scholarly journals Peripheral clocks and their role in circadian timing: insights from insects

2001 ◽  
Vol 356 (1415) ◽  
pp. 1791-1799 ◽  
Author(s):  
Jadwiga M. Giebultowicz
Keyword(s):  
Feedback Loop ◽  
Clock Genes ◽  
Expression Patterns ◽  
Isolated Organs ◽  
Peripheral Organs ◽  
Peripheral Clocks ◽  
Molecular Components ◽  
The Brain

Impressive advances have been made recently in our understanding of the molecular basis of the cell–autonomous circadian feedback loop; however, much less is known about the overall organization of the circadian systems. How many clocks tick in a multicellular animal, such as an insect, and what are their roles and the relationships between them? Most attempts to locate clock–containing tissues were based on the analysis of behavioural rhythms and identified brain–located timing centres in a variety of animals. Characterization of several essential clock genes and analysis of their expression patterns revealed that molecular components of the clock are active not only in the brain, but also in many peripheral organs of Drosophila and other insects as well as in vertebrates. Subsequent experiments have shown that isolated peripheral organs can maintain self–sustained and light sensitive cycling of clock genes in vitro . This, together with earlier demonstrations that physiological output rhythms persist in isolated organs and tissues, provide strong evidence for the existence of functionally autonomous local circadian clocks in insects and other animals. Circadian systems in complex animals may include many peripheral clocks with tissue–specific functions and a varying degree of autonomy, which seems to be correlated with their sensitivity to external entraining signals.

scholarly journals Effects of Melatonin on Peripheral Reproductive Function: Regulation of Testicular GnIH and Testosterone

Endocrinology ◽  
2011 ◽  
Vol 152 (9) ◽  
pp. 3461-3470 ◽  
Author(s):  
Nicolette L. McGuire ◽  
Kristina Kangas ◽  
George E. Bentley
Keyword(s):  
Expression Patterns ◽  
Reproductive Function ◽  
Melatonin Receptors ◽  
Sex Steroid ◽  
European Starlings ◽  
Steroid Secretion ◽  
Local Inhibition ◽  
Gonadotropin Inhibitory Hormone ◽  
The Brain

Study of seasonal reproduction has focused on the brain. Here, we show that the inhibition of sex steroid secretion can be seasonally mediated at the level of the gonad. We investigate the direct effects of melatonin on sex steroid secretion and gonadal neuropeptide expression in European starlings (Sturnus vulgaris). PCR reveals starling gonads express mRNA for gonadotropin inhibitory hormone (GnIH) and its receptor (GnIHR) and melatonin receptors 1B (Mel 1B) and 1C (Mel 1C). We demonstrate that the gonadal GnIH system is regulated seasonally, possibly via a mechanism involving melatonin. GnIH/ GnIHR expression in the testes is relatively low during breeding compared with outside the breeding season. The expression patterns of Mel 1B and Mel 1C are correlated with this expression, and melatonin up-regulates the expression of GnIH mRNA in starling gonads before breeding. In vitro, GnIH and melatonin significantly decrease testosterone secretion from LH/FSH-stimulated testes before, but not during, breeding. Thus local inhibition of sex steroid secretion appears to be regulated seasonally at the level of the gonad, by a mechanism involving melatonin and the gonadal GnIH system.

scholarly journals The Murine Neuronal Receptor NgR1 Is Dispensable for Reovirus Pathogenesis

2021 ◽  
Author(s):  
Pavithra Aravamudhan ◽  
Camila Guzman-Cardozo ◽  
Kelly Urbanek ◽  
Olivia Welsh ◽  
Jennifer Konopka-Anstadt ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Target Cells ◽  
Viral Attachment ◽  
Genetic Ablation ◽  
Murine Homolog ◽  
Intramuscular Inoculation ◽  
Neural Tissues ◽  
Mammalian Orthoreovirus ◽  
The Brain

Engagement of host receptors is essential for viruses to enter target cells and initiate infection. Expression patterns of receptors in turn dictate host and tissue tropism and disease pathogenesis during infection. Mammalian orthoreovirus (reovirus) displays serotype-dependent patterns of tropism in the murine central nervous system (CNS) that are dictated by viral attachment protein σ1. However, the receptor that mediates reovirus CNS tropism is unknown. Two proteinaceous receptors have been identified for reovirus, junctional adhesion molecule-A (JAM-A) and Nogo 66 receptor 1 (NgR1). Engagement of JAM-A is required for reovirus hematogenous dissemination but is dispensable for neural spread. To determine whether NgR1 functions in reovirus neuropathogenesis, we compared virus replication and disease following inoculation of wild-type (WT) and NgR1-/- mice. Genetic ablation of NgR1 did not alter replication of neurotropic reovirus strain T3SA- in the intestine and transmission to the brain following peroral inoculation. Viral titers in neural tissues following intramuscular inoculation, which provides access to neural dissemination routes, also were comparable in WT and NgR1-/- mice, suggesting that NgR1 is dispensable for reovirus neural spread to the CNS. The absence of both NgR1 and JAM-A also did not alter replication, neural tropism, and virulence of T3SA- following direct intracranial inoculation. In agreement with these findings, we found that the human but not the murine homolog of NgR1 functions as a receptor and confers efficient reovirus binding and infection of nonsusceptible cells in vitro. These results eliminate functions for JAM-A and NgR1 in shaping CNS tropism in mice and suggest that other receptors, yet to be identified, support this function.

scholarly journals Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism

2019 ◽  
Vol 20 (11) ◽  
pp. 2772 ◽  
Author(s):  
Consiglia Pacelli ◽  
Giovannina Rotundo ◽  
Lucia Lecce ◽  
Marta Menga ◽  
Eris Bidollari ◽  
...  
Keyword(s):  
Stem Cells ◽  
Quality Control ◽  
Energy Metabolism ◽  
Clock Genes ◽  
Expression Patterns ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Energy Metabolism ◽  
Tight Connection ◽  
Induced Pluripotent

Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases.

scholarly journals Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1532
Author(s):  
Víctor Fernández-Dueñas ◽  
Mingcheng Qian ◽  
Josep Argerich ◽  
Carolina Amaral ◽  
Martijn D.P. Risseeuw ◽  
...  
Keyword(s):  
Binding Sites ◽  
Metabotropic Glutamate Receptor ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Metabotropic Glutamate ◽  
Animal Disease Models ◽  
Fluorescent Ligands ◽  
The Brain

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter’ systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu5R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu5Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu5R allosteric modulators.

scholarly journals Insights into cadmium-induced carcinogenesis through an in-vitro study using C3H10T1/2Cl8 cells: the multifaceted role of mitochondria

2021 ◽  
Author(s):  
Monica Oldani ◽  
Anna Maria Villa ◽  
Marta Manzoni ◽  
Pasquale Melchioretto ◽  
Paolo Parenti ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Oxidative Phosphorylation ◽  
Cell Transformation ◽  
Expression Patterns ◽  
In Vitro Study ◽  
Atp Synthesis ◽  
Cadmium Treatment

Abstract In this paper we report the metabolic characterization of two foci, F1 and F3, obtained at the end of Cell Transformation Assay (CTA), performed by treating C3H10T1/2Cl8 mouse embryo fibroblasts with 1 µM CdCl2 for 24 h. The elucidation of cadmium action mechanism can be useful both to improve the in vitro CTA and to yield insights into carcinogenesis. We previously showed that, despite being both completely transformed type III foci, F1 and F3 foci display different morphologies, proliferative behaviors and gene expression patterns. In this work, the metabolism of the two foci was investigated through Seahorse and enzyme activity assays; moreover, mitochondria were studied in confocal microscopy and reactive oxygen species were detected by flow cytometry. Results showed that F1 focus has higher glycolytic and TCA fluxes compared to F3 focus, and a more negative mitochondrial membrane potential (Δψ), so that most ATP synthesis is performed through oxidative phosphorylation. Confocal microscopy showed mitochondria crowded in the perinuclear region. On the other hand, F3 focus showed lower metabolic rates, with ATP mainly produced by glycolysis and damaged mitochondria. On the whole, our results showed that cadmium treatment induced lasting metabolic alterations in both foci. Triggered by the loss of Pasteur effect in F1 focus and by mitochondrial impairment in F3 focus, these alterations lead to a loss of coordination among glycolysis, TCA and oxidative phosphorylation, which leads to malignant transformation.

scholarly journals Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1-40) Fibrils

2018 ◽  
Author(s):  
Francesco Tavanti ◽  
Alfonso Pedone ◽  
Maria Cristina Menziani
Keyword(s):  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Structure Stability ◽  
Insoluble Form ◽  
The Brain ◽  
Identification And Characterization ◽  
Insight Into

One of the principal hallmarks of Alzheimer’s disease (AD) is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists either in blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (-)-Epigallocatechin-3-gallate, Quercetin, and Rosmarinic acid) with the amyloid-β(1-40) fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulate the double-layered structure stability.

scholarly journals Cardiomyocyte transcription is controlled by combined mineralocorticoid receptor and circadian clock signalling

2019 ◽  
Vol 241 (1) ◽  
pp. 17-29 ◽  
Author(s):  
Elizabeth K Fletcher ◽  
Monica Kanki ◽  
James Morgan ◽  
David W Ray ◽  
Lea M Delbridge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Mineralocorticoid Receptor ◽  
Expression Patterns ◽  
Potential Interaction ◽  
Gene Promoters ◽  
Peripheral Clocks ◽  
Cortisol Release ◽  
The Brain ◽  
Circadian Transcription

We previously identified a critical pathogenic role for mineralocorticoid receptor (MR) activation in cardiomyocytes that included a potential interaction between the MR and the molecular circadian clock. While glucocorticoid regulation of the circadian clock is undisputed, studies on MR interactions with circadian clock signalling are limited. We hypothesised that the MR influences cardiac circadian clock signalling, and vice versa. Aldosterone or corticosterone (10 nM) regulated Cry1, Per1, Per2 and ReverbA (Nr1d1) gene expression patterns in H9c2 cells over 24 h. MR-dependent regulation of circadian gene promoters containing GREs and E-box sequences was established for CLOCK, Bmal, CRY1 and CRY2, PER1 and PER2 and transcriptional activators CLOCK and Bmal modulated MR-dependent transcription of a subset of these promoters. We also demonstrated differential regulation of MR target gene expression in hearts of mice 4 h after administration of aldosterone at 08:00 h vs 20:00 h. Our data support MR regulation of a subset of circadian genes, with endogenous circadian transcription factors CLOCK and BMAL modulating the response. This unsuspected relationship links MR in the heart to circadian rhythmicity at the molecular level and has important implications for the biology of MR signalling in response to aldosterone as well as cortisol. These data are consistent with MR signalling in the brain where, like the heart, it preferentially responds to cortisol. Given the undisputed requirement for diurnal cortisol release in the entrainment of peripheral clocks, the present study highlights the MR as an important mechanism for transducing the circadian actions of cortisol in addition to glucocorticoid receptor (GR) in the heart.

scholarly journals Antigenic and genetic characterization of a divergent African virus, Ikoma lyssavirus

2014 ◽  
Vol 95 (5) ◽  
pp. 1025-1032 ◽  
Author(s):  
Daniel L. Horton ◽  
Ashley C. Banyard ◽  
Denise A. Marston ◽  
Emma Wise ◽  
David Selden ◽  
...  
Keyword(s):  
Laboratory Mouse ◽  
Rabies Vaccine ◽  
Molecular Techniques ◽  
Phenotypic Characteristics ◽  
Nucleotide Divergence ◽  
The Brain

In 2009, a novel lyssavirus (subsequently named Ikoma lyssavirus, IKOV) was detected in the brain of an African civet (Civettictis civetta) with clinical rabies in the Serengeti National Park of Tanzania. The degree of nucleotide divergence between the genome of IKOV and those of other lyssaviruses predicted antigenic distinction from, and lack of protection provided by, available rabies vaccines. In addition, the index case was considered likely to be an incidental spillover event, and therefore the true reservoir of IKOV remained to be identified. The advent of sensitive molecular techniques has led to a rapid increase in the discovery of novel viruses. Detecting viral sequence alone, however, only allows for prediction of phenotypic characteristics and not their measurement. In the present study we describe the in vitro and in vivo characterization of IKOV, demonstrating that it is (1) pathogenic by peripheral inoculation in an animal model, (2) antigenically distinct from current rabies vaccine strains and (3) poorly neutralized by sera from humans and animals immunized against rabies. In a laboratory mouse model, no protection was elicited by a licensed rabies vaccine. We also investigated the role of bats as reservoirs of IKOV. We found no evidence for infection among 483 individuals of at least 13 bat species sampled across sites in the Serengeti and Southern Kenya.

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