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5 Ways To Improve Your Sleep Quality! Resveratrol and sleep quality is a fraction wnd a group of compounds called polyphenols. They act as antioxidants, protecting the quzlity against Resvertrol that can put you Resilient Power Systems higher risk for cancer and cardiovascular disease. It has been shown to widen blood vessels and lower the function of cells involved in blood clotting. Resveratrol is found to be present in red grapes and other berries. It is used to treat high cholesterol, cancer, heart disease, and various other ailments.Resveratrol and sleep quality -
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Parazzini F 1. Affiliations 1. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy - Authors Parazzini F 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook.
Sleep disorders, particularly decreased sleep quality, and irritability are also commonly reported. There is a clinical and epidemiological relationship between these symptoms. Common biological mechanisms may explain in part the relationship between hot flushes, sleep disorders and irritability.
For example, withdrawal of hormones causes change in the serotonin levels. Tryptophan is an essential amino acid. it is the precursor for the serotonin synthesis and is naturally found in food such as turkey, cheese, and nuts. The serotonergic system is implicated in sleep, mood, and hot flashes.
Glycine is an amino acid found mainly in protein-rich food such as meat, fish, dairy products, cheese and vegetables. It is an inhibitory neurotransmitter in the central nervous system. Studies have shown that glycine can promote a deeper level of sleep.
Resveratrol has a similar chemical structure to the diethylstilbestrol and beta estradiol and acts as a phytoestrogen. Resveratrol at doses of micromoles inhibited the estradiol-estrogen receptor binding and showed an estrogen-like activity.
Vitamin E is found naturally in some food and available as a dietary supplement. It has an antioxidant activity. It has been suggested that the oxidative stress may also play a role in sleep disorders. Some studies have shown protective effect of vitamins E on sleep quality. In this regard, it is not surprising that any disturbances in the circadian clock could unbalance the body homeostasis.
A prolong misalignment may have disastrous consequences for human health such as obesity, diabetes, allergies, cancer, heart diseases, and mental disorders [ 7 , 8 , 9 , 10 , 11 ]. One example in which the circadian cycle plays a crucial role is metabolism. The circadian system adapts metabolic needs between the active and rest phases in mammals.
As they eat mostly during their active phase, the metabolic processes related to food intake, such as insulin increase, nutrient uptake, and detoxification, are under circadian control and are activated when food is expected [ 12 ].
In addition, the composition of the meals and the resulting metabolic signals influence the circadian rhythm [ 13 , 14 ]. This bidirectional interaction enables the flexibility needed to adapt the metabolism to the current body requirements and environmental conditions [ 15 ].
Several small molecules, such as caffeine, epigallocatechin gallate, and nobiletin, which are present in the human diet, were shown to modulate the circadian rhythm in vitro as well as in animal models [ 16 ]. For instance, nobiletin improved glucose tolerance and overall glucolipid metabolism through clock reprogramming in metabolic disordered hepatocytes [ 17 ], as well as in diabetic mice [ 18 ].
Moreover, it restored an attenuated circadian clock and improved insulin secretion as seen in isolated human type 2 diabetes pancreatic islets [ 19 ], as well as in mice [ 20 ]. An increasing body of evidence indicates that another dietary phytochemical, resveratrol, may also be a promising clock modulator [ 16 ].
This natural phytoalexin belongs to the stilbene family and is commonly present in the diet; it is mostly found in grape seeds and skin, red wine, peanuts, various types of berries, soy and cocoa [ 22 , 23 , 24 , 25 ]. Resveratrol can modulate numerous signaling molecules and pathways.
The exploration of the link between resveratrol and the circadian rhythm shed a new light on possible applications of this unique phytochemical in clock-related diseases. However, despite a great deal of research on resveratrol, a summary of the findings on its role in clock regulation and chronobiology is still lacking.
This review presents studies related to the circadian clock modulation by resveratrol. A particular focus was set on the molecular mechanisms and therapeutic effects in related pathologies, as well as general limitations of resveratrol application in humans.
The molecular regulation of the circadian clock is based on transcription-translation feedback loops TTFL. The main loop is composed of the Brain and Muscle Arnt-like protein 1 BMAL1 and the Circadian Locomotor Output Cycles Kaput CLOCK that are positive regulators.
These are, among others, period PER and cryptochrome CRY genes that are the negative components of the main loop. When their level reaches a critical point, they form a protein complex that inhibits CLOCK-BMAL1 activity in a negative feedback loop.
Consequently, PER and CRY levels decrease, and CLOCK and BMAL1 expression can be restored, which closes the 24 h cycle Fig. Once expressed, they inhibit BMAL1 and CLOCK expression. Resveratrol induces SIRT1, which deacetylases BMAL1 resulting in the enhancement of its activity. SIRT1 was also shown to deacetylate PER2 leading to its degradation.
SIRT1 was shown to be an important circadian regulator [ 29 ]. SIRT1 codes for Sirtuin 1, the best studied member of the sirtuin protein family. It plays a role in metabolic and physiological processes through its ability to deacetylate histone and non-histone molecules.
NF-κB, p53 and peroxisome proliferator-activated receptor gamma-coactivator-1α PGC-1α are among the numerous targets of this protein. The BMAL1-CLOCK complex could induce SIRT1 transcription through binding to two E-box elements of the SIRT1 promoter region [ 31 ].
Circadian clock regulated SIRT1 mRNA and protein expression, as well as its activity. This was shown in a circadian misalignment model consisting of mice kept in constant darkness for 14 days.
Besides being regulated by the clock, SIRT1 could also affect the circadian regulation itself by being a positive regulator of the circadian rhythm.
Studies showed that Bmal1 and Sirt1 mRNA expressions were highly correlated, therefore suggesting mutual positive regulation [ 32 ]. SIRT1 influenced BMAL1 expression through PGC-1α [ 33 ] and enhanced BMAL1 activity by deacetylation.
It resulted in an improvement of the amplitude of the central circadian clock [ 34 ] Fig. SIRT1 was shown to bind to the BMAL1-CLOCK heterodimer [ 35 , 36 , 37 ] and the protein complexes were found in the nuclei — probably due to SIRT1 nuclear localization sequence.
The PAS-B domain of BMAL1 was identified as a possible region to interact with SIRT1 [ 37 ]. SIRT1 also improved the circadian clock by inhibiting the transcription of the negative clock component Per2 Fig.
SIRT1 deacetylated PER2, which resulted in its degradation [ 33 , 35 ]. On the contrary, some studies suggested that SIRT1 was a negative regulator of the clock. Deacetylation of BMAL1 by SIRT1 resulted in destabilization of the protein and disturbed the circadian rhythm [ 38 ].
Further investigations are therefore needed to fully understand the role of SIRT1 in body clock regulations. Resveratrol was shown to be an activator of SIRT1 expression [ 39 , 40 ] and it may consequently impact the circadian rhythm [ 29 , 31 , 35 , 38 ].
The first evidence appeared in when Oike and Kobori observed that treatment with resveratrol modulated circadian rhythm-related genes in Rat1 fibroblast cells [ 41 ]. A µM dose significantly increased the expression of Bmal1, Per1 and Per2.
Moreover, the mechanism of circadian regulation by the compound differed between serum shock, forskolin or glucose treatment, which are well known entrainers of the circadian rhythm. Treatment with resveratrol showed similar inhibitory effect on Per2 transcription than SIRT1, suggesting an impact on circadian rhythm through SIRT1 [ 36 ].
Nonetheless, resveratrol µM was not confirmed to have a direct effect on SIRT1 interaction with the clock proteins [ 37 ]. In the same study, resveratrol reduced the transcriptional activity of Ebox and Per1 promoters. The authors concluded that resveratrol induced SIRT1, which acted as a negative clock regulator due to deacetylation and repression of Per1 activity [ 37 ].
This stands in opposition to most other studies. Circadian rhythm misalignment can lead to various metabolic disorders such as dyslipidemia, hyperglycemia, insulin resistance, obesity and diabetes [ 7 , 8 ]. Resveratrol showed a wide range of positive effects in metabolic disorders mainly due to SIRT1 up-regulation [ 26 ].
The investigations on the link between resveratrol, circadian rhythm and metabolic disorders seems to be a valid approach to develop therapeutic strategies against them.
A recent in vitro study investigated the effect of resveratrol on the metabolic state and molecular clock in AML mouse hepatocytes [ 42 ].
Cells treated with 50 µM resveratrol for 6 h exhibited a decrease in the ratio between phosphorylated proteins and total level of several metabolic markers, such as protein phosphatase 2 PP2A , AKT, FOXO1, mTOR, and AMPK.
These changes indicated an inhibition of AMPK and an induction of the PP2A-FOXO1-PEPCK pathway, which is suggesting gluconeogenesis induction and a fasting state in the cells. Resveratrol also induced a decrease in the ratio between phosphorylated BMAL1 and BMAL1. Moreover, compound treatment caused phase advance and reduced the amplitude of BMAL1 , SREBP1 and PGC1Α mRNA oscillations.
On the other hand, the SIRT1 gene phase was delayed and its oscillation amplitude decreased. Together, this study suggested that resveratrol altered the metabolism and circadian rhythm of hepatocytes by mimicking fasting state activation. In another study, free fatty acids FFA were shown to cause circadian misalignment in hepatic HepG2 cells [ 43 ].
FFA down-regulated and attenuated oscillation amplitude of circadian clock-related gene expression, such as BMAL1 , CLOCK , CRY1 , PER1 , PER2 and REVERB-Α.
It also caused phase shift of BMAL1 and CLOCK. Pretreatment with resveratrol µM for 6 h restored these changes. Decreased protein expression levels BMAL1, CLOCK and SIRT1 induced by FFA and their phase shift were also partially reversed by resveratrol.
Besides, FFA reduced phosphorylation of acetyl-CoA carboxylase, AMPK, AKT and insulin receptor substrate 1 IRS It also up-regulated the expression of lipogenesis proteins, inhibited GSK-3 activation, as well as led to the accumulation of triglycerides TG and total cholesterol.
Resveratrol partially or totally prevented all these changes and therefore protected the cells from the negative effects of FFA treatment on lipid and glucose metabolism [ 43 ] Fig. Importantly, all of these resveratrol effects were proven to be BMAL1-dependent using knockdown experiments. Beneficial effects of resveratrol through interaction with the circadian clock in various diseases.
Sun et al. The administration of high fat diet containing resveratrol 0. SIRT1 protein level was down-regulated under high fat diet conditions, which confirmed its role in metabolism disorders and circadian rhythm disruption. Resveratrol increased the rhythmicity of Sirt1 leading to the restoration of circadian expression of lipogenesis and clock-related genes such as Acc1 , Fas , Pparα and Srebp-1c.
The high fat diet also contributed to an impaired rhythmicity of plasma lipids in mice, such as total cholesterol, TG, LDL, and plasma HDL, as well as increased plasma leptin and insulin levels.
Resveratrol restored these changes and improved the respiratory exchange ratio and heat production. Moreover, resveratrol supplementation significantly reduced body weight and improved the fasting blood glucose compared to animals fed only with a high fat diet Fig. However, the activity of the fatty acid synthase was reduced and body weight in resveratrol-treated rats was significantly lower, suggesting that resveratrol could prevent adipogenesis and lipogenesis in high fat diet conditions via Rev-Erbα.
Taken together, resveratrol could restore the negative effects of a fat diet through circadian rhythm improvement and therefore protect against metabolic-related diseases, such as dyslipidemia, dysglycemia and obesity Fig.
Insulin sensitivity is also closely related to circadian rhythm disturbances. mRNA and protein levels of CLOCK and BMAL1 were down-regulated in insulin-resistant primary mouse hepatocytes [ 31 ] and C2C12 myotubes [ 46 ], while ectopic expression of CLOCK and BMAL1 proteins increased insulin sensitivity.
Knockdown experiments confirmed that BMAL1 , CLOCK and SIRT1 played important roles in insulin signaling and circadian variations in insulin sensitivity. SIRT1 ectopic expression significantly reduced insulin resistance in hepatocytes and in muscle cells in which CLOCK and BMAL1 were knocked down.
Similar observations on insulin resistance were made in diabetic mice [ 31 , 46 ]. CLOCK and BMAL1 mRNA and protein levels were decreased in the liver and skeletal muscle of insulin resistant mice, and the ectopic expression of CLOCK and BMAL1 improved hepatic insulin sensitivity [ 31 ].
It was also shown that CLOCK, BMAL1 and SIRT1 were regulators of insulin sensitivity in vivo. In a circadian misalignment model mice kept in the dark for 14 days in which lower SIRT1 activity was observed, SIRT1 overexpression led to improved insulin sensitivity [ 31 ].
It also improved glucose and insulin intolerance. The treatment reverted impaired insulin signaling manifested by a decrease in phosphorylation of insulin receptor, Akt and GSK3β in both cell types. Resveratrol at a lower dose 2.
These studies showed that resveratrol had beneficial effects on insulin resistance by modulating clock components Fig. Reactive oxygen species ROS imbalance causes protein, lipid and DNA damages that can lead to cell dysfunction and even carcinogenesis [ 47 ].
Oxidative stress response is clock dependent, as many of the antioxidant enzymes display circadian variations [ 48 , 49 , 50 ] and BMAL1 plays an important role in their regulation [ 51 ].
Moreover, BMAL1 maintains redox balance [ 52 ], and mitochondrial function [ 53 , 54 ]. In physiological conditions, cellular defense systems are able to maintain redox homeostasis. In primary mice hepatocytes, acrylamide, a toxic compound causing redox imbalance and oxidative damage, disturbed the clock function by decreasing oscillatory amplitudes of Bmal1 and Clock , leading to their phase shift [ 55 ].
It also enhanced Cry1, Cry2 and Per1 amplitude, causing phase shift of Per1 , and decreased mRNA level of PGC-1α and Sirt1. Moreover, it reduced protein levels of BMAL1, CLOCK, CRY1 and SIRT1.
Resveratrol pretreatment 50 µM for 4 h prevented these effects. In HepG2 cells, acrylamide led to a decrease in nuclear factor erythroid 2-related factor 2 Nrf2 expression and its downstream antioxidant protein, NAD P H quinone dehydrogenase 1 NQO1 , which was reversed by resveratrol.
The polyphenol also prevented mitochondrial dysfunction in HepG2 cells manifested as calcium and ATP imbalance, loss of mitochondrial membrane potential and decrease in mitochondrial complex protein levels Fig. Importantly, the effects on the Nrf2 pathway and mitochondrial dysfunction were noticed to be BMAL1-dependent, which was shown in a knockdown model.
Resveratrol also reduced cytotoxicity and prevented morphological changes caused by acrylamide [ 55 ]. Moreover, resveratrol µM partially prevented the increase in intracellular ROS as well as the decrease in mitochondrial membrane potential in HepG2 cells treated by FFA [ 43 ]. Decrease in catalase CAT activity and expression inhibition of respiratory chain complexes I and III were partially restored.
Overall, resveratrol improved the hepatic lipid metabolism and mitochondria dysfunction through restoration of the antioxidant response and elimination of excessive ROS in a clock dependent manner Fig. In the cells, a decrease was observed in mRNA levels of Bmal1, Clock, Per2 , and Rorα , as well as in the level of antioxidant genes, namely Cat , glutathione peroxidase Gpx , glutathione S transferase Gst and superoxide dismutase Sod.
In rats, the same was observed except for an increase in Rorα and the alteration of Sod circadian rhythm with a shift of its peak by 12 h. Dysregulation of the circadian rhythm also occurred at the protein level. Simultaneously, the level of acetylated BMAL1 increased, indicating that SIRT1 deacetylated BMAL1.
It was also noticed that the interaction between BMAL1 and CRY proteins increased. Resveratrol partially prevented the effects of 6-hydroxydopamine with an increase in Cry1 , Per2 and Cat mRNA levels and a decrease in acetylated BMAL1 level.
Moreover, resveratrol reduced the BMAL1 and CRY1 interaction, suggesting it may improve the BMAL1-CLOCK interaction and expression of their target genes. Resveratrol also prevented vacuolization of mitochondria and mitochondrial biogenic dysfunction. The circadian variation of the thiobarbituric acid reactive species TBARS level was shown in different rat organs [ 58 ].
The TBARS level in the heart, liver and kidney was higher in dark span compared to light span. Since rats are nocturnal animals, authors suggested that it could be related to oxidative burst after food intake or changes in the anti- and pro-oxidative activity ratio in the organs.
To investigate the antioxidant properties of resveratrol, the compound was administrated intraperitoneally to rats at different concentrations 0. Four hours after administration, TBARS level was measured.
Resveratrol decreased TBARS level in the heart during the dark span in a dose-dependent manner, but when administrated during the light span, the outcome was opposite — it led to a dose-dependent increase in TBARS.
Similar trends were observed in rat liver and kidney. Taken together, the antioxidant response was closely linked to circadian rhythm regulation. However, the time of resveratrol administration seems to be crucial for achieving the desired antioxidant effect and has to be considered in in vivo studies.
NF-κB pathway activation and pro-inflammatory cytokine expression, which are the causes of several chronic inflammatory diseases, were shown to be partially regulated by CRY proteins [ 59 ]. Acrylamide induced an inflammatory response in HepG2 cells through NF-κB and IκB phosphorylation as well as the expression of the pro-inflammatory cytokines TNF-α, iNOS, and IL-6 [ 55 ].
Pretreatment with resveratrol 50 µM for 4 h prevented these events Fig. However, when Cry1 gene was silenced, the protective effect of resveratrol was not observed. This indicated that resveratrol anti-inflammatory properties was dependent on the circadian rhythm [ 55 ].
Sleep is regulated by the circadian rhythm, and it is an indicator of normal human brain function and health. The biological clock naturally changes with aging. This results in sleep behavior disturbances. Sleep time shifts to earlier hours and is characterized by frequent awakenings and shortening of slow wave sleep SWS [ 60 ].
Growth differentiation factor 11 GDF11 , a cytokine belonging to the TGFß family, was shown to decrease with age and its restoration may bring beneficial effects in age-related diseases [ 61 , 62 ].
Given its effects on circadian rhythm regulations, resveratrol may modulate age-related genes [ 32 ]. When human lung fibroblasts at low passage number 20 were compared to cells at high passage number 60 , a 4 h treatment with resveratrol µM led to an increase in BMAL1 , REV-ERBα and SIRT1 mRNA levels in cells with a low passage number while the levels of GDF11 , NRF2 , PER1 , and SIRT6 were decreased.
In high passage number cells, the effects of resveratrol differed partially — GDF11 , PER1 , and SIRT6 levels increased and SIRT1 expression decreased. The increase in GDF11 induced by resveratrol in old cells may suggest an anti-aging effect.
At the protein level, resveratrol down-regulated glucocorticoid receptor α GRα expression and up-regulated BMAL1 and SIRT1 levels in low passage cells. In high passage fibroblasts, resveratrol did not show any effect on BMAL1 and SIRT1 levels.
Based on these results and a calculated correlation between the genes and proteins, the authors suggested that resveratrol induced BMAL1 protein expression in young and old cells through SIRT6 down-regulation, which is contradictory to most of the studies indicating that this polyphenol rather acts through SIRT1 up-regulation.
There were no changes in body weight or body temperature. The reduced need for sleep induced by resveratrol supplementation in lemurs may be explained by an improved metabolism.
PS, SWS, and their ratio may be indicators of the body metabolic status [ 64 ]. As already mentioned, circadian rhythm and metabolism are strongly linked and therefore an improved metabolism may impact sleep regulation. Another explanation relies on the antioxidant properties of the compound.
It has been suggested that sleep is needed to protect the body against the negative effects of ROS produced during metabolic processes [ 65 ]. Lower brain temperature and slower metabolism during rest allows for a more efficient enzyme renewal. Resveratrol improved redox homeostasis and consequently could lead to lower sleep need.
In summary, results suggested that resveratrol could modulate sleep-wake cycles and as a consequence may influence the circadian rhythm and metabolism regulations. The impact of resveratrol on the circadian rhythm in grey mouse lemurs was also investigated in relation to age [ 66 ]. Subsequently locomotor activity and body temperature were measured to investigate changes in the biological clock of the animals.
After 4 weeks of supplementation, the locomotor activity of old lemurs significantly increased and showed similar values to young individuals Fig.
In both groups, the locomotor activity onset the time between activity onset and the start of the dark phase was reduced, suggesting a better adaptation to light and dark phase changes.
The night body temperature did not change significantly over the 4 weeks. However, the day body temperature increased in both age groups, and was significantly higher in old lemurs compared to young ones during most of the course of the experiment.
Lemurs naturally undergo daily torpor, during which the body temperature decreases and the metabolism slows down allowing them to save energy [ 67 , 68 , 69 ].
Daily hypothermia shortened in both age groups and the minimal temperature increased, suggesting an influence of resveratrol on energy metabolism.
The difference in effect of resveratrol supplementation between young and aged animals may be due to the deregulation of the circadian clock in elderly individuals reduction of the active phase and increase in the rest phase.
Aged animals may therefore benefit more from the effect of resveratrol. There is evidence that circadian clock disturbances contribute to a variety of psychiatric disorders [ 11 ].
Melatonin is a crucial player in circadian rhythm regulation. However, its action can be disturbed by G protein coupled receptor 50 GPR50 , which forms a heterodimer with the melatonin receptor MT1 and prevents melatonin binding [ 70 ].
A certain polymorphism of GPR50 seems to be connected to an elevated risk of bipolar disorder, schizophrenia and major depression in women [ 71 ]. It has been observed that Gpr50 is a target of SIRT1 [ 72 ] and treatment of HEK cells with resveratrol 50 µM for 48 h increased SIRT1 and GPR50 gene expressions, as well as SIRT1 protein expression.
Phospholipase C is an enzyme necessary for the transduction of photoperiodic signals and is activated via melatonin receptors. To investigate the effect of melatonin on phospholipase C activity in brain cells, SH-SY5Y human neuroblastoma cells were differentiated into dopamine neuronal phenotypes and treated with melatonin.
Phospholipase C activity was increased, indicating that the photoperiodic signal was successfully transduced via melatonin receptors. Resveratrol treatment suppressed this effect through SIRT1, which was confirmed in SIRT1 knockdown cells. This suggests that SIRT1 was involved in melatonin signaling, possibly due to GPR50 activation.
In vivo, 4 weeks of a diet supplemented with resveratrol induced an up-regulation of Gpr50 level in the brain of Sprague-Dawley rats Fig.
These findings indicate the potential effect of resveratrol consumption on sleep-wake cycles and brain functioning, and therefore its possible benefit for mental disorder therapies. The circadian clock also regulates key processes involved in cancer development and progession including cell cycle, apoptosis, metabolic regulation and DNA damage response [ 9 ].
To date there are only few publications linking the circadian rhythm, carcinogenesis and resveratrol. Melatonin, besides being a crucial circadian regulator, has also shown to inhibit breast cancer growth, angiogenesis, cancer cell invasion, and telomerase activity [ 73 ]. The treatment reduced the incidence of mammary tumors as well as the number of invasive tumors Fig.
As melatonin production varies with a peak during the night, the authors decided to investigate if a night administration of resveratrol impacted ER-positive breast cancer formation [ 75 ].
Therefore, rats received resveratrol 4 h after the beginning of the dark phase, which is supposed to overlap with Per2 and melatonin peaks. In the group treated with resveratrol, reduced body weight was noticed.
Tumor frequency and incidence, as well as tumor volume were significantly reduced, and the latency period extended compared to animals treated only with a carcinogen. In addition, an increased number of lymphocytes and higher levels of cytokines in the serum IL-1A, IL-1B and IL-2 were observed, which suggests that resveratrol stimulated the immune system.
ROS level was elevated in leukocytes. Resveratrol also improved metabolic parameters that are typical of carcinogenesis, namely hypoproteinemia and elevated urea concentration in the blood. The treatment increased total protein amount and reduced urea level Fig.
These results should encourage further exploration of the relationship between resveratrol anticancer properties and the circadian clock. Despite strong in vitro and in vivo links between circadian clock and resveratrol, only one clinical trial refers to its chronobiology [ 76 ].
The study focused on pharmacokinetics and safety of orally administrated resveratrol in healthy humans. The compound was given in the form of capsules every 4 h for 48 h at different doses 25, 50, and mg.
Resveratrol was well tolerated by the participants with rare to mild adverse effects. Nonetheless, the bioavailability and blood concentration remained low despite relatively high doses and short intervals between them.
Interestingly, diurnal variations in terms of pharmacokinetics were observed — resveratrol concentrations in the blood reached the highest values after morning administration and kept decreasing over the day, with the lowest concentration at night.
The enterohepatic circulation and glucuronidation process, which are regulated by the circadian clock may explain the differences in absorption of the compound depending on the time of administration.
In spite of promising in vitro and in vivo results, certain hurdles need to be overcome before resveratrol can be widely considered in humans. It is important to emphasize that the dose used in the majority of in vitro studies, which is µM [ 32 , 37 , 41 , 43 ], is not physiologically relevant in humans.
The systemic bioavailability of resveratrol is very low and administration of high doses is needed to reach a significant concentration in the blood [ 76 ] due to rapid metabolization in the intestine and the liver [ 77 ].
This leads to difficulties in transition to in vivo studies and shows that the promising impact on various diseases performed in in vitro studies must be treated with caution.
In the context of disease prevention, resveratrol properties are often overestimated when it is taken only from natural sources, since the concentration in food and drinks is very low [ 78 ] and it is estimated not to exceed 50 nM [ 79 ]. The administration of the pure compound at high doses in the form of capsules did not improve significantly the bioavailability [ 76 ].
After oral administration of mg of resveratrol to humans, the mean peak plasma concentration was of only Modifications using micronization [ 80 ], encapsulation or nanoparticles [ 81 ] have been used to overcome this hurdle.
Micronized resveratrol was better absorbed when taken orally compared to the non-modified compound [ 80 ]. In another study, the administration of 5 g of micronized resveratrol resulted in a plasma concentration of 4. Another option could be to change the administration route, e. intravenous, intraperitoneal, or, less invasive, intranasal.
Intranasal administration significantly improved the bioavailability of resveratrol in the lungs when given to mice compared to the oral route, and showed a significant decrease in tumor load in a lung cancer model [ 83 ].
The development of formulations that can be used in humans is also limited by resveratrol low solubility in water and other solvents. Besides bioavailability and solubility, another factor to consider is a time- and dose- dependent activity of resveratrol reported in some studies.
One of them showed that the pro- and antioxidant properties of resveratrol were dependent on day or night administration [ 58 ]. The prooxidant activity of resveratrol was also shown in other studies, suggesting that the dose, cell type and presence of certain metal ions, such as copper, are important factors affecting the treatment outcome [ 84 ].
Resveratrol is currently available as a dietary supplement in many countries, however it is barely used in medicine. Therefore, future work should concentrate on its chronobiology, solubility and delivery to facilitate the transition to research in humans.
Most of the studies implied that resveratrol exerted a positive effect on circadian regulation and pathologies associated with circadian misalignment through SIRT1 up-regulation. Therefore, resveratrol may represent a nutraceutical useful in a wide variety of circadian-related disorders.
Nonetheless, attention should be paid to the need for an improvement in bioavailability and delivery systems. This review will hopefully contribute to a greater awareness of the importance of circadian rhythm and chrononutrition in therapies but also in everyday life, as our lifestyle plays a pivotal role in clock disturbances.
Fagiani F, Di Marino D, Romagnoli A, Travelli C, Voltan D, Mannelli LDC, Racchi M, Govoni S, Lanni C Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther Article CAS PubMed PubMed Central Google Scholar.
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