Abstract 13133: Impact of Circadian Rhythm Disorders on Reparative Angiogenesis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kazuhito Tsuzuki ◽  
Yuuki Shimizu ◽  
Zhongyue Pu ◽  
Junya Suzuki ◽  
Shukuro Yamaguchi ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Clock Genes ◽  
Blood Perfusion ◽  
Jet Lag ◽  
Double Knockout ◽  
Tissue Ischemia ◽  
Circadian Rhythm Disorder ◽  
Rhythm Disorder ◽  
Reparative Angiogenesis ◽  
Circadian Rhythm Disorders

Introduction: Circadian rhythm disorder seen in shift-worker or jet-lag is major social health concerns in advanced industrialized countries. The aim of this study was to examine if circadian rhythm disorders would influence on angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia (HLI). Methods and Results: First, we established a jet-lag model in C57BL/6J (wild type; WT) mice (8-10 weeks old, N=10 for each) using a light controlled isolation box. Mice were exposed to advanced 8-hr light phase once every 4 days in a jet-lag group as previously described. Conversely, control mice were kept a regular condition of LD 12:12 (12-hr light and 12-hr dark). Then, we surgically induced HLI in each group. The results showed that the condition jet-lag deteriorated capillary formation detected by CD31-immunohistochemistry at post-operative day (POD) 28 and tissue blood perfusion recovery demonstrated by laser Doppler perfusion imaging (LDPI) in HLI. The expression of clock genes (i.e. Clock, Bmal1, Per2, Cry1 and 2 ) in ischemic muscles were regulated by jet-lag condition at POD7.Next, we examined whether inhibition of clock gene had any effects on angiogenesis. For this study, we focused on Cryptochrome ( Cry ), which is well known as one of the core-loop forming clock genes producing circadian rhythm in mammals. Our loss-of-function study revealed that the abilities of proliferation, migration and tube formation were significantly inhibited by CRY1 and CRY2 double knockdown in HUVECs. Interestingly, although the knockdown of CRY1 and CRY2 changed the mRNA expression of PERIOD2 , it did not affect those of BMAL1 and CLOCK in HUVECs. Finally, we tested if Cry1 and Cry2 double knockout ( Cry1/2 -DKO) mice of HLI models displayed worse blood perfusion recoveries with deterioration of angiogenesis. Cry1/2 -DKO mice were reported to display circadian rhythm disorder in previous reports. As results, compared with control WT mice, Cry1/2 -DKO mice revealed suppressed capillary density and tissue blood perfusion recovery in HLI model. Conclusion: Our data suggest that a maintenance of circadian rhythm plays an important role in reparative angiogenesis of the tissue ischemia model.

scholarly journals Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia

2021 ◽  
Author(s):  
Kazuhito Tsuzuki ◽  
Yuuki Shimizu ◽  
Junya Suzuki ◽  
Zhongyue Pu ◽  
Shukuro Yamaguchi ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Hind Limb ◽  
Umbilical Vein ◽  
Blood Perfusion ◽  
Limb Ischemia ◽  
Jet Lag ◽  
Double Knockout ◽  
Hind Limb Ischemia ◽  
Lag Model ◽  
Reparative Angiogenesis

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet‐lag model was established in C57BL/6J mice using a light‐controlled isolation box. Control mice were kept at a light/dark 12:12 (12‐hour light and 12‐hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet‐lag model ( P <0.05). The jet‐lag condition deteriorated tissue capillary formation ( P <0.001) and tissue blood perfusion recovery ( P <0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock , Bmal1 , and Cry ) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet‐lag condition. Next, Cry1 and Cry2 double‐knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double‐knockout mice revealed suppressed capillary density ( P <0.001) and suppressed tissue blood perfusion recovery ( P <0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5 . This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia‐induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

scholarly journals Gut Microbiota Mediates Oolong Tea Polyphenols Alleviation of Circadian Rhythm Disturbance

2021 ◽  
Author(s):  
Ruonan Yan ◽  
Chi-Tang Ho ◽  
Yanan Liu ◽  
Ruilin Zhang ◽  
Zufang Wu ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Gut Microbiota ◽  
Intestinal Microbiota ◽  
Clock Genes ◽  
Tea Polyphenols ◽  
Continuous Darkness ◽  
Circadian Rhythm Disorder ◽  
Host Health ◽  
Rhythm Disorder ◽  
Circadian Rhythm Disorders

Abstract BackgroundTea polyphenols can be digested in the intestinal tract so as to promote the growth of helpful gut microbiota, and through the production of catechin, tryptophan, acetic acid and other active substances which involved in the modulation of circadian rhythms mechanism to improve the circadian rhythm disorders and neurological weakness, while its specific mechanism is still unclear. The interaction between host circadian rhythm and gut microbes through the gut-brain axis (GBA) provides new clues for tea polyphenols to improve host health. Our present research mainly investigated the metabolites of the gut microbiota and the heterogeneous expression of circadian rhythm genes in the liver and hypothalamic, and then revealed the modulatory role of oolong tea polyphenols (OTP) of circadian rhythm disorder via the GBA. We used 16S rDNA and untargeted metabolomics sequencing techniques to analyze the effects of OTP on intestinal flora diversity and abundance of specific flora in mice with diurnal disorders, and to screen out marker metabolites which may be involved in circadian rhythm regulation. Transcriptomics and 10X single-cell sequencing were used to evaluate the effects of OTP on circadian rhythm genes in liver and hypothalamus and hypothalamus cell types in mice with diurnal disorders. The Y maze and Morris water maze experiments were investigated the effects of OTP on long-term and short-term memory impairment.ResultsBy establishing a circadian rhythm disorder mouse model, our experimental results showed that OTP improved the structural disorder of the intestinal microbiota caused by continuous darkness, especially significantly decreased the ratio of Firmicutes/Bacteroidetes (F/B), thereby modulating the production of metabolites related to pyruvate metabolism, glycolysis/gluconeogenesis, and tryptophan metabolism to alleviate the steady-state imbalance caused by circadian rhythm disorders. In addition, OTP can significantly ameliorate the rhythm oscillation disorder of specific gut microbes and liver clock genes induced by continuous darkness, and made dysrhythmic mice perform well in cognitive behavior tests. Simultaneously, OTP intervention increased the number of rhythmic expression genes in the liver which in the CD group has 156, while in the OTP group has 208. Transplanting fecal microbiota from the OTP group into germ-free mice exhibited that OTP significantly increased the number of hypothalamus cell clusters, up-regulated the number of astrocytes and fibroblasts, and enhanced the expression of circadian rhythm genes Cry2, Per3, Bhlhe41, Nr1d1, Nr1d2, Dbp, and Rorb in hypothalamic cells. ConclusionsOur results confirmed that OTP reduced the F/B ratio, made the daily oscillation of the intestinal microbiota tended to be regular, actively improve the intestinal microecological status, the content of important metabolite closely associated with circadian rhythm such as Tryptophan, Glutamine, 2-indolecarboxylic acid and some others has been significantly increased, the poor expression of clock genes (such as Cry2, Per3, Bhlhe41, Nr1d1, Nr1d2, Dbp and Rorb) in liver and hypothalamus cells has been improved. These results indicated that OTP can significantly improve the metabolic imbalance and cognitive impairment caused by the circadian rhythm disorder, maintain the host's homeostasis, which with potential prebiotic functional characteristics to positively contribute to host health.

Abstract MP141: Role of Cryptochrome in Angiogenesis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Kazuhito Tsuzuki ◽  
Yuuki Shimizu ◽  
Zhongyue Pu ◽  
Jyunya Suzuki ◽  
Toyoaki Murohara
Keyword(s):  
Growth Factors ◽  
Knockout Mice ◽  
Clock Genes ◽  
Umbilical Vein ◽  
Blood Perfusion ◽  
Gene Expressions ◽  
Double Knockout ◽  
Tissue Ischemia ◽  
Peripheral Clock

Background: Although clock genes generate oscillations in about 10 % of all gene expressions as a 24-hour cycle in the cellular level cooperating with the central clock, little is known about the role of clock genes in angiogenesis. Objective: The aim of this study was to determine if a peripheral clock would modulate angiogenesis in a hind limb ischemia (HLI) model. Methods and Results: First, we surgically induced the HLI model in C57BL/6J (wild type; WT) mice (N=6 for each time point) and checked mRNA expressions of clock genes in a local ischemic tissue by PCR array in the setting of blood perfusion recovery. In vitro study, we next investigated those gene expressions in human umbilical vein endothelial cells (HUVECs) with or without stimulation by growth factors. Those data demonstrated that the peripheral clock genes were modulated in ECs and tissues in the presence of growth factors and tissue ischemia. Then, we examined whether inhibition of clock gene expressions had any effects on angiogenesis. For this study, we focused on Cryptochrome (Cry), which is well known as one of the core-loop forming clock genes producing circadian rhythm in mammals. Our loss-of-function study revealed that the abilities of proliferation, migration and tube formation were significantly inhibited by Cry1 and Cry2 double knockdown in HUVECs. Interestingly, although the knockdown of Cry1 and Cry2 changed the mRNA expression of Period2, it did not affect those of BMAL1 and Clock in HUVECs. Finally, we tested if Cry1 and Cry2 double hetero knockout mice of HLI models displayed worse blood perfusion recoveries with deterioration of angiogenesis. As results, compared with control WT mice, Cry1 and Cry2 double knockout mice showed the low capillary density detected by CD31-immunohistochemistry and low tissue blood perfusion demonstrated by laser Doppler perfusion imaging (LDPI) in a HLI. Conclusion: Our data indicated that Cryptochrome as a peripheral clock plays an important role in angiogenesis of the reparative tissue ischemia model.

scholarly journals Study of the modulatory mechanism of the miR-182-Clock axis in circadian rhythm disturbance after hypoxic–ischemic brain damage

2020 ◽  
Vol 18 ◽  
pp. 205873922092915
Author(s):  
Dezhan Li ◽  
Wei Huang ◽  
Fang Yang ◽  
Bin Li ◽  
Shanshan Cai
Keyword(s):  
Circadian Rhythm ◽  
Pineal Gland ◽  
Circadian Clock ◽  
Sleep Disorders ◽  
Clock Genes ◽  
Ischemic Brain ◽  
The Core ◽  
Circadian Rhythm Disorder ◽  
Pineal Function ◽  
Rhythm Disorder

Hypoxic–ischemic encephalopathy (HIE) in neonates can lead to severe chronic neurological deficit, including mental retardation, epilepsy, and sleep–wake cycle (SWC) disorder. Among these defects, little is known about the molecular mechanism of circadian rhythm disorder after HIE. Therefore, further study of sleep problems and its mechanism in HIE children will provide new ideas for clinical treatment of HIE children. For pediatric patients with cerebral ischemia, somnipathy often occurs due to visual and airway abnormalities. From May 2010 to August 2013, 128 newborns with history of HIE were followed up. Meanwhile, 88 normal full-term newborns in the same period were taken as the control group. The clinical data of the patients were collected and the sleep status was assessed by questionnaire. To establish the hypoxic–ischemic brain injury model of neonatal rats and analyze the mechanism of mir-182 in the circadian rhythm disorder caused by pineal function injury. The core clock genes during the regulation of the circadian clock were explored by bioinformatics methods. Patients’ sleep quality was affected by the circadian rhythm and respiratory problems; the pineal gland can regulate the core clock genes in the circadian clock during regulation. miR-182 was highly expressed in the pineal gland after hypoxic–ischemic brain damage (HIBD). Children with mild and moderate HIE showed significant sleep disorders in varying degrees, which provided a clinical basis for improving the long-term prognosis of children with HIE through targeted treatment of sleep disorders. MiR-182 is highly expressed in the pineal gland and is related to the expression of CLOCK protein. CLOCK gene is the target gene of miR-182, which provides a new target for the treatment of rhythm disorder related to the damage of pineal function caused by HIBD.

Challenging Circadian Rhythm Disorder Cases

2019 ◽  
Vol 37 (3) ◽  
pp. 579-599
Author(s):  
Melanie Pogach ◽  
Robert Joseph Thomas
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythm Disorder ◽  
Rhythm Disorder

Omics Analyses of Gut Microbiota in a Circadian Rhythm Disorder Mouse Model Fed with Oolong Tea Polyphenols

2019 ◽  
Vol 67 (32) ◽  
pp. 8847-8854 ◽  
Author(s):  
Tongtong Guo ◽  
Dan Song ◽  
Chi-Tang Ho ◽  
Xin Zhang ◽  
Chundan Zhang ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Tea Polyphenols ◽  
Oolong Tea ◽  
Circadian Rhythm Disorder ◽  
Rhythm Disorder

scholarly journals The Intersection of Cultural Characteristics and Genetics on the Prevalence of Delayed Sleep Phase Syndrome in Brazilian and Japanese Adults

2020 ◽  
Vol 1 (4) ◽  
pp. 1-6
Author(s):  
Abram Estafanous ◽  
Karim Sedky
Keyword(s):  
Circadian Rhythm ◽  
Environmental Changes ◽  
Clock Genes ◽  
Cultural Characteristics ◽  
Sleep Phase ◽  
Delayed Sleep Phase Syndrome ◽  
Japanese Adults ◽  
Delayed Sleep Phase ◽  
Rhythm Disorder ◽  
Delayed Sleep

Delayed sleep phase syndrome (DSPS) is a circadian rhythm disorder where individuals experience difficulty modifying the time they go to sleep and wake up in response to environmental changes. The circadian rhythm itself is regulated by a variety of clock genes, and various other genes (e.g., AA-NAT gene, CKIϵ gene) code for proteins that regulate clock genes. Various polymorphisms of the clock gene influencers have been shown to increase susceptibility to DSPS. This paper seeks to examine how certain cultural characteristics (e.g., napping, timing of meals, exposure to artificial light) and the presence of the AA-NAT gene (G619A polymorphism) and the CKIϵ gene (S408N polymorphism) influence the prevalence of DSPS amongst Japanese and Brazilian populations.

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