scholarly journals Biased Ghrelin Receptor Signaling and the Dopaminergic System as Potential Targets for Metabolic and Psychological Symptoms of Anorexia Nervosa

2021 ◽  
Vol 12 ◽  
Author(s):  
Mariam S. Khelifa ◽  
Louise J. Skov ◽  
Birgitte Holst
Keyword(s):  
Anorexia Nervosa ◽  
Complex Disease ◽  
Dopaminergic System ◽  
Psychological Symptoms ◽  
Ghrelin Receptor ◽  
Promising Target ◽  
Gut Hormone ◽  
Biased Signaling ◽  
The Common ◽  
Intracellular Pathways

Anorexia Nervosa (AN) is a complex disease that impairs the metabolic, mental and physiological health of affected individuals in a severe and sometimes lethal way. Many of the common symptoms in AN patients, such as reduced food intake, anxiety, impaired gut motility or overexercising are connected to both the orexigenic gut hormone ghrelin and the dopaminergic system. Targeting the ghrelin receptor (GhrR) to treat AN seems a promising possibility in current research. However, GhrR signaling is highly complex. First, the GhrR can activate four known intracellular pathways Gαq, Gαi/o, Gα12/13 and the recruitment of β-arrestin. Biased signaling provides the possibility to activate or inhibit only one or a subset of the intracellular pathways of a pleiotropic receptor. This allows specific targeting of physiological functions without adverse effects. Currently little is known on how biased signaling could specifically modulate GhrR effects. Second, GhrR signaling has been shown to be interconnected with the dopaminergic system, particularly in the context of AN symptoms. This review highlights that a biased agonist for the GhrR may be a promising target for the treatment of AN, however extensive and systematic translational studies are still needed and the connection to the dopaminergic system has to be taken into account.

The Complex Signaling Pathways of the Ghrelin Receptor

Endocrinology ◽  
2020 ◽  
Vol 161 (4) ◽  
Author(s):  
Morten Adler Hedegaard ◽  
Birgitte Holst
Keyword(s):  
Signaling Pathways ◽  
Peptide Ligands ◽  
Ghrelin Receptor ◽  
Promising Target ◽  
Biased Signaling ◽  
Future Drug ◽  
Ligand Stimulation ◽  
Treatment Of Obesity ◽  
Complex Signaling ◽  
G Protein Coupled

Abstract The ghrelin receptor (GhrR) is known for its strong orexigenic effects in pharmacological doses and has long been considered as a promising target for the treatment of obesity. Several antagonists have been developed to decrease the orexigenic signaling, but none of these have been approved for the treatment of obesity because of adverse effects and lack of efficacy. Heterodimerization and biased signaling are important concepts for G-protein coupled receptor (GPCR) signaling, and the influence of these aspects on the GhrR may be important for feeding behavior and obesity. GhrR has been described to heterodimerize with other GPCRs, such as the dopamine receptors 1 and 2, leading to a modulation of the signaling properties of both dimerization partners. Another complicating factor of GhrR-mediated signaling is its ability to activate several different signaling pathways on ligand stimulation. Importantly, some ligands have shown to be “biased” or “functionally selective,” implying that the ligand favors a particular signaling pathway. These unique signaling properties could have a sizeable impact on the physiological functions of the GhrR system. Importantly, heterodimerization may explain why the GhrR is expressed in areas of the brain that are difficult for peptide ligands to access. One possibility is that the purpose of GhrR expression is to modulate the function of other receptors in addition to merely being independently activated. We suggest that a deeper understanding of the signaling properties of the GhrR will facilitate future drug discovery in the areas of obesity and weight management.

scholarly journals Translating biased signaling in the ghrelin receptor system into differential in vivo functions

2018 ◽  
Vol 115 (43) ◽  
pp. E10255-E10264 ◽  
Author(s):  
Franziska Mende ◽  
Cecilie Hundahl ◽  
Bianca Plouffe ◽  
Louise Julie Skov ◽  
Bjørn Sivertsen ◽  
...  
Keyword(s):  
Food Intake ◽  
G Protein ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Receptor System ◽  
Physiological Functions ◽  
Ghrelin Receptor ◽  
Gut Hormone ◽  
Biased Signaling

Biased signaling has been suggested as a means of selectively modulating a limited fraction of the signaling pathways for G-protein–coupled receptor family members. Hence, biased ligands may allow modulation of only the desired physiological functions and not elicit undesired effects associated with pharmacological treatments. The ghrelin receptor is a highly sought antiobesity target, since the gut hormone ghrelin in humans has been shown to increase both food intake and fat accumulation. However, it also modulates mood, behavior, growth hormone secretion, and gastric motility. Thus, blocking all pathways of this receptor may give rise to potential side effects. In the present study, we describe a highly promiscuous signaling capacity for the ghrelin receptor. We tested selected ligands for their ability to regulate the various pathways engaged by the receptor. Among those, a biased ligand, YIL781, was found to activate the Gαq/11 and Gα12 pathways selectively without affecting the engagement of β-arrestin or other G proteins. YIL781 was further characterized for its in vivo physiological functions. In combination with the use of mice in which Gαq/11 was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gαq/11, without antagonism at β-arrestin or other G-protein coupling is sufficient to decrease food intake.

scholarly journals Before writing that script: use of antipsychotic medication in patients with dementia in a CMHTOA

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S96-S96
Author(s):  
Adaora Obiekezie ◽  
Roohi Afshan ◽  
Jack Healy
Keyword(s):  
Antipsychotic Medication ◽  
Psychological Symptoms ◽  
Antipsychotic Treatment ◽  
Community Mental Health Team ◽  
Mental Health Team ◽  
Diagnosis Of Dementia ◽  
Independent Review ◽  
The Common ◽  
The Uk ◽  
Current Guidelines

AimsA 2009 independent review commissioned by the UK government to review the use of antipsychotic medication in patients diagnosed with dementia produced the Time for Action report, often referred to as the Banerjee Report. It highlighted the common practise of using antipsychotics in the treatment of Behavioural and Psychological Symptoms of Dementia (BPSD) and the clinical issues this could raise especially when these medications were not being regularly reviewed. The audti was therefore carried out to determine whether patinets with BPSD in a Community Mental Health Team for Older adults (CMHTOA) in Mid Surrey, who had been diagnosed with BPSD, were being adequately assessed and managed in line with the current guidelines.MethodPatients with a diagnosis of dementia open to one of three teams in the CMHTOA during the months of October and November 2019 were identified, those being prescribed antipsychotic medication were selected and data from their electronic records collected and analysed to determine if clinicians: a) identified and documented the target behaviours, b) carried out a structured assessment using an ABC chart before commencing medication, c) reviewed the antipsychotic medication 6 weeks after it was commenced.ResultOf the 87 patients with a diagnosis of Dementia from October to November 2019, 18 were on antipsychotic medication. 100% of these had target behaviours identified and clearly documented, a sixth had a structured assessment prior to starting medication and 61% had been reviewed after the first 6 weeks of starting antipsychotics.ConclusionThe findings showed that a good proprotion of patients did not have the required structured assessment before commencement of treatment and that more needed to be done by way of improving regular reviews after antipsychotic treatment is commenced.

A Haplotype Analysis System for Genes Discovery of Common Diseases

2011 ◽  
pp. 590-604
Author(s):  
Takashi Kido
Keyword(s):  
Haplotype Analysis ◽  
Complex Disease ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Current Theory ◽  
Theory And Practice ◽  
Discovery Research ◽  
Common Diseases ◽  
The Common ◽  
Analysis System

This chapter introduces computational methods for detecting complex disease loci with haplotype analysis. It argues that the haplotype analysis, which plays a major role in the study of population genetics, can be computationally modeled and systematically implemented as a means for detecting causative genes of complex diseases. In this chapter, the author provides a review of issues on haplotype analysis and proposes the analysis system which integrates a comprehensive spectrum of functions on haplotype analysis for supporting disease association studies. The explanation of the system and some real examples of the haplotype analysis will not only provide researchers with better understanding of current theory and practice of genetic association studies, but also present a computational perspective on the gene discovery research for the common diseases.

The Perception of the Common Cold, and other Ailments and Discomforts, as Related to Age

1975 ◽  
Vol 6 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Fred Thumin ◽  
Earl Wims
Keyword(s):  
Common Cold ◽  
Psychological Symptoms ◽  
Stiff Neck ◽  
Perceived Severity ◽  
The Common

Perception of the common cold and other discomforts was studied as a function of age among 456 normals ranging in age from 18 to 82. Respondents completed a questionnaire which dealt with the frequency and duration of their colds, their symptoms and treatments-and, finally, with the perceived severity of various discomforts. Though older Rs were found to suffer more than younger with body aches, the former had less difficulty with a variety of other physical and psychological symptoms-and also contracted relatively few colds. Older Rs treated their colds less often with Contac and Dristan, but more often by staying home and/or calling their doctor. As compared with younger Rs, older respondents perceived intestinal flu to be relatively less serious-but earache, sprained toe, indigestion, having a tooth filled, stiff neck, and hangover to be relatively more serious.

scholarly journals Common Factors Underlying the Five Facets of Mindfulness and Proposed Mechanisms: a Psychometric Study Among Meditators and Non-meditators

Mindfulness ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 2804-2817
Author(s):  
Kathrin Bednar ◽  
Martin Voracek ◽  
Ulrich S. Tran
Keyword(s):  
Structural Equation ◽  
Structural Equation Models ◽  
Psychological Symptoms ◽  
Common Factors ◽  
Five Facet Mindfulness Questionnaire ◽  
Beneficial Effects ◽  
Path Analyses ◽  
The Common ◽  
Meditation Experience ◽  
Mindfulness Facets

Abstract Objectives This study investigated whether common factors underlie the established mindfulness facets, as assessed by the Five Facet Mindfulness Questionnaire (FFMQ) and some of the mechanisms, which have been previously proposed to explain the beneficial effects of mindfulness on mental health. Methods Multigroup exploratory structural equation models (ESEM) were fitted to samples of non-meditators and meditators (total N = 3265) to (1) identify the number of factors that underlie the facets and mechanisms of mindfulness, (2) establish measurement invariance, and (3) conduct path analyses to determine the associations of extracted factors with psychological symptoms. Results Five measurement-invariant common factors were found to underlie the mechanisms and facets of mindfulness. The FFMQ facets loaded distinctly, but none of them highest, on these common factors. The common factors represented different ways of focusing, dealing with distress, and relating towards one’s own thoughts, feelings, emotions, and body sensations. Three of the common factors appeared to specifically reflect meditation experience. The FFMQ facets accounted for less variance of depression, anxiety, somatization, and stress scores than marker scales of the five common factors, all of which derived from the proposed mechanisms. Conclusions The common factors appear to be elements of the supporting mechanisms and psychological faculties of mindfulness. Their existence may explain the mutual interrelations between mechanisms and self-reported mindfulness but also suggests that self-reported mindfulness may not be factorially distinct from its assumed mechanisms. Longitudinal studies as well as behavioral data are needed to probe the generalizability and causality of these psychometric results.

A Haplotype Analysis System for Genes Discovery of Common Diseases

2011 ◽  
pp. 214-230
Author(s):  
Takashi Kido
Keyword(s):  
Haplotype Analysis ◽  
Complex Disease ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Current Theory ◽  
Theory And Practice ◽  
Discovery Research ◽  
Common Diseases ◽  
The Common ◽  
Analysis System

This chapter introduces computational methods for detecting complex disease loci with haplotype analysis. It argues that the haplotype analysis, which plays a major role in the study of population genetics, can be computationally modeled and systematically implemented as a means for detecting causative genes of complex diseases. In this chapter, the author provides a review of issues on haplotype analysis and proposes the analysis system which integrates a comprehensive spectrum of functions on haplotype analysis for supporting disease association studies. The explanation of the system and some real examples of the haplotype analysis will not only provide researchers with better understanding of current theory and practice of genetic association studies, but also present a computational perspective on the gene discovery research for the common diseases.

scholarly journals The Role of gp130 Cytokines in Tuberculosis

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2695
Author(s):  
Kristina Ritter ◽  
Jasmin Rousseau ◽  
Christoph Hölscher
Keyword(s):  
Inflammatory Diseases ◽  
Therapeutic Approaches ◽  
Duration Of Treatment ◽  
Common Receptor ◽  
Promising Target ◽  
Increased Risk ◽  
The Common ◽  
Combine Administration ◽  
Cytokine Networks

Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches.

Ghrelin – hormone with many faces. Central regulation and therapy

2020 ◽  
Author(s):  
Anna Wójcik-Gładysz
Keyword(s):  
Anorexia Nervosa ◽  
The Body ◽  
Energy Status ◽  
Clinical Safety ◽  
Ghrelin Receptor ◽  
Functional Changes ◽  
Amino Acid Peptide ◽  
In Vivo Experiments

Discovered in 1999, ghrelin, is one of the peptides co-creating the hypothalamicgastrointestinal axis, otherwise known as the brain-gut axis. Ghrelin participates in many physiological processes and spectrum of its activity is still being discovered. This 28 amino acid peptide ‒ a product of the ghrl gene, was found in all vertebrates and is synthesized and secreted mainly from enteroendocrine X/A cells located in the gastric mucosa of the stomach. Expression of the ghrelin receptor has been found in many nuclei of the hypothalamus involved in appetite regulation. Therefore it’s presumed that ghrelin is one of the crucial hormones deciphering the energy status required for the maintenance of organism homeostasis. Ghrelin acts as a signal of starvation or energy insufficiency and its level in plasma is reduced after the meal. Neuropeptide Y (NPY) and agouti-related peptide (AgRP; NPY/AgRP) neurons located in the arcuate nucleus (ARC) area are the main target of ghrelin in the hypothalamus. This subpopulation of neurons is indispensable for inducing orexigenic action of ghrelin. Moreover ghrelin acting as a neurohormone, mainly in the hypothalamus area, plays an important role in the regulation of growth and reproduction processes. Indeed, ghrelin action on reproductive processes has been observed in the systemic effects exerted at both hypothalamus-pituitary and gonadal levels. Similarly the GH-releasing ghrelin action was observed both on the hypothalamus level and directly on the somatotrophic cells in the pituitary and this dose-related GH releasing activity was found in in vitro as well as in in vivo experiments. In recent years, numerous studies revealed that ghrelin potentially takes part in the treatment of diseases associated with serious disturbances in the organism energy balance and/or functioning of the gastrointestinal tract. It was underlined that ghrelin may be a hormone with a broad spectrum of therapeutic effect on obesity and anorexia nervosa, as well as may also have protective effect on neurodegenerative diseases, inflammatory disorders or functional changes in the body caused by cancers. In overall, ghrelin treatment has been tested in over 100 preclinical studies with healthy volunteers as well as patients with various types of cancer, eating disorders such as anorexia nervosa and bulimia nervosa. It was observed that ghrelin has an excellent clinical safety profile and emerging side effects occurred only in 3–10% of patients and did not constitute a sufficient premise to discontinue the therapy. In general, it can be concluded that ghrelin may be sufficiently used as a prescription drug.

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