scholarly journals Elevated Circadian Period 2: A Missing Beneficial Factor in Sickle Cell Disease By Lowering Pulmonary Inflammation, Iron Overload and Mortality

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3644-3644
Author(s):  
Morayo Adebiyi ◽  
Zhaoyang Zhao ◽  
Jeanne Manalo ◽  
Cheng Chi Lee ◽  
Wa Xian ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Iron Overload ◽  
Circadian Clock ◽  
Sickle Cell ◽  
Systemic Inflammation ◽  
Iron Metabolism ◽  
Circadian Clocks ◽  
Mouse Lung ◽  
Period 2

Abstract Sickle-cell disase (SCD) is a life-threatening hemolytic genetic disorder. Chronic hemolysis and elevated inflammation that underlie SCD pathophysiology is difficult to treat in the clinic due to an unclear mechanism. The role of the circadian clock is required for maintaining inflammatory states which is important for proper cellular and organ function. Circadian clocks are regulated by a series of circadian clock genes which have known functions in inflammation, heme and iron metabolism. However, the function of circadian clocks in SCD remains unknown. Here, using an unbiased and robust microarray screen, we found that genes involved in circadian rhythms, inflammatory response, heme and iron metabolism were significantly altered in the lungs of SCD Berkeley transgenic mice compared to C57BL/6 (WT) mice used as controls (N=3, P<0.05, normalized to WT). Period 2 (Per2) gene plays a role in regulating the circadian clock. Since the role of Per2 is not known in SCD, we transplanted bone marrow (BM) of SCD and WT mice to Per2Luciferase (Per2Luc) bioluminescence reporter mice to generate SCD → Per2 Luc and WT→ Per2 Luc mice. Per2 circadian rhythms were determined by amplitude and periodicity in ex-vivo derived lung tissue explants. Although the period of the Per2 rhythms remained persistent throughout three circadian cycles, we demonstrated that the amplitude of circadian rhythm of Per2 was significantly upregulated in SCD mouse lung compared to WT mouse lung (N=3 per group, P<0.05). However, Per2 circadian rhythms in SCD mouse livers and kidneys did not show differences in amplitude or period compared to controls (N= 3 per group). To assess the importance of elevated Per1 and Per2 homologue genes in SCD, we transplanted BM of SCD mice to Per1/Per2 double deficient (Per1/Per2 dKO) and WT mice, respectively. To our surprise, Per1/Per2 dKO transplanted with SCD mouse BM (SCD→ Per1/Per2 dKO) displayed severe irradiation sensitivity and were more susceptible to an early death compared to WT BM transplanted mice. Mechanistically, we revealed that peripheral deletion of Per1/Per2 led to increased systemic inflammation featured with an increase of peripheral white blood cells (WBCs) in SCD→ Per1/Per2 dKO mice compared to SCD→ WT mice (50.47 ± 6.74 and 31.68 ± 1.04, respectfully, N=5 mice per group, P<0.01) without an effect on sickling in both groups of SCD chimeric mice. Moreover, we found that peripheral deletion of Per1/Per2 resulted in severe lung damage characterized by elevated congestion, neutrophil infiltration and secretion of IL-6 in lavage fluid in SCD→ Per1/Per2 dKO mouse lung compared to SCD→ WT mouse lung. Additionally, we identified that peripheral deletion of Per1/Per2 induced iron overload, heme deposits and macrophage infiltration in the lung of SCD→Per1/Per2 dKO mice compared to SCD→ WT mice. In conclusion, we discovered that Per2 is induced in SCD mouse lung but not in other organs such as kidney and liver and that its elevation is beneficial to counteract systemic inflammation, reduce pulmonary inflammatory responses, iron overload, tissue damage and thus increase survival in SCD mice. Overall, our studies reveal new molecular insight applicable to two burgeoning fields, circadian biology and SCD which pave a way for innovative therapeutic avenue for SCD. Disclosures D'Alessandro: Omix Technologies inc: Equity Ownership; Hemanext inc: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Interaction between photoperiod and variation in circadian rhythms in tomato

2022 ◽  
Author(s):  
Yanli Xiang ◽  
Thomas Sapir ◽  
Pauline Rouillard ◽  
Marina Ferrand ◽  
Jose M Jimenez-Gomez
Keyword(s):  
Seasonal Variation ◽  
Circadian Rhythms ◽  
Phase Shift ◽  
Circadian Clock ◽  
Environmental Changes ◽  
Circadian Clocks ◽  
Biological Processes ◽  
Near Isogenic Lines ◽  
Transcriptomic Profiling ◽  
Isogenic Lines

Many biological processes follow circadian rhythmicity and are controlled by the circadian clock. Predictable environmental changes such as seasonal variation in photoperiod can modulate circadian rhythms, allowing organisms to adjust to the time of the year. Modification of circadian clocks is especially relevant in crops to enhance their cultivability in specific regions by changing their sensibility to photoperiod. In tomato, the appearance of mutations in EMPFINDLICHER IM DUNKELROTEN LICHT 1 (EID1, Solyc09g075080) and NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED GENE 2 (LNK2, Solyc01g068560) during domestication delayed its circadian rhythms, and allowed its expansion outside its equatorial origin. Here we study how variation in circadian rhythms in tomato affects its perception of photoperiod. To do this, we create near isogenic lines carrying combinations of wild alleles of EID1 and LNK2 and perform transcriptomic profiling under two different photoperiods. We observe that EID1, but not LNK2, has a large effect on the tomato transcriptome and its response to photoperiod. This large effect of EID1 is likely a consequence of the global phase shift elicited by this gene in tomato's circadian rhythms.

scholarly journals Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

2020 ◽  
Author(s):  
Yangbo Xiao ◽  
Ye Yuan ◽  
Mariana Jimenez ◽  
Neeraj Soni ◽  
Swathi Yadlapalli
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Nuclear Envelope ◽  
Circadian Clock ◽  
Clock Genes ◽  
Circadian Clocks ◽  
Spatiotemporal Organization ◽  
Clock Proteins ◽  
Expression Behavior ◽  
Clock Protein

ABSTRACTCircadian clocks regulate ∼24 hour oscillations in gene expression, behavior, and physiology. While the molecular and neural mechanisms of circadian rhythms are well characterized, how cellular organization of clock components controls circadian clock regulation remains poorly understood. Here, we elucidate how clock proteins regulate circadian rhythms by controlling the spatiotemporal organization of clock genes. Using high-resolution live imaging techniques we demonstrate that Drosophila clock proteins are concentrated in a few discrete foci and are organized at the nuclear envelope; these results are in contrast to longstanding expectations that clock proteins are diffusely distributed in the nucleus. We also show that clock protein foci are highly dynamic and change in number, size, and localization over the circadian cycle. Further, we demonstrate that clock genes are positioned at the nuclear periphery by the clock proteins precisely during the circadian repression phase, suggesting that subnuclear localization of clock genes plays an important role in the control of rhythmic gene expression. Finally, we show that Lamin B receptor, a nuclear envelope protein, is required for peripheral localization of clock protein foci and clock genes and for normal circadian rhythms. These results reveal that clock proteins form dynamic nuclear foci and play a hitherto unexpected role in the subnuclear reorganization of clock genes to control circadian rhythms, identifying a novel mechanism of circadian regulation. Our results further suggest a new role for clock protein foci in the clustering of clock-regulated genes during the repression phase to control gene co-regulation and circadian rhythms.SIGNIFICANCEAlmost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate ∼24-hour oscillations in gene expression, behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of clock proteins and clock genes and its critical role in circadian clock function. We show, in contrast to current expectations, that clock proteins are concentrated in a few discrete, dynamic nuclear foci at the nuclear envelope during the repression phase. Further, we uncovered several unexpected features of clock protein foci, including their role in positioning the clock genes at the nuclear envelope precisely during the repression phase to enable circadian rhythms. These studies provide fundamental new insights into the cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian clocks.

scholarly journals Regulation of amyloid-β dynamics and pathology by the circadian clock

2018 ◽  
Vol 215 (4) ◽  
pp. 1059-1068 ◽  
Author(s):  
Geraldine J. Kress ◽  
Fan Liao ◽  
Julie Dimitry ◽  
Michelle R. Cedeno ◽  
Garret A. FitzGerald ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Brain Parenchyma ◽  
Targeted Deletion ◽  
Plaque Deposition ◽  
The Brain ◽  
Core Clock Gene

Nighttime restlessness and daytime drowsiness are common and early symptoms of Alzheimer’s Disease (AD). This symptomology implicates dysfunctional biological timing, yet the role of the circadian system in AD pathogenesis is unknown. To evaluate the role of the circadian clock in amyloid-β (Aβ) dynamics and pathology, we used a mouse model of β-amyloidosis and disrupted circadian clock function either globally or locally in the brain via targeted deletion of the core clock gene Bmal1. Our results demonstrate that loss of central circadian rhythms leads to disruption of daily hippocampal interstitial fluid Aβ oscillations and accelerates amyloid plaque accumulation, whereas loss of peripheral Bmal1 in the brain parenchyma increases expression of Apoe and promotes fibrillar plaque deposition. These results provide evidence that both central circadian rhythms and local clock function influence Aβ dynamics and plaque formation and demonstrate mechanisms by which poor circadian hygiene may directly influence AD pathogenesis.

High Transferrin Saturation Is Associated with Lower Monocytic Ferritin Heavy Chain Expression in Sickle Cell Anemia Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4058-4058
Author(s):  
Kleber Yotsumoto Fertrin ◽  
Carolina Lanaro ◽  
Carla Fernanda Franco-Penteado ◽  
Dulcinéia Martins Albuquerque ◽  
Betania Lucena Hatzlhofer ◽  
...  
Keyword(s):  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Iron Metabolism ◽  
Sickle Cell Anemia ◽  
Transferrin Saturation ◽  
C Reactive Protein ◽  
Iron Storage ◽  
Reactive Protein ◽  
Ferroxidase Activity

Abstract The pathophysiology of sickle cell anemia (SCA) involves hemolysis, vaso-occlusion and a chronic inflammatory state. Iron overload secondary to blood transfusions is a frequent complication in these patients, but cannot be adequately estimated by serum ferritin levels, because ferritin is also an acute phase reactant. Although excess iron elevates both ferritin levels and transferrin saturation (TSAT) in SCA patients, there is notorious discrepancy between these parameters. Ferritin is composed of heavy (FHC) and light chains (FLC), and ferroxidase activity by FHC is an important cytoprotective mechanism against redox-iron, a product of heme breakdown and largely present in overt iron overload. Previous studies have shown that overexpression of FHC in sickle cell mice prevented free hemoglobin-induced vaso-occlusion. Since ferritin is also highly expressed in circulating monocytes, and these cells have been shown to interact with other cellular types in the sickle cell vaso-occlusive process, we aimed to characterize ferritin chains in monocytes and investigate the relationship with biomarkers of iron metabolism, inflammation and hemolysis. Peripheral blood monocytes from sixteen adult sickle cell anemia patients in steady state were isolated using a double Ficoll-Percoll density gradient to separate monocytes from neutrophils and lymphocytes. FHC, FLC, TLR4 (toll-like receptor 4), and SLC40A1(ferroportin) gene expressions were determined by RT-qPCR. Blood samples were also collected to determine serum ferritin, iron, and TSAT, and plasma levels of lactate dehydrogenase, soluble transferrin receptor, erythropoietin, and C reactive protein. We found that the expression of TLR4, a receptor known to be activated by heme, correlated with FLC, but not FHC expression. Higher TLR4 expression was also associated with higher serum iron, but not with ferritin, TSAT, or LDH. Interestingly, we did not find a correlation between C reactive protein levels and ferritin in this group of patients. As expected, the expressions of both ferritin chains were correlated with each other (P=0.027, r=0.55), but we found the strongest correlation between FHC and TSAT (P=0.0008, r=-0.652). Patients with a TSAT over 40% had significantly lower expression of monocytic FTH (P=0.003). This suggests that either excessive iron can lead to FHC downregulation in monocytes, or that a decrease in monocytic ferritin ferroxidase activity in some SCA patients may impair safe iron storage in ferritin and contribute to the development of higher TSAT, independently from ferritin levels. Our data support that human monocyte regulation of ferritin chains in SCA patients mirrors what has been described in hepatic cells in a sickle cell mouse model. Patients with increased TSAT may be relatively deprived of the cytoprotective ferroxidase activity of FHC, and a relationship between FHC deficiency and complications in SCA remains to be investigated. Further studies should also address whether FHC in monocytes influences cell adhesion, thus supporting an important role for iron trafficking in cells involved in sickle cell vaso-occlusion, and corroborating other studies associating organ damage in SCA with iron metabolism dysregulation. Disclosures No relevant conflicts of interest to declare.

scholarly journals The sweet tooth of the circadian clock

2017 ◽  
Vol 45 (4) ◽  
pp. 871-884 ◽  
Author(s):  
Minnie Fu ◽  
Xiaoyong Yang
Keyword(s):  
Circadian Clock ◽  
Metabolic Response ◽  
Circadian Clocks ◽  
Molecular Clocks ◽  
Post Translational Modifications ◽  
The Core ◽  
Input And Output ◽  
Intracellular Proteins ◽  
Translational Mechanisms

The endogenous circadian clock is a key regulator of daily metabolic processes. On the other hand, circadian clocks in a broad range of tissues can be tuned by extrinsic and intrinsic metabolic cues. The bidirectional interaction between circadian clocks and metabolism involves both transcriptional and post-translational mechanisms. Nuclear receptors exemplify the transcriptional programs that couple molecular clocks to metabolism. The post-translational modifications of the core clock machinery are known to play a key role in metabolic entrainment of circadian clocks. O-linked N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is a key mediator of metabolic response to nutrient availability. This review highlights our current understanding of the role of protein O-GlcNAcylation in mediating metabolic input and output of the circadian clock.

Circadian Rhythms, Disease and Chronotherapy

2021 ◽  
pp. 074873042110443
Author(s):  
Yool Lee ◽  
Jeffrey M. Field ◽  
Amita Sehgal
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clocks ◽  
Cellular Mechanisms ◽  
Medical Interventions ◽  
Timing Mechanisms ◽  
Parasite Infections ◽  
Circadian Physiology ◽  
And Behavior ◽  
Internal Body

Circadian clocks are biological timing mechanisms that generate 24-h rhythms of physiology and behavior, exemplified by cycles of sleep/wake, hormone release, and metabolism. The adaptive value of clocks is evident when internal body clocks and daily environmental cycles are mismatched, such as in the case of shift work and jet lag or even mistimed eating, all of which are associated with physiological disruption and disease. Studies with animal and human models have also unraveled an important role of functional circadian clocks in modulating cellular and organismal responses to physiological cues (ex., food intake, exercise), pathological insults (e.g. virus and parasite infections), and medical interventions (e.g. medication). With growing knowledge of the molecular and cellular mechanisms underlying circadian physiology and pathophysiology, it is becoming possible to target circadian rhythms for disease prevention and treatment. In this review, we discuss recent advances in circadian research and the potential for therapeutic applications that take patient circadian rhythms into account in treating disease.

scholarly journals Clock at the Core of Cancer Development

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 150
Author(s):  
Sonal A. Patel ◽  
Roman V. Kondratov
Keyword(s):  
Circadian Clock ◽  
Metabolic Pathway ◽  
Treatment Options ◽  
Circadian Clocks ◽  
Cancer Therapies ◽  
Temporal Regulation ◽  
Evolutionarily Conserved ◽  
Management And Development ◽  
Pharmaceutical Agents

To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in the temporal regulation of behavior, physiology and metabolism. Multiple pathological changes associated with circadian disruption support the importance of the clocks in mammals. Emerging links have revealed interplay between circadian clocks and signaling networks in cancer. Understanding the cross-talk between the circadian clock and tumorigenesis is imperative for its prevention, management and development of effective treatment options. In this review, we summarize the role of the circadian clock in regulation of one important metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, and how dysregulation of this metabolic pathway could lead to uncontrolled cancer cell proliferation and growth. Targeting the circadian clock and rhythms either with recently discovered pharmaceutical agents or through environmental cues is a new direction in cancer chronotherapy. Combining the circadian approach with traditional methods, such as radiation, chemotherapy or the recently developed, immunotherapy, may improve tumor response, while simultaneously minimizing the adverse effects commonly associated with cancer therapies.

scholarly journals Light exposure mediates circadian rhythms of rhizosphere microbial communities

2021 ◽  
Author(s):  
Kankan Zhao ◽  
Bin Ma ◽  
Yan Xu ◽  
Erinne Stirling ◽  
Jianming Xu
Keyword(s):  
Circadian Rhythms ◽  
Microbial Communities ◽  
Light Exposure ◽  
Circadian Clocks ◽  
Ecological Niches ◽  
Host Health ◽  
Regulation Mechanisms ◽  
Role Of Light ◽  
Constant Dark

AbstractMicrobial community circadian rhythms have a broad influence on host health and even though light-induced environmental fluctuations could regulate microbial communities, the contribution of light to the circadian rhythms of rhizosphere microbial communities has received little attention. To address this gap, we monitored diel changes in the microbial communities in rice (Oryza sativa L.) rhizosphere soil under light–dark and constant dark regimes, identifying microbes with circadian rhythms caused by light exposure and microbial circadian clocks, respectively. While rhizosphere microbial communities displayed circadian rhythms under light–dark and constant dark regimes, taxa possessing circadian rhythms under the two conditions were dissimilar. Light exposure concealed microbial circadian clocks as a regulatory driver, leading to fewer ecological niches in light versus dark communities. These findings disentangle regulation mechanisms for circadian rhythms in the rice rhizosphere microbial communities and highlight the role of light-induced regulation of rhizosphere microbial communities.

scholarly journals Circadian rhythm and neurodegenerative disorders

2020 ◽  
Vol 6 (2) ◽  
pp. 71-80
Author(s):  
Michelle Werdann ◽  
Yong Zhang
Keyword(s):  
Circadian Rhythm ◽  
Early Intervention ◽  
Circadian Rhythms ◽  
Neurodegenerative Diseases ◽  
Circadian Clock ◽  
Neurodegenerative Disorders ◽  
Circadian Clocks ◽  
Daily Rhythms ◽  
Animal Physiology ◽  
And Behavior

The circadian clock controls daily rhythms in animal physiology, metabolism, and behavior, such as the sleep‐wake cycle. Disruption of circadian rhythms has been revealed in many diseases including neurodegenerative disorders. Interestingly, patients with many neurodegenerative diseases often show problems with circadian clocks even years before other symptoms develop. Here we review the recent studies identifying the association between circadian rhythms and several major neurodegenerative disorders. Early intervention of circadian rhythms may benefit the treatment of neurodegeneration.

Sign in / Sign up

Export Citation Format

Share Document