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Nature Communications Feb 2022The intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal...
The intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal information to other organs to coordinate systemic energy balance. However, the gut-derived hormones affecting metabolic and behavioral responses are poorly defined. Here we show that the endocrine cells of the Drosophila gut sense nutrient stress through a mechanism that involves the TOR pathway and in response secrete the peptide hormone allatostatin C, a Drosophila somatostatin homolog. Gut-derived allatostatin C induces secretion of glucagon-like adipokinetic hormone to coordinate food intake and energy mobilization. Loss of gut Allatostatin C or its receptor in the adipokinetic-hormone-producing cells impairs lipid and sugar mobilization during fasting, leading to hypoglycemia. Our findings illustrate a nutrient-responsive endocrine mechanism that maintains energy homeostasis under nutrient-stress conditions, a function that is essential to health and whose failure can lead to metabolic disorders.
Topics: Animals; Animals, Genetically Modified; Drosophila Proteins; Drosophila melanogaster; Eating; Energy Metabolism; Enteroendocrine Cells; Gastrointestinal Hormones; Gene Knockout Techniques; Homeostasis; Humans; Hypoglycemia; Insect Hormones; Nutrients; Oligopeptides; Pyrrolidonecarboxylic Acid; Receptors, G-Protein-Coupled; Signal Transduction; Somatostatin; Survival Analysis
PubMed: 35121731
DOI: 10.1038/s41467-022-28268-x -
International Journal of Molecular... Apr 2024Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving...
Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01's properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use.
Topics: Humans; Rats; Animals; Mice; Analgesics, Opioid; Ligands; Receptors, Opioid; Morphine; Opioid Peptides; Pain; Oligopeptides; Pyrrolidonecarboxylic Acid
PubMed: 38612817
DOI: 10.3390/ijms25074007 -
Molecules (Basel, Switzerland) Oct 2022The importance of insects in our ecosystems is undeniable. The indiscriminate use of broad-spectrum insecticides is a factor in the decline in insect biomass. We...
The importance of insects in our ecosystems is undeniable. The indiscriminate use of broad-spectrum insecticides is a factor in the decline in insect biomass. We identify and sequence a prominent neuropeptide hormone in insects with an overarching goal to elucidate relatedness and create a database of bioactive peptides that could inform possible cross-activity in biological assays for the identification of a biorational lead compound. The major task of an adipokinetic hormone (AKH) in an insect is the regulation of metabolic events, such as carbohydrate and lipid breakdown in storage tissue during intense muscular work. From genomic and/or transcriptomic information one may predict the genes encoding neuropeptides such as the AKHs of insects. Definite elucidation of the primary structure of the mature peptide with putative post-translational modifications needs analytical chemical methods. Here we use high-resolution mass spectrometry coupled with liquid chromatography to identify unequivocally the AKHs of five insect species (one cockroach, two moths, and two flies) of which either genomic/transcriptomic information was available or sequences from related species. We confirm predicted sequences and discover novel AKH sequences, including one with a post-translational hydroxyproline modification. The additional sequences affirm an evolutionary pattern of dipteran AKHs and a conserved pattern in crambid moths.
Topics: Amino Acid Sequence; Animals; Carbohydrates; Ecosystem; Hydroxyproline; Insect Hormones; Insecta; Insecticides; Lipids; Mass Spectrometry; Moths; Neuropeptides; Oligopeptides; Peptides; Pyrrolidonecarboxylic Acid
PubMed: 36235010
DOI: 10.3390/molecules27196469 -
Scientific Reports Jun 2015Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic...
Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and energy mobilization are regulated by the glucagon-related adipokinetic hormone (AKH) and the Drosophila insulin-like peptides (DILPs). Here, we provide evidence that the Drosophila neuropeptide Allatostatin A (AstA) regulates AKH and DILP signaling. The AstA receptor gene, Dar-2, is expressed in both the insulin and AKH producing cells. Silencing of Dar-2 in these cells results in changes in gene expression and physiology associated with reduced DILP and AKH signaling and animals lacking AstA accumulate high lipid levels. This suggests that AstA is regulating the balance between DILP and AKH, believed to be important for the maintenance of nutrient homeostasis in response to changing ratios of dietary sugar and protein. Furthermore, AstA and Dar-2 are regulated differentially by dietary carbohydrates and protein and AstA-neuronal activity modulates feeding choices between these types of nutrients. Our results suggest that AstA is involved in assigning value to these nutrients to coordinate metabolic and feeding decisions, responses that are important to balance food intake according to metabolic needs.
Topics: Animals; Drosophila; Drosophila Proteins; Eating; Energy Metabolism; Female; Insect Hormones; Lipid Metabolism; Male; Neurons; Neuropeptides; Oligopeptides; Pyrrolidonecarboxylic Acid; RNA Interference; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptors, Neuropeptide; Signal Transduction; RNA, Guide, CRISPR-Cas Systems
PubMed: 26123697
DOI: 10.1038/srep11680 -
Scientific Reports Jun 2016Gonadotropin-releasing hormone (GnRH) is a key regulator of reproductive maturation in humans and other vertebrates. Homologs of GnRH and its cognate receptor have been...
Gonadotropin-releasing hormone (GnRH) is a key regulator of reproductive maturation in humans and other vertebrates. Homologs of GnRH and its cognate receptor have been identified in invertebrates-for example, the adipokinetic hormone (AKH) and corazonin (CRZ) neuropeptide pathways in arthropods. However, the precise evolutionary relationships and origins of these signalling systems remain unknown. Here we have addressed this issue with the first identification of both GnRH-type and CRZ-type signalling systems in a deuterostome-the echinoderm (starfish) Asterias rubens. We have identified a GnRH-like neuropeptide (pQIHYKNPGWGPG-NH2) that specifically activates an A. rubens GnRH-type receptor and a novel neuropeptide (HNTFTMGGQNRWKAG-NH2) that specifically activates an A. rubens CRZ-type receptor. With the discovery of these ligand-receptor pairs, we demonstrate that the vertebrate/deuterostomian GnRH-type and the protostomian AKH systems are orthologous and the origin of a paralogous CRZ-type signalling system can be traced to the common ancestor of the Bilateria (Urbilateria).
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Gonadotropin-Releasing Hormone; Insect Hormones; Insect Proteins; Invertebrates; Neuropeptides; Oligopeptides; Phylogeny; Pyrrolidonecarboxylic Acid; Receptors, LHRH; Receptors, Neuropeptide; Sequence Homology, Amino Acid; Signal Transduction; Starfish; Vertebrates
PubMed: 27350121
DOI: 10.1038/srep28788 -
Molecules (Basel, Switzerland) Jul 2017Bombesin-related peptides are a family of peptides whose prototype was discovered in amphibian skin and which exhibit a wide range of biological activities. Since the...
Bombesin-related peptides are a family of peptides whose prototype was discovered in amphibian skin and which exhibit a wide range of biological activities. Since the initial isolation of bombesin from skin, diverse forms of bombesin-related peptides have been found in the skins across Anura. In this study, a novel bombesin-related peptide of the ranatensin subfamily, named ranatensin-HL, was structurally-characterised from the skin secretion of the broad-folded frog, , through combination of molecular cloning and mass spectrometric methodologies. It is composed of 13 amino acid residues, pGlu-RAGNQWAIGHFM-NH₂, and resembles an N-terminally extended form of neuromedin B. Ranatensin-HL and its C-terminal decapeptide (ranatensin-HL-10) were chemically synthesised and subjected to in vitro smooth muscle assays in which they were found to display moderate stimulatory effects on rat urinary bladder and uterus smooth muscles with EC values in the range of 1-10 nM. The prepro-ranatensin-HL was highly homological to a bombesin-like peptide from at both nucleotide and amino acid levels, which might provide a clue for the taxonomic classification of ranid frogs in the future.
Topics: Amino Acid Sequence; Animals; Bombesin; Cloning, Molecular; Female; Mass Spectrometry; Molecular Docking Simulation; Myocytes, Smooth Muscle; Oligopeptides; Pyrrolidonecarboxylic Acid; Ranidae; Rats; Skin; Tissue Extracts; Urinary Bladder; Uterus
PubMed: 28677620
DOI: 10.3390/molecules22071110 -
Pest Management Science Jun 2019Neuropeptides are regulators of critical life processes in insects and, due to their high specificity, represent potential targets in the development of greener...
BACKGROUND
Neuropeptides are regulators of critical life processes in insects and, due to their high specificity, represent potential targets in the development of greener insecticidal agents. Fundamental to this drive is understanding neuroendocrine pathways that control key physiological processes in pest insects and the screening of potential analogues. The current study investigated neuropeptide binding sites of kinin and CAPA (CAPA-1) in the aphids Myzus persicae and Macrosiphum rosae and the effect of biostable analogues on aphid fitness under conditions of desiccation, starvation and thermal (cold) stress.
RESULTS
M. persicae and M. rosae displayed identical patterns of neuropeptide receptor mapping along the gut, with the gut musculature representing the main target for kinin and CAPA-1 action. While kinin receptor binding was observed in the brain and VNC of M. persicae, this was not observed in M. rosae. Furthermore, no CAPA-1 receptor binding was observed in the brain and VNC of either species. CAP2b/PK analogues (with CAPA receptor cross-activity) were most effective in reducing aphid fitness under conditions of desiccation and starvation stress, particularly analogues 1895 (2Abf-Suc-FGPRLa) and 2129 (2Abf-Suc-ATPRIa), which expedited aphid mortality. All analogues, with the exception of 2139-Ac, were efficient at reducing aphid survival under cold stress, although were equivalent in the strength of their effect.
CONCLUSION
In demonstrating the effects of analogues belonging to the CAP2b neuropeptide family and key analogue structures that reduce aphid fitness under stress conditions, this research will feed into the development of second generation analogues and ultimately the development of neuropeptidomimetic-based insecticidal agents. © 2019 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Topics: Animals; Aphids; Binding Sites; Heat-Shock Response; Kinins; Neuropeptides; Oligopeptides; Pyrrolidonecarboxylic Acid; Receptors, Neuropeptide; Stress, Physiological
PubMed: 30734498
DOI: 10.1002/ps.5372 -
PloS One 2012Obesity's association with hand osteoarthritis cannot be fully explained by mechanical loading. We examined the relationship between adipokines and radiographic hand...
INTRODUCTION
Obesity's association with hand osteoarthritis cannot be fully explained by mechanical loading. We examined the relationship between adipokines and radiographic hand osteoarthritis severity and pain.
METHODS
In a pilot study of 44 hand osteoarthritis patients (39 women and 5 men), serum adipokine concentrations and hand x-ray Kallman-scores were analyzed using linear regression models. Secondary analyses examined correlates of hand pain.
RESULTS
The cohort had a mean age of 63.5 years for women and 72.6 for men; mean (standard deviation) Kallman-scores were 43.3(17.4) for women and 46.2(10.8) for men. Mean body-mass-index was 30 kg/m(2) for women and men. Mean leptin concentration was 32.2 ng/ml (women) and 18.5 ng/ml (men); mean adiponectin-total was 7.9 ng/ml (women) and 5.3 ng/ml (men); mean resistin was 7.3 ng/ml (women) and 9.4 ng/ml (men). No association was found between Kallman-scores and adipokine concentrations (R(2) = 0.00-0.04 unadjusted analysis, all p-values>0.22). Secondary analyses showed mean visual-analog-scale pain of 4.8(2.4) for women and 6.6(0.9) for men. Leptin, BMI, and history of coronary artery disease were found to be associated with visual-analog-scale scores for chronic hand pain (R(2) = 0.36 unadjusted analysis, p-values≤0.04).
CONCLUSION
In this pilot study, we found that adipokine serum concentrations were not associated with hand osteoarthritis radiographic severity; the most important correlates of joint damage were age and disease duration. Leptin serum concentration, BMI, and coronary artery disease were associated with the intensity of chronic hand OA pain.
Topics: Age Factors; Aged; Body Mass Index; Cohort Studies; Coronary Artery Disease; Female; Hand; Humans; Insect Hormones; Leptin; Linear Models; Male; Middle Aged; Musculoskeletal Pain; Oligopeptides; Osteoarthritis; Pyrrolidonecarboxylic Acid; Radiography; Resistin
PubMed: 23110114
DOI: 10.1371/journal.pone.0047860 -
Alcohol (Fayetteville, N.Y.) Dec 2013Previously we have shown that chronic alcohol intake causes alcohol-induced ciliary dysfunction (AICD), leading to non-responsive airway cilia. AICD likely occurs...
Previously we have shown that chronic alcohol intake causes alcohol-induced ciliary dysfunction (AICD), leading to non-responsive airway cilia. AICD likely occurs through the downregulation of nitric oxide (NO) and cyclic nucleotide-dependent kinases, protein kinase G (PKG) and protein kinase A (PKA). Studies by others have shown that dietary supplementation with the antioxidants N-acetylcysteine (NAC) and procysteine prevent other alcohol-induced lung complications. This led us to hypothesize that dietary supplementation with NAC or procysteine prevents AICD. To test this hypothesis, C57BL/6 mice drank an alcohol/water solution (20% w/v) ad libitum for 6 weeks and were concurrently fed dietary supplements of either NAC or procysteine. Ciliary beat frequency (CBF) was measured in mice tracheas, and PKG/PKA responsiveness to β-agonists and NOx levels were measured from bronchoalveolar lavage (BAL) fluid. Long-term alcohol drinking reduced CBF, PKG and PKA responsiveness to β-agonists, and lung NOx levels in BAL fluid. In contrast, alcohol-drinking mice fed NAC or procysteine sustained ciliary function and PKG and PKA responsiveness to β-agonists. However, BAL NO levels remained low despite antioxidant supplementation. We also determined that removal of alcohol from the drinking water for as little as 1 week restored ciliary function, but not PKG and PKA responsiveness to β-agonists. We conclude that dietary supplementation with NAC or procysteine protects against AICD. In addition, alcohol removal for 1 week restores cilia function independent of PKG and PKA activity. Our findings provide a rationale for the use of antioxidants to prevent damage to airway mucociliary functions in chronic alcohol-drinking individuals.
Topics: Acetylcysteine; Adrenergic beta-2 Receptor Agonists; Animals; Antioxidants; Bronchoalveolar Lavage Fluid; Cilia; Ciliary Motility Disorders; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Dietary Supplements; Ethanol; Female; Mice; Procaterol; Pyrrolidonecarboxylic Acid; Reactive Nitrogen Species; Thiazolidines; Trachea
PubMed: 24169090
DOI: 10.1016/j.alcohol.2013.09.004 -
Neurobiology of Aging Jan 2015Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated,...
Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated, pyroglutamate-modified Aβ (NpE3) forms, and their correlations to cognitive dysfunction in AD, are unknown. We quantified AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 concentrations in soluble (nonfibrillar) and insoluble (fibrillar) pools in PCC from subjects with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild-moderate AD. In clinical AD, increased PCC concentrations of Aβ were observed for all Aβ forms in the insoluble pool but only for Aβ1-42 in the soluble pool. Lower Mini-Mental State Exam and episodic memory scores correlated most strongly with higher concentrations of soluble and insoluble Aβ1-42. Greater neuropathology severity by Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging-Reagan pathologic criteria was associated with higher concentrations of all measured Aβ forms, except soluble AβNpE3-40. Low concentrations of soluble pyroglutamate Aβ across clinical groups likely reflect its rapid sequestration into plaques, thus, the conversion to fibrillar Aβ may be a therapeutic target.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cognition; Disease Progression; Female; Gyrus Cinguli; Humans; Male; Molecular Targeted Therapy; Peptide Fragments; Pyrrolidonecarboxylic Acid; Solubility
PubMed: 25048160
DOI: 10.1016/j.neurobiolaging.2014.06.021