AIM: Exposure to light at night and meal time misaligned with the light/dark (LD) cycle-typical features of daily life in modern 24/7 society-are associated with negative effects on health. To understand the mechanism, we developed a novel protocol of complex chronodisruption (CD) in which we exposed female rats to four weekly cycles consisting of 5-day intervals of constant light and 2-day intervals of food access restricted to the light phase of the 12:12 LD cycle. METHODS: We examined the effects of CD on behavior, estrous cycle, sleep patterns, glucose homeostasis and profiles of clock- and metabolism-related gene expression (using RT qPCR) and liver metabolome and lipidome (using untargeted metabolomic and lipidomic profiling). RESULTS: CD attenuated the rhythmic output of the central clock in the suprachiasmatic nucleus via Prok2 signaling, thereby disrupting locomotor activity, the estrous cycle, sleep patterns, and mutual phase relationship between the central and peripheral clocks. In the periphery, CD abolished Per1,2 expression rhythms in peripheral tissues (liver, pancreas, colon) and worsened glucose homeostasis. In the liver, it impaired the expression of NAD+, lipid, and cholesterol metabolism genes and abolished most of the high-amplitude rhythms of lipids and polar metabolites. Interestingly, CD abolished the circadian rhythm of Cpt1a expression and increased the levels of long-chain acylcarnitines (ACar 18:2, ACar 16:0), indicating enhanced fatty acid oxidation in mitochondria. CONCLUSION: Our data show the widespread effects of CD on metabolism and point to ACars as biomarkers for CD due to misaligned sleep and feeding patterns.
- MeSH
- Circadian Clocks physiology MeSH
- Circadian Rhythm * physiology MeSH
- Photoperiod MeSH
- Liver * metabolism MeSH
- Carnitine * analogs & derivatives metabolism MeSH
- Rats MeSH
- Metabolome * MeSH
- Suprachiasmatic Nucleus metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.
- MeSH
- Chronobiology Disorders physiopathology complications MeSH
- Circadian Rhythm * physiology MeSH
- Diabetes Mellitus, Type 2 physiopathology metabolism MeSH
- Cardiovascular Diseases * etiology physiopathology MeSH
- Humans MeSH
- Metabolic Diseases * physiopathology metabolism etiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Cell lineage trees inferred from these mutations reflect the somatic evolutionary process, and thus, it has been conjectured, the aging status of the body. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge. Here, we show that somatic mutations detected using single-cell RNA sequencing (scRNA-seq) from thousands of cells can be used to construct a cell lineage tree whose structure correlates with chronological age. De novo single-nucleotide variants (SNVs) are detected in human peripheral blood mononuclear cells using a modified protocol. A default model based on penalized multiple regression of chronological age on 31 metrics characterizing the phylogenetic tree gives a Pearson correlation of 0.81 and a median absolute error of ~4 years between predicted and chronological ages. Testing of the model on a public scRNA-seq dataset yields a Pearson correlation of 0.85. In addition, cell tree age predictions are found to be better predictors of certain clinical biomarkers than chronological age alone, for instance glucose, albumin levels, and leukocyte count. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality of aging timer. In addition to providing a numerical estimate of "cell tree age," it unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. Cell Tree Rings complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.
- MeSH
- Biomarkers MeSH
- Longevity MeSH
- Phylogeny MeSH
- Leukocytes, Mononuclear * MeSH
- Humans MeSH
- Aging * genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Background: Selective attention and visuospatial orienting attention are important cognitive functions for children's development. Testing based on touch-based mobile technology platforms is becoming increasingly widespread in psychological assessment. Objective: The aim of the study was to investigate the reliability and validity of the newly developed touchscreen tablet-based test of selective and orienting attention (t-SOA test) in typical developing children aged 7-10 years. Methods: Two age groups of children, the group7-8 (7-8 years, 9 girls, 10 boys) and the group9-10 (9-10 years, 9 girls, 9 boys), performed the t-SOA test on a tablet (Android operating system) and a stylus, as well as the Reaction test of selective attention of the Vienna Test System (RT4-VTS). The criterion validity of the t-SOA test was verified by the RT4-VTS, and the construct validity via an analysis of the effect of age on the results of the t-SOA test. The reliability of the t-SOA test was assessed through internal consistency. Results: The internal consistency of the response time (RT) to the target stimulus was demonstrated to be excellent, Cronbach's α = .944. The mixed linear model with two factors - the central and the spatial (peripheral) cues, showed no significant effect on mean RT. Mean RT, median RT, and the coefficient of variation for RTs (CVRT) in the t-SOA test correlated significantly with analogous test scores of the RT4-VTS test, but not in the case of the number of correct responses, omissions, and commissions. A statistically significant effect of the age group was found for mean RT, median RTs, CVRT, and omission of the t-SOA test. Conclusions: The study demonstrated that the newly constructed t- SOA test may be a valid and reliable tool for assessing the level of visual selective attention of children during middle childhood. The study supported the current suggestion that the assessment of cognitive functions with a touchscreen tablet and a digital stylus is feasible and accepted by school-age children.
- Keywords
- t-SOA test,
- MeSH
- Child MeSH
- Cognition MeSH
- Humans MeSH
- Neuropsychological Tests MeSH
- Pilot Projects MeSH
- Computers, Handheld * MeSH
- Attention MeSH
- Research MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
The mammalian circadian system consists of a major circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks in the body, including brain structures. The SCN depends on glutamatergic neurotransmission for transmitting signals from the retina, and it exhibits spontaneous 24-h rhythmicity in neural activity. The aim of this work was to evaluate the degree and circadian rhythmicity of AMPA receptor GluA2 subunit R/G editing and alternative flip/flop splicing in the SCN and other brain structures in Wistar rats. Our data show that the circadian rhythmicity in the SCN's GluA2 mRNA level was highest at dawn, while the circadian rhythm in R/G editing peaked at CT10 and the rhythmic flip varied with the acrophase at the late subjective night. The circadian rhythmicity was confirmed for R/G editing and splicing in the CA3 hippocampal area, and rhythmic variation of the flip isoform was also measured in the olfactory bulbs and cerebellum. The correlations between the R/G editing and alternative flip/flop splicing revealed a structure-dependent direction. In the hippocampus, the edited (G)-form level was positively correlated with the flip variant abundance, in accord with published data; by contrast, in the SCN, the flip variant was in associated more with the unedited (R) form. The edited (G) form and flop isoform also predominated in the retina and cerebellum.
- MeSH
- Receptors, AMPA genetics metabolism MeSH
- Circadian Rhythm genetics MeSH
- RNA Editing genetics MeSH
- Exons genetics MeSH
- RNA, Messenger genetics metabolism MeSH
- Suprachiasmatic Nucleus metabolism MeSH
- RNA Processing, Post-Transcriptional genetics MeSH
- Rats, Wistar MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: The maternal part of the rodent placenta harbors a circadian clock which robustly responds to glucocorticoids, however, its sensitivity to other hormones has not been elucidated. In this study, we tested five selected hormones (dopamine, melatonin, insulin, leptin and ghrelin) for their effectiveness to affect the clock in decidual region of mouse placenta in vitro. METHODS: We administered the hormones or corresponding vehicles at various time points over 24 h to organotypic placental explants of mPer2Luc mice containing the decidua basalis (DB) region and monitored their effects on amplitude, period, median expression level (mesor) and phase of PER2-driven bioluminescence rhythms. RESULTS: Dopamine significantly increased the amplitude, robustly dampened the mesor, and during a narrow time interval (corresponding to daytime) induced phase delays of the rhythms. In contrast, melatonin had no effect on amplitude, but induced phase advances of the rhythms at the opposite time window than dopamine (corresponding to nighttime). Leptin and ghrelin, but not insulin, slightly increased amplitudes and moderately modulated phase delays of the clock, suggesting that the DB clock, in contrast to other peripheral clocks, is rather resilient to abrupt changes in levels of feeding- and metabolism-related hormones. DISCUSSION: The results demonstrate for the first time that dopamine and melatonin exhibit delicate yet specific effects on parameters of the DB clock and may thus potentially contribute to fine-tuning of its phase under in vivo conditions. It also implies that dysregulation of their levels, which accompany various pathologies, may account for malfunction of the clock in DB.
- MeSH
- Circadian Clocks * MeSH
- Circadian Rhythm * MeSH
- Dopamine physiology MeSH
- Hormones physiology MeSH
- Mice MeSH
- Placenta metabolism MeSH
- Pregnancy MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Aging and tumorigenesis are associated with decline and disruption of circadian rhythms in many tissues and accumulating evidence indicates molecular link between circadian clock and cell cycle. The aim of this study was to investigate the effect of aging and tumorigenesis on coupling between cell cycle and circadian clock oscillators in colon, which undergoes regular rhythmicity of cell cycle and expresses peripheral circadian clock. Using healthy 14-week-old mice and 33-week-old mice with and without colorectal tumors, we showed that the 24-h expression profiles of clock genes and clock-controlled genes were mostly unaffected by aging, whereas the genes of cell cycle and cell proliferation were rhythmic in the young colons but were silenced during aging. On the other hand, tumorigenesis completely silenced or dampened the circadian rhythmicity of the clock genes but only a few genes associated with cell cycle progression and cell proliferation. These results suggest that aging impacts the colonic circadian clock moderately but markedly suppresses the rhythms of cell cycle genes and appears to uncouple the cell cycle machinery from circadian clock control. Conversely, tumorigenesis predominantly affects the rhythms of colonic circadian clocks but is not associated with uncoupling of circadian clock and cell cycle.
- MeSH
- Cell Cycle physiology MeSH
- Circadian Clocks physiology MeSH
- Circadian Rhythm physiology MeSH
- Carcinogenesis * metabolism pathology MeSH
- Colon physiology MeSH
- Colorectal Neoplasms * metabolism pathology MeSH
- Mice MeSH
- Cell Transformation, Neoplastic MeSH
- Cell Proliferation MeSH
- Aging * metabolism pathology MeSH
- Intestinal Mucosa * metabolism pathology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Circadian clocks coordinate physiological and behavioral rhythms that allow the organism to anticipate and adapt to daily changes in environment. The clock-driven cellular oscillations are highly tissue specific to efficiently fine-tune local signaling, manage energy use and segregate incompatible processes. In most peripheral tissues, food acts as the main cue that entrains the oscillations to external time. Food intake and energy balance are under control of endocannabinoid (EC) signaling. Despite this obvious link between the circadian and EC systems, evidence for their interaction started to emerge only recently. We used targeted lipidomics to analyze circadian variations in EC tone in rat plasma, liver and adrenal tissue. The results provide the evidence that ECs, monoacylglycerols, N-acylethanolamines and their precursors oscillate with a tissue-specific circadian phase in plasma and liver. We then identified a set of rhythmically expressed genes likely responsible for the variations in EC tissue tone. In contrast to the liver, EC levels did not oscillate in the adrenal glands. Instead, we revealed that local EC receptor genes are under circadian regulation. To explore the impact of metabolic signals on expression of these genes, we used daytime-restricted feeding schedule. We subsequently showed that daytime feeding strongly suppressed liver-expressed fatty acid binding protein 5 (Fabp5) and adrenal-expressed non-canonical endocannabinoid receptors Gpr55 and Trpv1, whereas it upregulated liver-expressed Trpv1 and glycerophosphodiester phosphodiesterase 1 (Gde1). Our results reveal tissue-specific mechanisms involved in interaction between endocannabinoid signaling, circadian system and metabolism.
- MeSH
- Circadian Clocks MeSH
- Circadian Rhythm * MeSH
- Endocannabinoids blood metabolism MeSH
- Energy Metabolism MeSH
- Photoperiod MeSH
- Liver metabolism MeSH
- Rats MeSH
- Adrenal Glands metabolism MeSH
- Rats, Wistar MeSH
- Appetite Regulation MeSH
- Feeding Behavior MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The circadian clock system drives many physiological processes, including plasma concentration of glucocorticoids and epithelial transport of some ions and nutrients. As glucocorticoids entrain the circadian rhythms in various peripheral organs, we examined whether adrenalectomy affects the expression and circadian rhythmicity of intestinal transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) families, which participate in intestinal barriers for absorption of nutrients, nonnutrients and oral drugs. The rat jejunum showed rhythmic circadian profiles of Sglt1, Pept1, Nhe3, Mdr1 and Mrp2 but not Mct1, Oct1, Octn1, Oatp1, Cnt1 and Bcrp. With the exception of Pept1 and Mct1, adrenalectomy decreased the expression of all rhythmic and arrhythmic transporters including the amplitude of Sglt1 and Nhe3 rhythms but minimally affected the phases of rhythmic transporters except of Nhe3. Similarly, adrenalectomy downregulated the expression of rhythmic (Pparα, Hlf, Pgc1α) and arrhythmic (Hnf1β, Hnf4α) transcription factors, which are known to regulate the expression of transporters. We conclude that endogenous corticosteroids have a profound effect on the expression of intestinal SLC and ABC transporters and their nuclear transcription factors. The circulating corticosteroids are necessary for maintaining upregulated expression of Sglt1, Oct1, Octn1, Oatp1, Cnt1, Nhe3, Mdr1, Bcrp, Mrp2, Pparα, Pgc1α, Hnf1β, Hnf4α and Hlf and for maintaining the high amplitude of Sglt1, Nhe3, Pparα, Pgc1α and Hlf circadian rhythms. The study demonstrates that signals from the adrenal gland are necessary for maintaining the expression of arrhythmic and rhythmic intestinal transporters and that changes in the secretion of corticosteroids associated with stress might reorganize intestinal transport barriers.
Tenzní typ bolesti hlavy je nejčastějším typem bolesti hlavy. V článku je krátce zmíněna patofyziologie včetně periferních a centrálních mechanismů. Podstatou periferních mechanismů může být dysfunkce v myofasciálních spouštěcích bodech, podkladem centrálních mechanismů je pravděpodobně centrální senzitizace. Je popsána léčba akutních atak a profylaktická léčba u časté epizodické a chronické formy. Cluster headache je typ primární bolesti hlavy ze skupiny trigeminových autonomních neuralgií (TACs). Je popsán klinický obraz i možnosti akutní, překlenovací a profylaktické léčby.
Tension type headache is the most frequent type of headache. The pathophysiology is shortly mentioned including the peripheral and central mechanisms. The basis of peripheral mechanisms can be the dysfunction in myofascial trigger points, the basis of central mechanisms is probably the central sensitization. The treatment of acute attacks and prophylactic treatment in frequent episodic and chronic forms are described. Cluster headache (CH) is a primary headache from the TACs group. The clinical manifestation and the existing knowledge about the acute, bridging and prophylactic treatment are described.
- MeSH
- Amitriptyline administration & dosage MeSH
- Anti-Inflammatory Agents, Non-Steroidal administration & dosage MeSH
- Anticonvulsants administration & dosage MeSH
- Chemoprevention MeSH
- Glucocorticoids administration & dosage MeSH
- Humans MeSH
- Headache Disorders, Primary * classification MeSH
- Tension-Type Headache diagnosis drug therapy physiopathology MeSH
- Trigeminal Autonomic Cephalalgias diagnosis drug therapy physiopathology MeSH
- Tryptamines administration & dosage MeSH
- Check Tag
- Humans MeSH
