoxymelatonin was measured by radioimmunoassay and the data were normalized to urinary creatinine. RESULTS: A distinct melatonin production rhythm was found and 6-sulphatoxymelatonin concentration in urine of the patient was comparable with the values obtained by the control group. No differences in 6-sulphatoxymelatonin levels were found between the nights with and without the phototherapy applied. CONCLUSIONS: We conclude that the whole night treatment of hyperbilirubinemia with intense blue light has negligible side effect on the rhythmic melatonin production, when the eyes are sufficiently protected by the sleep mask.

Circadian and extracircadian exploration during daytime hours of circulating corticosterone and other endocrine chronomes.

During 7 consecutive days, blood and several tissues were collected during daytime working hours only, three times per day at 4-h intervals from inbred Wistar rats, which had been previously standardized for 1 month in two rooms on a regimen of 12 h of light (L) alternating with 12 h of darkness (LD12:12). In one room, lights were on from 09:00 to 21:00 and in the other room, lights were on from 21:00 to 09:00 (DL12:12; reversed lighting regimen). This setup provides a convenient design to study circadian and extracircadian variations over long (e.g., 7-day) spans. Prior checking of certain circadian rhythms in animals reared in the room on reversed lighting (DL) as compared with animals in the usual (LD) regimen provided evidence that the 180 degrees phase-shift had occurred. These measurements were limited to the circadian (and not extended to infradian) variation. As marker rhythm, the core temperature of a subsample of rats was measured every 4 h around the clock (by night as well as by day) before the start of the 7-day sampling. An antiphase of the circadian rhythm in core temperature was thus demonstrated between rats in the LD vs. DL rooms. A sex difference in core temperature was also found in each room. A reversed rhythm in animals kept in DL and an antiphase between rats kept in DL vs. LD was again shown for the circulating corticosterone rhythm documented in subsamples of 8 animals of each sex sampled around the clock during the first approximately 1.5 day of the 7-day sampling. The findings were in keeping with the proposition that sampling rats at three timepoints 4 h apart during daytime from two rooms on opposite lighting regimens allows the assessment of circadian changes, the daytime samples from animals kept on the reversed lighting regimen accounting for the samples that would have to be obtained by night from animals kept in the room with the usual lighting regimen. During the 7-day-long follow-up, circadian and extracircadian spectral components were mapped for serum corticosterone, taking into account the large day-to-day variability. A third check on the synchronization of the animals to their respective lighting regimen was a comparison (and a good agreement) between studies carried out earlier on the same variables and the circadian results obtained on core temperature and serum corticosterone in this study as a whole. The present study happened to start on the day of the second extremum of a moderate double magnetic storm. The study of any associations of corticosterone with the storm is beyond our scope herein, as are the results on circulating prolactin, characterized by a greater variability and a larger sex difference than corticosterone. Sex differences and extracircadian aspects of prolactin and endothelin determined in the same samples are reported elsewhere, as are results on melatonin. Prior studies on melatonin were confirmed insofar as a circadian profile is concerned by sampling on two antiphasic lighting regimens, as also reported elsewhere. Accordingly, a circadian map for the rat will eventually be extended by the result of this study and aligned with other maps with the qualification of the unassessed contribution in this study of a magnetic storm.

Chronomics reveal and quantify circadian rhythmic melatonin in duodenum of rats.

A circadian rhythm is documented in duodenal melatonin in rats, peaking 16.8 hours after light onset. This component is more readily detected after log10-transformation of the data. It differs between male and female rats, females having a larger circadian amplitude and an earlier acrophase. The circadian rhythm in duodenal melatonin is also found to lead that of pineal melatonin. The results are qualified by the presence at the start of mapping of the second extremum of a double magnetic storm.

Chronomics: circadian lead of extrapineal vs. pineal melatonin rhythms with an infradian hypothalamic exploration.

A circadian rhythm is documented for plasma, pineal, and hypothalamic melatonin of male and female rats kept on staggered lighting regimens. Log[_10]-transformation of the data usually normalizes, when need be, the distribution of residuals from the 24-hour cosine curve fits. A tentative circadian acrophase chart is presented that shows a lead in circadian acrophase of duodenal over pineal melatonin. The use of antiphasic lighting regimens facilitates circadian studies that can be carried out for several days, thereby allowing the assessment of infradian components such as a circasemiseptan variation in hypothalamic melatonin documented herein. The results are qualified by the presence of a second extremum of a double magnetic storm at the start of mapping.

Chronomics affirm extending scope of lead in phase of duodenal vs. pineal circadian melatonin rhythms.

In Göttingen, Germany, circadian variations in melatonin had been determined time-macroscopically in pineal glands, blood plasma and duodenum of chicken and rats. When these data were meta-analyzed, they agreed with the results from an independent survey on tissues from rats collected in a laboratory in Pécs, Hungary. In the latter study, tissues were analyzed chemically in Bratislava, Slovakia, and numerically in Minneapolis, MN, USA, all by single- and multiple-component cosinor and parameter tests. In rats and chickens, these inferential statistical procedures clearly demonstrated a lead in phase of the 24-h cosine curves best fitting all of the duodenal vs. those best fitting all of the pineal melatonin values in each species in 2 geographic (geomagnetic) locations. The 24-h cosine curve of circulating melatonin was found to be in an intermediate phase position. Mechanisms of the phase differences and the contribution of gastrointestinal melatonin to circulating hormone concentrations are discussed.

Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts--forecasts of geomagnetics.

A multi-center four-hourly sampling of many tissues for 7 days (00:00 on April 5-20:00 to April 11, 2004), on rats standardized for 1 month in two rooms on antiphasic lighting regimens happened to start on the day after the second extremum of a moderate double magnetic storm gauged by the planetary geomagnetic Kp index (which at each extremum reached 6.3 international [arbitrary] units) and by an equatorial index Dst falling to -112 and -81 nT, respectively, the latter on the first day of the sampling. Neuroendocrine chronomes (specifically circadian time structures) differed during magnetically affected and quiet days. The circadian melatonin rhythm had a lower MESOR and lower circadian amplitude and tended to advance in acrophase, while the MESOR and amplitude of the hypothalamic circadian melatonin rhythm were higher during the days with the storm. The circadian parameters of circulating corticosterone were more labile during the days including the storm than during the last three quiet days. Feedsidewards within the pineal-hypothalamic-adrenocortical network constitute a mechanism underlying physiological and probably also pathological associations of the brain and heart with magnetic storms. Investigators in many fields can gain from at least recording calendar dates in any publication so that freely available information on geomagnetic, solar and other physical environmental activity can be looked up. In planning studies and before starting, one may gain from consulting forecasts and the highly reliable nowcasts, respectively.