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Nutrients Dec 2022The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a... (Review)
Review
The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a significant improvement in our understanding of the pivotal roles of peptide hormones and small proteohormones in the crosstalk between different organs, regulating vitamin D metabolism. The interaction of vitamin D, FGF23 and PTH in the kidney is essential for maintaining mineral homeostasis. The proteohormone FGF23 is mainly secreted from osteoblasts and osteoclasts in the bone. FGF23 acts on proximal renal tubules to decrease production of the active form of vitamin D (1,25(OH)D) by downregulating transcription of 1α-hydroxylase (), and by activating transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase (). Conversely, the peptide hormone PTH stimulates 1,25(OH)D renal production by upregulating the expression of 1α-hydroxylase and downregulating that of 24-hydroxylase. The circulating concentration of 1,25(OH)D is a positive regulator of FGF23 secretion in the bone, and a negative regulator of PTH secretion from the parathyroid gland, forming feedback loops between kidney and bone, and between kidney and parathyroid gland, respectively. In recent years, it has become clear that vitamin D signaling has important functions beyond mineral metabolism. Observation of seasonal variations in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in non-renal tissues such as cardiomyocytes, endothelial and smooth muscle cells, suggested that vitamin D may play a role in maintaining cardiovascular health. Indeed, observational studies in humans have found an association between vitamin D deficiency and hypertension, left ventricular hypertrophy and heart failure, and experimental studies provided strong evidence for a role of vitamin D signaling in the regulation of cardiovascular function. One of the proposed mechanisms of action of vitamin D is that it functions as a negative regulator of the renin-angiotensin-aldosterone system (RAAS). This finding established a novel link between vitamin D and RAAS that was unexplored until then. During recent years, major progress has been made towards a more complete understanding of the mechanisms by which FGF23, PTH, and RAAS regulate vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the interaction between vitamin D, FGF23, PTH, and RAAS, and to discuss the role of these mechanisms in physiology and pathophysiology.
Topics: Humans; Fibroblast Growth Factors; Parathyroid Hormone; Peptide Hormones; Renin-Angiotensin System; Vitamin D; Vitamin D3 24-Hydroxylase; Vitamins
PubMed: 36501215
DOI: 10.3390/nu14235186 -
Endocrine Reviews Jul 2020DNA damage response (DDR) and DNA repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR... (Review)
Review
DNA damage response (DDR) and DNA repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR functioning results in accumulation of unrepaired DNA damage, increased frequency of tumorigenic mutations, and premature aging. Recent evidence suggests that polypeptide hormones play a role in modulating DDR and DNA damage repair, while DNA damage accumulation may also affect hormonal status. We review the available reports elucidating involvement of insulin-like growth factor 1 (IGF1), growth hormone (GH), α-melanocyte stimulating hormone (αMSH), and gonadotropin-releasing hormone (GnRH)/gonadotropins in DDR and DNA repair as well as the current understanding of pathways enabling these actions. We discuss effects of DNA damage pathway mutations, including Fanconi anemia, on endocrine function and consider mechanisms underlying these phenotypes. (Endocrine Reviews 41: 1 - 19, 2020).
Topics: Animals; DNA Damage; DNA Repair; Gonadotropin-Releasing Hormone; Gonadotropins; Growth Hormone; Humans; Insulin-Like Growth Factor I; Peptide Hormones; alpha-MSH
PubMed: 32270196
DOI: 10.1210/endrev/bnaa009 -
Peptides Oct 2015The Human Genome Project provided the opportunity to use bioinformatic approaches to discover novel, endogenous hormones. Using this approach we have identified two... (Review)
Review
The Human Genome Project provided the opportunity to use bioinformatic approaches to discover novel, endogenous hormones. Using this approach we have identified two novel peptide hormones and review here our strategy for the identification and characterization of the hormone, neuronostatin. We describe in this mini-review our strategy for determining neuronostatin's actions in brain, heart and pancreas. More importantly, we detail our deductive reasoning strategy for the identification of a neuronostatin receptor and our progress in establishing the physiological relevance of the peptide.
Topics: Brain; Genome, Human; Humans; Myocardium; Pancreas; Peptide Hormones
PubMed: 26051024
DOI: 10.1016/j.peptides.2015.05.011 -
Methods in Molecular Biology (Clifton,... 2023Many peptide hormones and growth factors in plants, particularly the small posttranslationally modified signaling peptides, are synthesized as larger precursor proteins....
Many peptide hormones and growth factors in plants, particularly the small posttranslationally modified signaling peptides, are synthesized as larger precursor proteins. Proteolytic processing is thus required for peptide maturation, and additional posttranslational modifications may contribute to bioactivity. To what extent these posttranslational modifications impact on processing is largely unknown. Likewise, it is poorly understood how the cleavage sites within peptide precursors are selected by specific processing proteases, and whether or not posttranslational modifications contribute to cleavage site recognition. Here, we describe a mass spectrometry-based approach to address these questions. We developed a method using heavy isotope labeling to directly compare cleavage efficiency of different precursor-derived synthetic peptides by mass spectrometry. Thereby, we can analyze the effect of posttranslational modifications on processing and the specific sequence requirements of the processing proteases. As an example, we describe how this method has been used to assess the relevance of tyrosine sulfation for the processing of the Arabidopsis CIF4 precursor by the subtilase SBT5.4.
Topics: Peptide Hormones; Protein Processing, Post-Translational; Signal Transduction; Arabidopsis; Isotopes; Peptide Hydrolases
PubMed: 36413328
DOI: 10.1007/978-1-0716-2784-6_23 -
Cell Metabolism Apr 2022Asprosin is a fasting-induced glucogenic and centrally acting orexigenic hormone. The olfactory receptor Olfr734 is known to be the hepatic receptor for asprosin that...
Asprosin is a fasting-induced glucogenic and centrally acting orexigenic hormone. The olfactory receptor Olfr734 is known to be the hepatic receptor for asprosin that mediates its effects on glucose production, but the receptor for asprosin's orexigenic function has been unclear. Here, we have identified protein tyrosine phosphatase receptor δ (Ptprd) as the orexigenic receptor for asprosin. Asprosin functions as a high-affinity Ptprd ligand in hypothalamic AgRP neurons, regulating the activity of this circuit in a cell-autonomous manner. Genetic ablation of Ptprd results in a strong loss of appetite, leanness, and an inability to respond to the orexigenic effects of asprosin. Ablation of Ptprd specifically in AgRP neurons causes resistance to diet-induced obesity. Introduction of the soluble Ptprd ligand-binding domain in the circulation of mice suppresses appetite and blood glucose levels by sequestering plasma asprosin. Identification of Ptprd as the orexigenic asprosin receptor creates a new avenue for the development of anti-obesity therapeutics.
Topics: Agouti-Related Protein; Animals; Fibrillin-1; Glucose; Ligands; Mice; Obesity; Peptide Fragments; Peptide Hormones; Receptor-Like Protein Tyrosine Phosphatases, Class 2
PubMed: 35298903
DOI: 10.1016/j.cmet.2022.02.012 -
Proceedings of the Japan Academy.... 2018The identification of hormones and their receptors in multicellular organisms is one of the most exciting research areas and has lead to breakthroughs in understanding... (Review)
Review
The identification of hormones and their receptors in multicellular organisms is one of the most exciting research areas and has lead to breakthroughs in understanding how their growth and development are regulated. In particular, peptide hormones offer advantages as cell-to-cell signals in that they can be synthesized rapidly and have the greatest diversity in their structure and function. Peptides often undergo post-translational modifications and proteolytic processing to generate small oligopeptide hormones. In plants, such small post-translationally modified peptides constitute the largest group of peptide hormones. We initially explored this type of peptide hormone using bioassay-guided fractionation and later by in silico gene screening coupled with biochemical peptide detection, which led to the identification of four types of novel peptide hormones in plants. We also identified specific receptors for these peptides and transferases required for their post-translational modification. This review summarizes how we discovered these peptide hormone-receptor pairs and post-translational modification enzymes, and how these molecules function in plant growth, development and environmental adaptation.
Topics: Cell Communication; Computer Simulation; Enzymes; Peptide Hormones; Plant Development; Plant Proteins; Plants; Protein Processing, Post-Translational; Receptors, Peptide; Signal Transduction
PubMed: 29434080
DOI: 10.2183/pjab.94.006 -
Plant & Cell Physiology Aug 2017Plant genomes encode a variety of short peptides acting as signaling molecules. Since the discovery of tomato systemin, a myriad of peptide signals, ranging in size,... (Review)
Review
Plant genomes encode a variety of short peptides acting as signaling molecules. Since the discovery of tomato systemin, a myriad of peptide signals, ranging in size, structure and modifications, have been found in plants. Moreover, new peptides are still being identified. Surprisingly, non-plant organisms, especially pathogens, also produce peptides which exert hormonal activities against host plants by hijacking their endogenous reception systems. In this review, we focus on short secretory peptides ranging from five to 20 amino acids. We first summarize recent advances in understanding relationships between the bioactivities and structures of plant peptide hormones. Subsequently, we introduce the topic of peptides produced by non-plant organisms. Lastly, we describe artificial peptides synthesized in laboratories, which possess intriguing bioactive properties beyond those of natural peptide hormones.
Topics: Evolution, Molecular; Host-Parasite Interactions; Host-Pathogen Interactions; Peptide Hormones; Plant Growth Regulators; Plant Roots; Plants
PubMed: 28961990
DOI: 10.1093/pcp/pcx069 -
Cellular and Molecular Life Sciences :... Feb 2021Proinsulin C-peptide (C-peptide) has drawn much research attention. Even if the peptide has turned out not to be important in the treatment of diabetes, every phase of...
Proinsulin C-peptide (C-peptide) has drawn much research attention. Even if the peptide has turned out not to be important in the treatment of diabetes, every phase of C-peptide research has changed our view on insulin and peptide hormone biology. The first phase revealed that peptide hormones can be subject to processing, and that their pro-forms may involve regulatory stages. The second phase revealed the possibility that one prohormone could harbor more than one activity, and that the additional activities should be taken into account in the development of hormone-based therapies. In the third phase, a combined view of the evolutionary patterns in hormone biology allowed an assessment of C-peptide´s role in physiology, and of how biological activities and physiological functions are shaped by evolutionary processes. In addition to this distinction, C-peptide research has produced further advances. For example, C-peptide fragments are successfully administered in immunotherapy of type I diabetes, and plasma C-peptide levels remain a standard for measurement of beta cell activity in patients. Even if the concept of C-peptide as a hormone is presently not supported, some of its bioactivities continue to influence our understanding of evolutionary changes of also other peptides.
Topics: C-Peptide; Diabetes Mellitus, Type 1; Evolution, Molecular; Humans; Protein Aggregates; Protein Conformation
PubMed: 32959070
DOI: 10.1007/s00018-020-03636-2 -
Ageing Research Reviews Nov 2023Elabela (ELA), Apela or Toddler peptide is a hormone peptide belonging to the adipokine group and a component of apelinergic system, discovered in 2013-2014. Given its... (Review)
Review
Elabela (ELA), Apela or Toddler peptide is a hormone peptide belonging to the adipokine group and a component of apelinergic system, discovered in 2013-2014. Given its high homology with apelin, the first ligand of APJ receptor, ELA likely mediates similar effects. Increasing evidence shows that ELA has a critical function not only in embryonic development, but also in adulthood, contributing to physiological and pathological conditions, such as the onset of age-related diseases (ARD). However, still little is known about the mechanisms and molecular pathways of ELA, as well as its precise functions in ARD pathophysiology. Here, we report the mechanisms by which ELA/APJ signaling acts in a very complex network of pathways for the maintenance of physiological functions of human tissue and organs, as well as in the onset of some ARD, where it appears to play a central role. Therefore, we describe the possibility to use the ELA/APJ pathway, as novel biomarker (predictive and diagnostic) and target for personalized treatments of ARD. Its potentiality as an optimal peptide candidate for therapeutic ARD treatments is largely described, also detailing potential current limitations.
Topics: Pregnancy; Female; Humans; Peptide Hormones; Apelin Receptors; Signal Transduction; Aging
PubMed: 37776977
DOI: 10.1016/j.arr.2023.102076 -
International Journal of Molecular... Jun 2018Phoenixin is a recently discovered brain peptide initially thought to be restricted to reproductive functions. The subsequent identification of phoenixin’s expression... (Review)
Review
Phoenixin is a recently discovered brain peptide initially thought to be restricted to reproductive functions. The subsequent identification of phoenixin’s expression in peripheral tissues was accompanied by the description of several other actions of this hormone, such as effects on behavior, sensory perception, memory retention, the cardiovascular system as well as food intake, pointing towards a pleiotropic role of this peptide. The present review will discuss the present knowledge on phoenixin and the signaling involved as well as highlight gaps in knowledge to stimulate further research.
Topics: Animals; Brain; Eating; Gastrointestinal Tract; Humans; Memory; Models, Biological; Peptide Hormones
PubMed: 29891773
DOI: 10.3390/ijms19061726