Behavioral and Gene Regulatory Responses to Developmental Drug Exposures in Zebrafish

Developmental consequences of prenatal drug exposure have been reported in many human cohorts and animal studies. The long-lasting impact on the offspring—including motor and cognitive impairments, cranial and cardiac anomalies and increased prevalence of ADHD—is a socioeconomic burden worldwide. Identifying the molecular changes leading to developmental consequences could help ameliorate the deficits and limit the impact. In this study, we have used zebrafish, a well-established behavioral and genetic model with conserved drug response and reward pathways, to identify changes in behavior and cellular pathways in response to developmental exposure to amphetamine, nicotine or oxycodone. In the presence of the drug, exposed animals showed altered behavior, consistent with effects seen in mammalian systems, including impaired locomotion and altered habituation to acoustic startle. Differences in responses seen following acute and chronic exposure suggest adaptation to the presence of the drug. Transcriptomic analysis of exposed larvae revealed differential expression of numerous genes and alterations in many pathways, including those related to cell death, immunity and circadian rhythm regulation. Differential expression of circadian rhythm genes did not correlate with behavioral changes in the larvae, however, two of the circadian genes, arntl2 and per2, were also differentially expressed at later stages of development, suggesting a long-lasting impact of developmental exposures on circadian gene expression. The immediate-early genes, egr1, egr4, fosab, and junbb, which are associated with synaptic plasticity, were downregulated by all three drugs and in situ hybridization showed that the expression for all four genes was reduced across all neuroanatomical regions, including brain regions implicated in reward processing, addiction and other psychiatric conditions. We anticipate that these early changes in gene expression in response to drug exposure are likely to contribute to the consequences of prenatal exposure and their discovery might pave the way to therapeutic intervention to ameliorate the long-lasting deficits.

Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases

Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.

Sleep and circadian rhythms in Parkinson’s disease and preclinical models

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson’s disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson’s disease. However, it is important that models accurately encompass important facets of the disease to allow for comprehensive mechanistic understanding and translational significance. Circadian rhythm and sleep issues are tightly correlated to Parkinson’s disease, and often arise prior to the presentation of typical motor deficits. It is essential that models used to understand Parkinson’s disease reflect these dysfunctions in circadian rhythms and sleep, both to facilitate investigations into mechanistic interplay between sleep and disease, and to assist in the development of circadian rhythm-facing therapeutic treatments. This review describes the extent to which various genetically- and neurotoxically-induced murine models of Parkinson’s reflect the sleep and circadian abnormalities of Parkinson’s disease observed in the clinic.

Circadian Regulation Patterns With Distinct Immune Landscapes in Gliomas Aid in the Development of a Risk Model to Predict Prognosis and Therapeutic Response

Circadian disruption in tumorigenesis has been extensively studied, but how circadian rhythm (CR) affects the formation of tumor microenvironment (TME) and the crosstalk between TME and cancer cells is largely unknown, especially in gliomas. Herein, we retrospectively analyzed transcriptome data and clinical parameters of glioma patients from public databases to explore circadian rhythm-controlled tumor heterogeneity and characteristics of TME in gliomas. Firstly, we pioneered the construction of a CR gene set collated from five datasets and review literatures. Unsupervised clustering was used to identify two CR clusters with different CR patterns on the basis of the expression of CR genes. Remarkably, the CR cluster-B was characterized by enriched myeloid cells and activated immune-related pathways. Next, we applied principal component analysis to construct a CRscore to quantify CR patterns of individual tumors, and the function of the CRscore in prognostic prediction was further verified by univariate and multivariate regression analyses in combination with a nomogram. The CRscore could not only be an independent factor to predict prognosis of glioma patients but also guide patients to choose suitable treatment strategies: immunotherapy or chemotherapy. A glioma patient with a high CRscore might respond to immune checkpoint blockade, whereas one with a low CRscore could benefit from chemotherapy. In this study, we revealed that circadian rhythms modulated tumor heterogeneity, TME diversity, and complexity in gliomas. Evaluating the CRscore of an individual tumor would contribute to gaining a greater understanding of the tumor immune status of each patient, enhancing the accuracy of prognostic prediction, and suggesting more effective treatment options.

New uses of Melatonin as a Drug, a Review

Melatonin is a simple compound with a proper chemical name N-acetyl-5-methoxy tryptamine and known as a hormone controlling circadian rhythm. Humans produce melatonin at night which is the reason for sleeping in the night and awakening over the day. Melatonin interacts with melatonin receptors MT1 and MT2 but it was also revealed that melatonin is a strong antioxidant and it also has a role in regulation of cell cycle. Currently, melatonin is used as a drug for some types of sleep disorder but the recent research points to the fact that melatonin can also serve for the other purposes including prophylaxis or therapy of lifestyle diseases, cancer, neurodegenerative disorders and exposure to chemicals. This review summarizes basic facts and direction of the current research on melatonin. The actual literature was scrutinized for the purpose of this review.

The Impact of Heart Rate Circadian Rhythm on In-hospital Mortality in Stroke and Critically Ill Patients: Insights from the eICU Collaborative Research Database

Background: The dysregulation of the heart rate circadian rhythm has been documented to be an independent risk factor in multiple diseases. However, data showing the impact of dysregulated heart rate circadian rhythm in stroke and critically ill patients are scarce.Methods: Stroke and critically ill patients in the ICU between 2014 and 2015 from the recorded eICU Collaborative Research Database were included in the current analyses. The impact of circadian rhythm of heart rate on in-hospital mortality was analyzed. Three variables, Mesor (rhythm-adjusted mean of heart rate), Amplitude (distance from the highest point of circadian rhythm of heart rate to Mesor), and Peak time (time when the circadian rhythm of heart rate reaches the highest point) were used to evaluate the heart rate circadian rhythm. The incremental value of circadian rhythm variables in addition to Acute Physiology and Chronic Health Evaluation (APACHE) IV score to predict in-hospital mortality was also explored.Results: A total of 6,201 eligible patients were included. The in-hospital mortality was 16.2% (1,002/6,201). The circadian rhythm variables of heart rate, Mesor, Amplitude, and Peak time, were identified to be independent risk factors of in-hospital mortality. After adjustments, Mesor per 10 beats per min (bpm) increase was associated with a 1.17-fold (95%CI: 1.11, 1.24, P<0.001) and Amplitude per 5 bpm was associated with a 1.14-fold (95%CI: 1.06, 1.24, P<0.001) increase in the risk of in-hospital mortality, respectively. The risk of in-hospital mortality was lower in patients who had Peak time reached between 18:00-24:00 or 00:00-06:00; whereas the risk was highest in patients who had Peak time reached between 12:00-18:00 (OR: 1.33, 95%CI: 1.05, 1.68, P=0.017). Compared with APACHE IV score only (c-index=0.757), combining APACHE IV score and circadian rhythm variables of heart rate (c-index=0.766) was associated with increased discriminative ability (P=0.003).Conclusion: Circadian rhythm of heart rate is an independent risk factor of the in-hospital mortality in stroke and critically ill patients. Including circadian rhythm variables regarding heart rate might increase the discriminative ability of the risk score to predict the short-term prognosis of patients.