scholarly journals Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement

2021 ◽  
Vol 14 (6) ◽  
pp. 496
Author(s):  
Yong Uk Jeong ◽  
Hyo-Eon Jin ◽  
Hye Young Lim ◽  
Goyeong Choi ◽  
Hansol Joo ◽  
...  
Keyword(s):  
Molecular Clock ◽  
Hydrolysis Product ◽  
Biological Processes ◽  
Acid Moiety ◽  
Drug Candidates ◽  
Bioisosteric Replacement ◽  
Acid Type ◽  
Increased Risk ◽  
E Box ◽  
Attractive Therapeutic Target

Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an attractive therapeutic target with novel mechanisms of action. Based on the previous structure–activity relationship study of small molecule cryptochrome (CRY) inhibitors possessing an ethoxypropanoic acid moiety, non-ethoxypropanoic acid-type inhibitors have been developed by bioisosteric replacement. They were evaluated as potent and effective enhancers of E-box-mediated transcription, and, in particular, ester 5d and its hydrolysis product 2d exhibited desirable metabolic and pharmacokinetic profiles as promising drug candidates. Compound 2d directly bound to both CRY1 and 2 in surface plasmon resonance analyses, suggesting that the molecular target is CRY. Effects of compound 5d and 2d on suppressive action of CRY1 on CLOCK:BMAL1-activated E-box-LUC reporter activity revealed that both compounds inhibited the negative feedback actions of CRY on CLOCK:BMAL1. Most importantly, compounds 5d and 2d exhibited significant effects on molecular circadian rhythmicity to be considered circadian clock-enhancers, distinct from the previously developed CRY inhibitors possessing an ethoxypropanoic acid moiety.

Cardiovascular Complications of Sleep Disorders: A Better Night’s Sleep for a Healthier Heart / From Bench to Bedside

2020 ◽  
Vol 19 (2) ◽  
pp. 210-232 ◽  
Author(s):  
Theodora A. Manolis ◽  
Antonis A. Manolis ◽  
Evdoxia J. Apostolopoulos ◽  
Helen Melita ◽  
Antonis S. Manolis
Keyword(s):  
Sleep Disorders ◽  
Disease Risk ◽  
Behavioral Therapy ◽  
Benzodiazepine Receptor ◽  
Cardiovascular Complications ◽  
Gamma Aminobutyric Acid ◽  
Acid Type ◽  
Increased Risk ◽  
Cv Disease ◽  
Meta Analyses

: Sleep is essential to and an integral part of life and when lacking or disrupted, a multitude of mental and physical pathologies ensue, including cardiovascular (CV) disease, which increases health care costs. Several prospective studies and meta-analyses show that insomnia, short (<7h) or long (>9h) sleep and other sleep disorders are associated with an increased risk of hypertension, metabolic syndrome, myocardial infarction, heart failure, arrhythmias, CV disease risk and/or mortality. The mechanisms by which insomnia and other sleep disorders lead to increased CV risk may encompass inflammatory, immunological, neuro-autonomic, endocrinological, genetic and microbiome perturbations. Guidelines are emerging that recommend a target of >7 h of sleep for all adults >18 years for optimal CV health. Treatment of sleep disorders includes cognitive-behavioral therapy considered the mainstay of non-pharmacologic management of chronic insomnia, and drug treatment with benzodiazepine receptor agonists binding to gamma aminobutyric acid type A (benzodiazepine and non-benzodiazepine agents) and some antidepressants. However, observational studies and meta-analyses indicate an increased mortality risk of anxiolytics and hypnotics, although bias may be involved due to confounding and high heterogeneity in these studies. Nevertheless, it seems that the risk incurred by the non-benzodiazepine hypnotic agents (Z drugs) may be relatively less than the risk of anxiolytics, with evidence indicating that at least one of these agents, zolpidem, may even confer a lower risk of mortality in adjusted models. All these issues are herein reviewed.

scholarly journals In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Toxics ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 97
Author(s):  
Tristan Furnary ◽  
Rolando Garcia-Milian ◽  
Zeyan Liew ◽  
Shannon Whirledge ◽  
Vasilis Vasiliou
Keyword(s):  
Autism Spectrum Disorder ◽  
Prenatal Exposure ◽  
Pesticide Exposure ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Biomedical Literature ◽  
Spectrum Disorder ◽  
Biological Processes ◽  
Genetic Associations ◽  
Increased Risk

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

scholarly journals Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro

2021 ◽  
Vol 22 (6) ◽  
pp. 3163
Author(s):  
Hirofumi Ohashi ◽  
Feng Wang ◽  
Frank Stappenbeck ◽  
Kana Tsuchimoto ◽  
Chisa Kobayashi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Cultured Cells ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Membrane Vesicles ◽  
Drug Candidates ◽  
Increased Risk ◽  
Derivatives Of

The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.

scholarly journals Systems medicine links microbial inflammatory response with glycoprotein-associated mortality risk

2015 ◽  
Author(s):  
Scott C Ritchie ◽  
Peter Würtz ◽  
Artika P Nath ◽  
Gad Abraham ◽  
Aki S Havulinna ◽  
...  
Keyword(s):  
Mortality Risk ◽  
Complex Traits ◽  
Integrative Approach ◽  
Low Grade ◽  
Omics Data ◽  
Biological Processes ◽  
Systems Medicine ◽  
Standard Deviation Increase ◽  
Health Records ◽  
Increased Risk

Integrative analyses of high-throughput omics data have elucidated the aetiology and pathogenesis for complex traits and diseases, and the linking of omics information to electronic health records promises new insights into human health and disease. Recent nuclear magnetic resonance (NMR) spectroscopy biomarker profiling has implicated glycoprotein acetyls (GlycA) as a biomarker for cardiovascular risk and all-cause mortality. To elucidate biological processes contributing to GlycA- associated mortality risk, we leveraged human omics data from three population- based cohorts together with nation-wide Finnish hospital and mortality records. Elevated GlycA was associated with myriad infection-related inflammatory processes. Within individuals, elevated GlycA levels were stable over long time periods, up to a decade, and chronically elevated GlycA was also associated with modest elevation of numerous cytokines. Individuals with elevated GlycA also showed increased expression of a transcriptional sub-network, the Neutrophil Degranulation Module (NDM), suggesting an increased activity of microbe-driven immune response. Subsequent analysis of nation-wide hospitalisation and death records was consistent with a microbial basis for GlycA-associated mortality, with each standard deviation increase in GlycA raising an individual's future risk of hospitalization and death from non-localized infection by 40% and 136%, respectively. These results show that, beyond its established role in acute-phase response, elevated GlycA is more broadly a biomarker for low-grade chronic inflammation and increased neutrophil activity. Further, increased risk of susceptibility to severe microbial-infection events in healthy individuals suggests this inflammation is a contributor to mortality risk. Taken together, this study demonstrates the power of an integrative approach that combines omics data and health records to delineate the biological processes underlying a newly discovered biomarker, providing a model strategy for future systems medicine studies.

scholarly journals MYC-associated factor MAX is an essential regulator of the clock core network

2019 ◽  
Author(s):  
Olga Blaževitš ◽  
Nityanand Bolshette ◽  
Donatella Vecchio ◽  
Ana Guijarro ◽  
Ottavio Croci ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Clock ◽  
Circadian Regulation ◽  
Factor X ◽  
Core Network ◽  
Associated Factor ◽  
Rhythmic Expression ◽  
The Core ◽  
E Box

SummaryThe circadian transcriptional network is based on a competition between transcriptional activator and repressor complexes regulating the rhythmic expression of clock-controlled genes. We show here that the MYC-Associated factor X, MAX, plays a repressive role in this network and operates through its MYC-independent binding to E-box-containing regulatory regions within the promoters of circadian BMAL1 targets. This clock function of MAX is essential for maintaining a proper circadian rhythm but separated by the role of MAX as a partner of MYC in controlling cell proliferation. We also identified MAX Network Transcriptional repressor, MNT, as a fundamental partner of MAX-mediated circadian regulation. Collectively, our data indicate that MAX is an integral part of the core molecular clock and keeps the balance between positive and negative elements of the molecular clock machinery. Accordingly, alteration of MAX transcriptional complexes may contribute to circadian dysfunction in pathological contexts.

scholarly journals Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy

2021 ◽  
Author(s):  
Christopher Hatton ◽  
Simona S. Ghanem ◽  
David Koss ◽  
Ilham Yahya Abdi ◽  
Elizabeth Gibbons ◽  
...  
Keyword(s):  
Lewy Body ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Krabbe Disease ◽  
Biological Processes ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Galc Gene ◽  
The Brain ◽  
Lewy Body Diseases

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to α-synuclein localisation and expression of modifications associated with LBD. To determine whether α-synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of α-synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

scholarly journals MYOD1 functions as a clock amplifier as well as a critical co-factor for downstream circadian gene expression in muscle

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Brian A Hodge ◽  
Xiping Zhang ◽  
Miguel A Gutierrez-Monreal ◽  
Yi Cao ◽  
David W Hammers ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Clock ◽  
Bimolecular Fluorescence Complementation ◽  
Regulatory Factor ◽  
Circadian Gene ◽  
Myogenic Regulatory Factor ◽  
E Box ◽  
Positive Modulator ◽  
Positive Core ◽  
Synergistic Regulation

In the present study we show that the master myogenic regulatory factor, MYOD1, is a positive modulator of molecular clock amplitude and functions with the core clock factors for expression of clock-controlled genes in skeletal muscle. We demonstrate that MYOD1 directly regulates the expression and circadian amplitude of the positive core clock factor Bmal1. We identify a non-canonical E-box element in Bmal1 and demonstrate that is required for full MYOD1-responsiveness. Bimolecular fluorescence complementation assays demonstrate that MYOD1 colocalizes with both BMAL1 and CLOCK throughout myonuclei. We demonstrate that MYOD1 and BMAL1:CLOCK work in a synergistic fashion through a tandem E-box to regulate the expression and amplitude of the muscle specific clock-controlled gene, Titin-cap (Tcap). In conclusion, these findings reveal mechanistic roles for the muscle specific transcription factor MYOD1 in the regulation of molecular clock amplitude as well as synergistic regulation of clock-controlled genes in skeletal muscle.

scholarly journals How can the study of biological processes help design new interventions for children with severe antisocial behavior?

2008 ◽  
Vol 20 (3) ◽  
pp. 941-973 ◽  
Author(s):  
Stephanie H. M. van Goozen ◽  
Graeme Fairchild
Keyword(s):  
Clinical Practice ◽  
Antisocial Behavior ◽  
Behavioral Problems ◽  
Social Factors ◽  
Behavioral Outcomes ◽  
Childhood Adversity ◽  
Genetic Influences ◽  
Biological Processes ◽  
Childhood Onset ◽  
Increased Risk

AbstractChildren with severe antisocial behavior have an increased risk of showing violently aggressive and other forms of problem behavior in adolescence and adulthood. It is well established that both biological and social factors are involved in the development of antisocial behavior. The primary aim of this paper is to discuss the evidence that specific neurobiological systems are involved in the etiology of childhood-onset antisocial behavior. These factors are responsible for the severity of the behavioral problems observed in antisocial children, but they also play a role in their persistence, because they influence children's interactions with their environment. We will discuss the possible causes of disruptions in neurobiological systems in childhood antisocial behavior and point out the implications of these findings for theory and clinical practice. We will argue that familial factors (e.g., genetic influences, early childhood adversity) are linked to negative behavioral outcomes (e.g., antisocial behavior problems) through the mediating and transactional interplay with neurobiological deficits. An investigation of neurobiological functioning in antisocial children might not only indicate which children are most likely to persist in engaging in severe antisocial behavior, but also guide the development of new interventions.

scholarly journals Circadian Biology in Obstructive Sleep Apnea

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1082
Author(s):  
Bala S. C. Koritala ◽  
Zachary Conroy ◽  
David F. Smith
Keyword(s):  
Blood Pressure ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Molecular Clock ◽  
Cognitive Outcomes ◽  
Biological Processes ◽  
Complex Process ◽  
Obstructive Sleep ◽  
Clinical Tools ◽  
Circadian Biology

Obstructive sleep apnea (OSA) is a complex process that can lead to the dysregulation of the molecular clock, as well as 24 h rhythms of sleep and wake, blood pressure, and other associated biological processes. Previous work has demonstrated crosstalk between the circadian clock and hypoxia-responsive pathways. However, even in the absence of OSA, disrupted clocks can exacerbate OSA-associated outcomes (e.g., cardiovascular or cognitive outcomes). As we expand our understanding of circadian biology in the setting of OSA, this information could play a significant role in the diagnosis and treatment of OSA. Here, we summarize the pre-existing knowledge of circadian biology in patients with OSA and examine the utility of circadian biomarkers as alternative clinical tools.

scholarly journals Phosphoproteomic Landscape of AML Cells Treated with the ATP-Competitive CK2 Inhibitor CX-4945

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 338
Author(s):  
Mauro Rosales ◽  
Arielis Rodríguez-Ulloa ◽  
Vladimir Besada ◽  
Ailyn C. Ramón ◽  
George V. Pérez ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Protein Kinase Ck2 ◽  
Functional Enrichment ◽  
Biological Processes ◽  
Attractive Therapeutic Target ◽  
Kinase Ck2 ◽  
The Impact ◽  
Ck2 Inhibitor ◽  
Target Effects

Casein kinase 2 (CK2) regulates a plethora of proteins with pivotal roles in solid and hematological neoplasia. Particularly, in acute myeloid leukemia (AML) CK2 has been pointed as an attractive therapeutic target and prognostic marker. Here, we explored the impact of CK2 inhibition over the phosphoproteome of two cell lines representing major AML subtypes. Quantitative phosphoproteomic analysis was conducted to evaluate changes in phosphorylation levels after incubation with the ATP-competitive CK2 inhibitor CX-4945. Functional enrichment, network analysis, and database mining were performed to identify biological processes, signaling pathways, and CK2 substrates that are responsive to CX-4945. A total of 273 and 1310 phosphopeptides were found differentially modulated in HL-60 and OCI-AML3 cells, respectively. Despite regulated phosphopeptides belong to proteins involved in multiple biological processes and signaling pathways, most of these perturbations can be explain by direct CK2 inhibition rather than off-target effects. Furthermore, CK2 substrates regulated by CX-4945 are mainly related to mRNA processing, translation, DNA repair, and cell cycle. Overall, we evidenced that CK2 inhibitor CX-4945 impinge on mediators of signaling pathways and biological processes essential for primary AML cells survival and chemosensitivity, reinforcing the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy.

Sign in / Sign up

Export Citation Format

Share Document