Genome-wide CRISPR Screening Reveals Pyrimidine Metabolic Reprogramming in 5-FU Chronochemotherapy of Colorectal Cancer.

Objective: Disruption of the circadian rhythm is associated with cancer occurrence, response to chemotherapy, and poor prognosis. Thus, using internal clock-based chronotherapy to optimize the administration time may improve the therapeutic effects of anticancer drugs while reducing the side effects. Chronotherapy with 5-fluorouracil (5-FU) has been observed in colorectal cancer (CRC) for a long time, but its effect is under controversial and the mechanism remains unclear.

BMAL1 modulates smooth muscle cells phenotypic switch towards fibroblast-like cells and stabilizes atherosclerotic plaques by upregulating YAP1.

Background: Ischemic heart diseases and ischemic stroke are closely related to circadian clock and unstable atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) can stabilize or destabilize an atherosclerotic lesion through phenotypic switch. BMAL1 is not only an indispensable core component in circadian clock but also an important regulator in atherosclerosis and VSMCs proliferation.

CLOCK regulates Drp1 mRNA stability and mitochondrial homeostasis by interacting with PUF60.

Circadian genes such as Clock, Bmal1, Cryptochrome1/2, and Period1/2/3 constitute the precise circadian system. Clock is a commonly used mouse model harboring a circadian clock gene mutation, which lacks the EXON-19-encoded 51 amino acids. Previous reports have shown that Clock mice have severe metabolic abnormalities.

The circadian clock regulates metabolic responses to physical exercise.

It has been proposed for years that physical exercise ameliorates metabolic diseases. Optimal exercise timing in humans and mammals has indicated that circadian clocks play a vital role in exercise and body metabolism. Skeletal muscle metabolism exhibits a robust circadian rhythm under the control of the suprachiasmatic nucleus of the hypothalamus.

Clock Gene Bmal1 Disruption in Vascular Smooth Muscle Cells Worsens Carotid Atherosclerotic Lesions.

Background: Clock system disruptions are associated with cardiovascular diseases. We previously demonstrated Bmal1 (brain muscle aryl nuclear translocase like-1) expression is significantly attenuated in plaque-derived vascular smooth muscle cells (VSMCs). However, the influence of Bmal1 disruption in VSMCs and its molecular targets are still unclear.

miR-455-5p regulates circadian rhythms by accelerating the degradation of Clock mRNA.

Circadian rhythms are approximately 24-hr cycles generated by organisms to adapt to daily rhythms. Core circadian proteins such as CLOCK, BMAL1, PER1/2, and CRY1/2/3 form a transcription-translation feedback loop (TTFL) to maintain circadian rhythms. MicroRNAs are involved in regulating circadian rhythms; however, the detailed mechanisms remain unclear.

BMAL1 induces colorectal cancer metastasis by stimulating exosome secretion.

Background: To adapt to daily changes in the external environment, organisms have developed circadian rhythm systems with a period of approximately 24 h. Many studies have reported that both circadian rhythms and exosomes play important roles in the development and metastasis of tumors. However, whether circadian clock genes can affect the progression of tumors by regulating exosomes remains unclear.

E2A ablation enhances proportion of nodal-like cardiomyocytes in cardiac-specific differentiation of human embryonic stem cells.

Background: Human sinoatrial cardiomyocytes are essential building blocks for cell therapies of conduction system disorders. However, current differentiation protocols for deriving nodal cardiomyocytes from human pluripotent stem cells (hPSCs) are very inefficient.

Methods: By employing the hPSCs to cardiomyocyte (CM) in vitro differentiation system and generating E2A-knockout hESCs using CRISPR/Cas9 gene editing technology, we analyze the functions of E2A in CM differentiation.

Identification of potential therapeutic targets for atherosclerosis by analysing the gene signature related to different immune cells and immune regulators in atheromatous plaques.

Background: Atherosclerosis is a chronic inflammatory disease that affects multiple arteries. Numerous studies have shown the inherent immune diversity in atheromatous plaques and suggest that the dysfunction of different immune cells plays an important role in atherosclerosis. However, few comprehensive bioinformatics analyses have investigated the potential coordinators that might orchestrate different immune cells to exacerbate atherosclerosis.

BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy.

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans.

Engineering human ventricular heart tissue based on macroporous iron oxide scaffolds.

Myocardial infarction (MI) is a primary cardiovascular disease threatening human health and quality of life worldwide. The development of engineered heart tissues (EHTs) as a transplantable artificial myocardium provides a promising therapy for MI. Since most MIs occur at the ventricle, engineering ventricular-specific myocardium is therefore more desirable for future applications.

Establishment of a PRKAG2 cardiac syndrome disease model and mechanism study using human induced pluripotent stem cells.

PRKAG2 cardiac syndrome is a distinct form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and progressive cardiac conduction disorder. However, it remains unclear how mutations in the PRKAG2 gene give rise to such a complicated disease. To investigate the underlying molecular mechanisms, we generated disease-specific hiPSC-derived cardiomyocytes from two brothers both carrying a heterozygous missense mutation c.

Clock mediates liver senescence by controlling ER stress.

Accumulated evidence indicates that circadian genes regulate cell damage and senescence in most mammals. Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) regulate longevity in many organisms. However, the specific mechanisms of the relationship between the circadian clock and the two stress processes in organisms are poorly understood.

Clock represses preadipocytes adipogenesis via GILZ.

Adiposity is a worldwide health threat that needs to be prevented. Circadian gene Clock (circadian locomotor output cycles kaput) is closely correlated to adiposity; for example, weight gain, adipocytes size expansion, and serum lipid level rise in Clock mice compared to C57BL/6J mice. However, the precise role of Clock during adipogenic differentiation is unknown.

Engineering human ventricular heart muscles based on a highly efficient system for purification of human pluripotent stem cell-derived ventricular cardiomyocytes.

Background: Most infarctions occur in the left anterior descending coronary artery and cause myocardium damage of the left ventricle. Although current pluripotent stem cells (PSCs) and directed cardiac differentiation techniques are able to generate fetal-like human cardiomyocytes, isolation of pure ventricular cardiomyocytes has been challenging. For repairing ventricular damage, we aimed to establish a highly efficient purification system to obtain homogeneous ventricular cardiomyocytes and prepare engineered human ventricular heart muscles in a dish.

Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells.

Background: The clock genes are involved in regulating cardiovascular functions, and their expression disorders would lead to circadian rhythm disruptions of clock-controlled genes (CCGs), resulting in atherosclerotic plaque formation and rupture. Our previous study revealed the rhythmic expression of clock genes were attenuated in human plaque-derived vascular smooth muscle cells (PVSMCs), but failed to detect the downstream CCGs expressions and the underlying molecular mechanism. In this study, we examined the difference of CCGs rhythmic expression between human normal carotid VSMCs (NVSMCs) and PVSMCs.

Upregulation of circadian gene 'hClock' contribution to metastasis of colorectal cancer.

Recent studies have shown that disruption of the circadian rhythm was one of the endogenous factors contributing to tumorigenesis of various human malignancies, including colorectal cancer (CRC). However, the roles of circadian genes in the development of CRC are still unexplored. In this study, we investigated the expression pattern and the underlying mechanism of human Clock gene (hClock) in CRC progression.

hCLOCK induction by hypoxia promotes inflammatory responses by activating the NF‑κB pathway.

The expression and secretion of infla-mmation‑associated cytokines are induced by hypoxia. Circadian locomotor output cycles protein kaput (CLOCK) has previously been shown to activate the nuclear factor‑κB (NF‑κB) pathway, which is a key transcription factor during hypoxia. The present study evaluated the role of the NF‑κB pathway in the CLOCK‑induced inflammatory response.

CLOCK Promotes Endothelial Damage by Inducing Autophagy through Reactive Oxygen Species.

A number of recent studies have implicated that autophagy was activated by reactive oxygen species (ROS). Our previous report indicated that CLOCK increased the accumulation of ROS under hypoxic conditions. In this study, we investigated the mechanisms by which CLOCK mediated endothelial damage, focusing on the involvement of oxidative damage and autophagy.

The Circadian Gene Clock Regulates Bone Formation Via PDIA3.

The expression patterns of clock-controlled genes (ccgs) are regulated by circadian rhythm, which is a major regulatory and physiological mechanism tied to the solar day. Disruptions in circadian rhythm contribute to the development of cardiovascular diseases, cancer, metabolic syndromes, and aging. It has been reported that bone remodeling is also regulated by circadian rhythm.

Role of circadian gene Clock during differentiation of mouse pluripotent stem cells.

Biological rhythms controlled by the circadian clock are absent in embryonic stem cells (ESCs). However, they start to develop during the differentiation of pluripotent ESCs to downstream cells. Conversely, biological rhythms in adult somatic cells disappear when they are reprogrammed into induced pluripotent stem cells (iPSCs).

Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition.

Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice.