Abrupt Photoperiod Changes Differentially Modulate Hepatic Antioxidant Response in Healthy and Obese Rats: Effects of Grape Seed Proanthocyanidin Extract (GSPE).

Disruptions of the light/dark cycle and unhealthy diets can promote misalignment of biological rhythms and metabolic alterations, ultimately leading to an oxidative stress condition. Grape seed proanthocyanidin extract (GSPE), which possesses antioxidant properties, has demonstrated its beneficial effects in metabolic-associated diseases and its potential role in modulating circadian disruptions. Therefore, this study aimed to assess the impact of GSPE administration on the liver oxidant system of healthy and diet-induced obese rats undergoing a sudden photoperiod shift. To this end, forty-eight photoperiod-sensitive Fischer 344/IcoCrl rats were fed either a standard (STD) or a cafeteria diet (CAF) for 6 weeks. A week before euthanizing, rats were abruptly transferred from a standard photoperiod of 12 h of light/day (L12) to either a short (6 h light/day, L6) or a long photoperiod (18 h light/day, L18) while receiving a daily oral dose of vehicle (VH) or GSPE (25 mg/kg). Alterations in body weight gain, serum and liver biochemical parameters, antioxidant gene and protein expression, and antioxidant metabolites were observed. Interestingly, GSPE partially ameliorated these effects by reducing the oxidative stress status in L6 through an increase in GPx1 expression and in hepatic antioxidant metabolites and in L18 by increasing the NRF2/KEAP1/ARE pathway, thereby showing potential in the treatment of circadian-related disorders by increasing the hepatic antioxidant response in a photoperiod-dependent manner.

Spent coffee grounds and its antioxidant dietary fiber promote different colonic microbiome signatures: Benefits for subjects with chronodisruption.

Chronodisruption, commonly displayed by people living with obesity (PLO), is linked to colonic microbiota dysbiosis, and may increase the risk of many chronic non-communicable diseases, whereas dietary interventions-called chrononutrition may mitigate it. We evaluated the in vitro effects of spent coffee grounds (SCG), and their antioxidant dietary fiber (SCG-DF) on the colonic microbiota of an obese donor displaying dysbiosis and chronodisruption. Basal microbiota pattern was associated with an increased risk of non-communicable chronic diseases. Both samples decrease species richness and increase microbiota diversity (p < 0.05; Chao and Shannon index, respectively), positively enhancing Firmicutes/Bacteroidetes index (SCG, p < 0.04; SCG-DF, p < 0.02). SCG and SCG-DF modulated the microbiota, but SCG-DF induced greater changes, significantly increasing. p_Actonobacterias (SCG p < 0.04; SCG-DF, p < 0.02), and reducing g_Alistipes; s_putredinis, g_Prevotella;s_copri. The highest increase was displayed by p_Proteobacteria (f_Desulfovibrionaceae and f_Alcanigenaceae, p < 0.05), while g_Haemophilus; s_parainfluenzae decreased (p < 0.05). However, neither SCG nor SCG-DF modulated g_Alistipes (evening-type colonic microbial marker) beneficially. SCG and SCG-DF reduced (p < 0.05) g_Lachnospira, a microbial evening-type marker, among other microbial populations, of an obese donor displaying chronodisruption and dysbiosis. SCG and SCG-DF displayed a prebiotic effect with the potential to mitigate diseases linked to chronodisruption.

Circadian Disruption and Mental Health: The Chronotherapeutic Potential of Microbiome-Based and Dietary Strategies.

Mental illness is alarmingly on the rise, and circadian disruptions linked to a modern lifestyle may largely explain this trend. Impaired circadian rhythms are associated with mental disorders. The evening chronotype, which is linked to circadian misalignment, is a risk factor for severe psychiatric symptoms and psychiatric metabolic comorbidities. Resynchronization of circadian rhythms commonly improves psychiatric symptoms. Furthermore, evidence indicates that preventing circadian misalignment may help reduce the risk of psychiatric disorders and the impact of neuro-immuno-metabolic disturbances in psychiatry. The gut microbiota exhibits diurnal rhythmicity, as largely governed by meal timing, which regulates the host's circadian rhythms. Temporal circadian regulation of feeding has emerged as a promising chronotherapeutic strategy to prevent and/or help with the treatment of mental illnesses, largely through the modulation of gut microbiota. Here, we provide an overview of the link between circadian disruption and mental illness. We summarize the connection between gut microbiota and circadian rhythms, supporting the idea that gut microbiota modulation may aid in preventing circadian misalignment and in the resynchronization of disrupted circadian rhythms. We describe diurnal microbiome rhythmicity and its related factors, highlighting the role of meal timing. Lastly, we emphasize the necessity and rationale for further research to develop effective and safe microbiome and dietary strategies based on chrononutrition to combat mental illness.

Circadian rhythm disruption in critically ill patients.

Patients admitted to the intensive care unit (ICU) are in need of continuous organ replacement strategies and specialized care, for example because of neurological dysfunction, cardio-pulmonary instability, liver or kidney failure, trauma, hemorrhagic or septic shock or even preterm birth. The 24-h nursing and care interventions provided to critically ill patients significantly limit resting and/or recovery phases. Consecutively, the patient's endogenous circadian rhythms are misaligned and disrupted, which in turn may interfere with their critical condition. A more thorough understanding of the complex interactions of circadian effectors and tissue-specific molecular clocks could therefore serve as potential means for enhancing personalized treatment in critically ill patients, conceivably restoring their circadian network and thus accelerating their physical and neurocognitive recovery. This review addresses the overarching issue of how circadian rhythms are affected and disturbed in critically ill newborns and adults in the ICU, and whether the conflicting external or environmental cues in the ICU environment further promote disruption and thus severity of illness. We direct special attention to the influence of cell-type specific molecular clocks on with severity of organ dysfunctions such as severity of brain dysfunction, pneumonia- or ventilator-associated lung inflammation, cardiovascular instability, liver and kidney failure, trauma, and septic shock. Finally, we address the potential of circadian rhythm stabilization to enhance and accelerate clinical recovery.

Maternal melatonin treatment rescues endocrine, inflammatory, and transcriptional deregulation in the adult rat female offspring from gestational chronodisruption.

Introduction: Gestational chronodisruption impact maternal circadian rhythms, inhibiting the nocturnal increase of melatonin, a critical hormone that contributes to maternal changes adaptation, entrains circadian rhythms, and prepares the fetus for birth and successful health in adulthood. In rats, we know that gestational chronodisruption by maternal chronic photoperiod shifting (CPS) impaired maternal melatonin levels and resulted in long-term metabolic and cardiovascular effects in adult male offspring. Here, we investigated the consequences of CPS on mother and adult female offspring and explored the effects of melatonin maternal supplementation. Also, we tested whether maternal melatonin administration during gestational chronodisruption rescues maternal circadian rhythms, pregnancy outcomes, and transcriptional functions in adult female offspring. Methods: Female rats raised and maintained in photoperiod 12:12 light: dark were mated and separated into three groups: (a) Control photoperiod 12:12 (LD); (b) CPS photoperiod; and (c) CPS+Mel mothers supplemented with melatonin in the drinking water throughout gestation. In the mother, we evaluated maternal circadian rhythms by telemetry and pregnancy outcomes, in the long-term, we study adult female offspring by evaluating endocrine and inflammatory markers and the mRNA expression of functional genes involved in adrenal, cardiac, and renal function. Results: In the mothers, CPS disrupted circadian rhythms of locomotor activity, body temperature, and heart rate and increased gestational length by almost 12-h and birth weight by 12%, all of which were rescued by maternal melatonin administration. In the female offspring, we found blunted day/night differences in circulating levels of melatonin and corticosterone, abnormal patterns of pro-inflammatory cytokines Interleukin-1a (IL1a), Interleukin-6 (IL6), and Interleukin-10 (IL10); and differential expression in 18 out of 24 adrenal, cardiac, and renal mRNAs evaluated. Conclusion: Maternal melatonin contributed to maintaining the maternal circadian rhythms in mothers exposed to CPS, and the re-establishing the expression of 60% of the altered mRNAs to control levels in the female offspring. Although we did not analyze the effects on kidney, adrenal, and heart physiology, our results reinforce the idea that altered maternal circadian rhythms, resulting from exposure to light at night, should be a mechanism involved in the programming of Non-Communicable Diseases.

Circadian rhythm and disease: Relationship, new insights, and future perspectives.

The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or chronodisruption has been associated with several diseases, from mental to autoimmune diseases, and with life quality change. Following this, some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. In this manuscript, we describe the circadian-related diseases so far investigated, and studies reporting relevant data on this topic, evidencing this relationship, are included. Despite the actual limitations in published work, there is clear evidence of the correlation between circadian rhythm dysregulation and disease origin/development, and, in this way, clock-related therapies emerge as great progress in the clinical field. Future improvements in such interventions can lead to the development of successful chronotherapy strategies, deeply contributing to enhanced therapeutic outcomes.

Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy.

Age and age-dependent inflammation are two main risk factors for cardiovascular diseases. Aging can also affect clock gene-related impairments such as chronodisruption and has been linked to a decline in melatonin synthesis and aggravation of the NF-κB/NLRP3 innate immune response known as inflammaging. The molecular drivers of these mechanisms remain unknown. This study investigated the impact of aging and NLRP3 expression on the cardiac circadian system, and the actions of melatonin as a potential therapy to restore daily rhythms by mitigating inflammaging. We analyzed the circadian expression and rhythmicity of clock genes in heart tissue of wild-type and NLRP3-knockout mice at 3, 12, and 24 months of age, with and without melatonin treatment. Our results support that aging, NLRP3 inflammasome, and melatonin affected the cardiac clock genes expression, except for Rev-erbα, which was not influenced by genotype. Aging caused small phase changes in Clock, loss of rhythmicity in Per2 and Rorα, and mesor dampening of Clock, Bmal1, and Per2. NLRP3 inflammasome influenced the acrophase of Clock, Per2, and Rorα. Melatonin restored the acrophase and the rhythm of clock genes affected by age or NLRP3 activation. The administration of melatonin re-established murine cardiac homeostasis by reversing age-associated chronodisruption. Altogether, these results highlight new findings about the effects aging and NLRP3 inflammasome have on clock genes in cardiac tissue, pointing to continuous melatonin as a promising therapy to placate inflammaging and restore circadian rhythm in heart muscle. Additionally, light microscopy analysis showed age-related morphological impairments in cardiomyocytes, which were less severe in mice lacking NLRP3. Melatonin supplementation preserved the structure of cardiac muscle fibers in all experimental groups.

Misaligned hormonal rhythmicity: Mechanisms of origin and their clinical significance.

Rhythmic hormonal secretion is key for sustaining health. While a central pacemaker in the hypothalamus is the main driver of circadian periodicity, many hormones oscillate with different frequencies and amplitudes. These rhythms carry information about healthy physiological functions, while at the same time they must be able to respond to external cues and maintain their robustness against severe perturbations. Since endocrine disruptions can lead to hormonal misalignment and disease, understanding the clinical significance of these rhythms can help support diagnosis and disease management. While the misalignment of dynamic hormone profiles can be quantitatively analysed though statistical and computational techniques, mathematical modelling can provide fundamental understanding about the mechanisms underpinning endocrine rhythms, particularly around the question of what makes them robust to some perturbations but fragile to others. In this study, I will review the key challenges of understanding hormonal rhythm misalignment from a mathematical perspective, including their causes and clinical significance. By reviewing modelling examples of coupled endocrine axes, I will address the question of how perturbations in one endocrine axis propagate to another, leading to the more complex issue of disentangling the contribution of each endocrine system to a robust dynamic environment.

Continuous artificial light potentially disrupts central and peripheral reproductive clocks leading to altered uterine physiology and reduced pregnancy success in albino mice.

AIMS: The mechanism behind clock coordination in female reproductive disorders is poorly understood despite the known importance of coordinated and synchronized timing of central and clocks in reproductive organs. We investigated the effect of continuous artificial light (LL) on the central and peripheral reproductive clock gene (Bmal1, Clock, Per1, Per2 and Cry1) and its downstream regulators (Hgf, PR-A and HOXA10) during non-pregnancy and pregnancy phases of female mice. MAIN METHODS: Mice (n = 60) in two sets, were maintained under continuous light (LL) and natural day cycle (LD;12L: 12D) for both non-pregnant and pregnant study. Tissues from hypothalamus-containing SCN, ovary, uterus and serum were collected at different zeitgeber time points (ZT; at 4-h intervals across 24-h periods). KEY FINDINGS: LL exposure desynchronized the expressions of the clock mRNAs (Bmal1, Clock, Per1, Per2 and Cry1) in SCN, ovary, and uterus along with Hgf mRNA rhythm. LL significantly increased the thickness of endometrial tissues. Furthermore, the pregnant study revealed lower serum progesterone level during peri- and post-implantation under LL along with downregulated expression of progesterone receptor (PR) as well as progesterone dependent uterine Homeobox A-10 (Hoxa10) proteins with lowered pregnancy outcomes. SIGNIFICANCE: Our result suggests that LL disrupted the circadian coordination between central and clock genes in reproductive tissue leading to interrupted uterine physiology and altered pregnancy in mice. This led us to propose that duration of light exposure at work-places or home for females is very important in prevention of pregnancy anomalies.

Melatonin stabilizes age-dependent alterations in erythrocyte membrane induced by 'Artificial Light at Night' in a chronodisrupted model of rat.

Growing evidence has shown that Artificial light at night (ALAN) is one of the threatening risk factors which disrupt circadian homeodynamics of cellular processes. The chronobiological role of melatonin seems to represent an important aspect of its contribution to healthy aging. In the present study, we examined the age dependent effect of melatonin on erythrocyte membrane transporters and oxidative stress biomarkers against ALAN to understand the degree of photo-oxidative damage in chronodisrupted rat model. Young (3 months) and old (24 months) male Wistar rats were subdivided in the following four young groups (n = 4) ; (i) control (ii) melatonin (10 mg/kg) (iii) ALAN (500 lx) (iv) ALAN (500 lx) + melatonin (10 mg/kg) and four old groups (n = 4); (v) control (vi) melatonin (10 mg/kg) (vii) ALAN (500 lx) (viii) ALAN (500 lx) + melatonin (10 mg/kg) to the experimental conditions for 10 days. Our findings demonstrated that ALAN significantly enhanced erythrocyte membrane lipid hydroperoxides (LHPs), protein carbonyl (PCO) while reduced total thiol (T-SH), and sialic acid (SA) level with higher amplitude in old ALAN group is restored by exogenous supplementation of melatonin. Activity of membrane transporters, sodium potassium ATPase (NKA) and plasma membrane calcium ion ATPase (PMCA) is significantly reduced meanwhile sodium hydrogen exchanger (NHE) activity is enhanced under the influence of ALAN with higher extent in old groups is effectively ameliorated by melatonin treatment. Further melatonin reduced osmotic fragility of erythrocyte in both young and old rats. It has been concluded from results that ALAN provoked redox insult and disrupt transporters activity more prominently in erythrocyte membrane of aged groups. Exogenous supplementation of melatonin is one of the possible therapeutic approaches to reinforce circadian modulations against ALAN in aged populations.

Age-dependent effect of continuous 'artificial light at night' on circadian rhythm in male rats: neuroprotective role of melatonin.

Circadian disruption due to artificial light at night (ALAN) is an alarming threat to modern society. In the present study we evaluated the protective effect of melatonin on age dependent redox insults and neurochemical deficits induced by ALAN in the brain of chronodisrupted rat model. Young (3 months) and old (22 months) male Wistar rats were exposed to ALAN along with melatonin supplementation (10 mg Kg-1, oral) for 10 days. Results demonstrated significant increment in the pro-oxidant biomarkers: reactive oxygen species, lipid hydroperoxidation, protein carbonyl, nitric oxide while suppression in the total thiol, ferric reducing antioxidant potential level, superoxide dismutase and catalase activities in the brain of ALAN exposed groups with higher amplitude in aged rats. Further these oxidative modifications were protected by subsequent administration of melatonin. Mitochondrial complexes (C-I to C-IV) activity was significantly altered in young and old ALAN exposed groups with melatonin showing protective effect. Histopathological analysis show dense cytosolic staining and neuronal degeneration in cerebral cortex and different hippocampus regions with greater extent in old ALAN rats effectively moderated by melatonin supplementation. RT-PCR data analysis revealed melatonin effectively downregulated neuroinflammatory (IL-6, TNF α) and neurodegenerative marker (Ngb) while upregulating the aging (Sirt 1) gene expression in both young and old melatonin supplemented ALAN exposed groups. Our results may help in understanding the degree of ALAN induced photo-oxidative damage in neuronal redox homeostasis during aging. We also show that melatonin supplementation might provide a basis for amelioration of oxidative disturbances to improve circadian entrainment in aged populations.

Obese Neotomodon alstoni mice exhibit sexual dimorphism in the daily profile of circulating melatonin and clock proteins PER1 and BMAL1 in the hypothalamus and peripheral oscillators.

Obesity is a global health threat and a risk factor for several metabolic conditions. Though circadian dysfunction has been considered among the multiple causes of obesity, little work has been done to explore the relationship between obesity, circadian dysfunction, and sexual dimorphism. The Neotomodon alstoni mouse is a suitable model for such research. This study employed N. alstoni mice in a chronobiological analysis to determine whether there is circadian desynchronization of relative PER1 and BMAL1 protein levels in the hypothalamus, liver, visceral white adipose tissue, kidney, and heart. It also compared differences between sexes and lean and obese N. alstoni adult mice, by recording behavior and daily circulating serum melatonin as markers of circadian output. We found that obese mice display reduced locomotor activity. Additionally, Cosinor analyses of the relative expression of PER1 and BMAL1 show differences between lean and obese mice in a sex-linked manner. The PER1 24 h rhythm was absent in all tissues of obese males and significant in the tissues of obese females. The BMAL1 24 h rhythm also was significant in most of the tissues tested in lean males, whereas it was significant and shifted the acrophase (peak time of rhythm) in most of the tissues in obese females. Both lean male and female mice showed a rhythmic 24 h pattern of circulating serum melatonin. This daily profile was not only absent in obese mice of both sexes but showed sexual dimorphism. Obese male mice showed lower circulating levels of melatonin compared to lean male mice, but they were higher in obese females compared to lean females. Our results suggest that obesity in N. alstoni is associated with an internal circadian desynchronization in a sex-dependent manner. Overall, this study reinforces the need for further research on the neuroendocrinology of obesity and circadian rhythms using this biological model.