ABSTRACT
Prokineticin 1 (PROK1) is an important factor in pregnancy establishment in pigs, acting at the embryo-maternal interface and the corpus luteum (CL). Estradiol-17ß (E2) is the primary pregnancy recognition signal in pigs, and its effects are augmented by luteotropic prostaglandin E2 (PGE2). On the contrary, prostaglandin F2α (PGF2α) exerts mainly a luteolytic effect. The present study aimed to elucidate whether E2, PGE2, and PGF2α regulate the expression of PROK1 and its receptors in the porcine CL and to determine the PROK1 effect on luteal endothelial cells and pathways that may be involved in this regulation. The effects of E2, PGE2, and PGF2α on the expressions of PROK1 and its receptors in the CL were studied using an in vitro model of ultrathin luteal tissue explants model. Additionally, the effects of E2 and PGE2 on the PROK1 system were determined using an in vivo approach, in which the hormones were administered into the uterine lumen to imitate their secretion by embryos. Endothelial cell proliferation was measured using the colorimetric method. E2 acting via estrogen receptors simulated the mRNA and protein expressions of PROK1 and PROKR1 in CL explants in vitro (p < 0.05). The simultaneous action of E2 with PGE2 enhanced the expression of luteal PROK1 mRNA in vitro (p < 0.05). Estradiol-17ß acting alone significantly increased PROK1 mRNA levels in vivo, whereas E2 simultaneously administered with PGE2 significantly elevated the PROK1 mRNA expression and PROKR1 mRNA and protein contents in CLs adjacent to uterine horns receiving hormonal infusion compared with CLs adjacent to placebo-treated uterine horns (p < 0.01). The PROK1 protein expression was significantly higher in the CLs of pigs treated with E2, PGE2, and E2 together with PGE2 than in the control group. PGF2α increased the PROK1 mRNA content in CLs on days 12 and 14 of the estrous cycle (p < 0.05). The expression of PROKR2 at the mRNA and protein levels remained unchanged in response to in vitro and in vivo treatments. PROK1 stimulated the proliferation of luteal endothelial cells by activating the MAPK, AKT, and mTOR pathways (p < 0.05). In summary, the luteal expressions of PROK1 and PROKR1 in early pregnancy are regulated by E2 and PGE2. PROK1 stimulates luteal angiogenesis by activating the MAPK, AKT, and mTOR pathways. The regulation of luteal PROK1 expression by PGF2α indicates PROK1's putative role during luteolysis. We conclude that PROK1-PROKR1 signaling supports luteal function during CL rescue in pregnancy in pigs.
Subject(s)
Corpus Luteum , Gastrointestinal Hormones , Gene Expression Regulation , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived , Animals , Female , Pregnancy , Corpus Luteum/metabolism , Corpus Luteum/drug effects , Dinoprost/metabolism , Dinoprostone/metabolism , Endothelial Cells/metabolism , Endothelial Cells/drug effects , Estradiol/pharmacology , Estradiol/metabolism , Gastrointestinal Hormones/metabolism , Gastrointestinal Hormones/genetics , Gene Expression Regulation/drug effects , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Swine , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/metabolism , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/geneticsABSTRACT
Prokineticin 1 (PROK1) is a secreted protein involved in a range of physiological activities such as cell proliferation, migration, angiogenesis, and neuronal cell proliferation. Emerging evidences show that PROK1/PROK receptors (PROKRs) are expressed by trophoblasts, and decidual stroma cells at the maternal-fetal interface. PROK1 plays a critical role in successful pregnancy establishment by regulating the decidualization, implantation and placental development. Dysregulation of prokineticin signaling has been described in certain pathological states associated with pregnancy, including pre-eclampsia, recurrent miscarriage and fetal growth restriction. In this review, the expression and pleiotropic roles of PROK1 under physiological and pathological pregnancy conditions are discussed.
Subject(s)
Gastrointestinal Hormones , Pre-Eclampsia , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived , Pregnancy , Female , Humans , Placenta/metabolism , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/genetics , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/metabolism , Signal Transduction/genetics , Trophoblasts , Pre-Eclampsia/genetics , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolismABSTRACT
The gut microbiota plays a vital role in maintaining gastrointestinal homeostasis, however, whether it is influenced by gut hormones remains unknown. Secretin is a well-known gastrointestinal hormone produced by enteroendocrine S cells. This study utilized 16S rRNA amplicon sequencing to characterize the effect of SCT deficiency on the gut microbiota. Our results show that systemic SCT knockout alters the composition and abundance of the mouse gut microbiota but does not affect fecal short-chain fatty acids and lipids concentrations. At the genus level, the abundance of Turicibacter, Bacteroides, Ruminococcu, Romboutsia, Asaccharobacter, and Parasutterella increased in SCT-/- mice, whereas the abundance of Akkermansia and Escherichia decreased. Functional prediction results showed that lack of SCT reduced the abundance of carbohydrate metabolism-related pathways but increased the abundance of linoleic acid metabolism and branched-chain amino acid degradation. Overall, systemic SCT knockout had only minor effects on gut microbiota composition and function in adult male mice fed a standard chow diet.
Subject(s)
Gastrointestinal Microbiome , Secretin , Animals , Male , Mice , Gastrointestinal Hormones/genetics , Gene Knockout Techniques , RNA, Ribosomal, 16S/genetics , Secretin/geneticsABSTRACT
Energy homeostasis is a complex system involving multiple hormones, neuropeptides, and receptors. Prokineticins (PK1 and PK2) are agonists to two G protein-coupled receptors, prokineticin receptor 1 and 2 (PKR1 and PKR2), which decrease food intake when injected in rodents. The relative contribution of PKR1 and PKR2 to the anorexigenic effect of PK2 and their site of action in the brain have not yet been elucidated. While PKR1 and PKR2 are both expressed in the hypothalamus, a central region involved in the control of energy homeostasis, PKR2 is also present in the amygdala, which has recently been shown to regulate food intake in response to several anorexigenic signals. PKR trafficking and signaling are inhibited by the melanocortin receptor accessory protein 2 (MRAP2), thus suggesting that MRAP2 has the potential to alter the anorexigenic activity of PK2 in vivo. In this study, we investigated the importance of PKR1 and PKR2 for PK2-mediated inhibition of food intake, the brain region involved in this function, and the effect of MRAP2 on PK2 action in vivo. Using targeted silencing of PKR2 and chemogenetic manipulation of PKR2 neurons, we show that the anorexigenic effect of PK2 is mediated by PKR2 in the amygdala and that altering MRAP2 expression in PKR2 neurons modulates the activity of PK2. Collectively, our results provide evidence that inhibition of food intake by PKs is not mediated through activation of hypothalamic neurons but rather amygdala PKR2 neurons and further establishes the importance of MRAP2 in the regulation of energy homeostasis.
Subject(s)
Gastrointestinal Hormones , Neuropeptides , Carrier Proteins/metabolism , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Gastrointestinal Hormones/pharmacology , Neurons/metabolism , Neuropeptides/genetics , Neuropeptides/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal TransductionABSTRACT
STUDY OBJECTIVE: East Asians have a higher risk of bleeding than Europeans when treated with ticagrelor. This study aimed to explore genetic indicators related to the high bleeding propensity in East Asian patients with acute coronary syndrome (ACS) using ticagrelor. DESIGN: A multicenter prospective cohort study. SETTING: Four sub center hospitals participating the study. PATIENTS: Between March 2018 and July 2021, 208 patients with ACS were administered ticagrelor and underwent genetic testing. INVERTENTION: Patients were enrolled and followed up for bleeding events for 12 months. Single-nucleotide polymorphisms (SNPs) were detected using whole-exome sequencing. SNPs significantly associated with cumulative bleeding events within 1-, 6-, and 12-month follow-ups were selected (p < 0.01). Among these, SNPs showing a difference of ≥2 fold in their distribution frequency among East Asians and Europeans were selected. MEASUREMENTS AND MAIN RESULTS: Among all patients, 96.60% received ticagrelor plus aspirin or cilostazol, and 42.3% suffered from bleeding events during 12-month follow-up. Furthermore, 22 SNPs of 15 genes were found to have a significant association with cumulative bleeding events within 1-, 6-, and 12-month follow-ups. Among these SNPs, FIG4 rs2295837 (A>T) variant had the strongest association with bleeding events within 1 month (p = 1.28 × 10-4 ), with an increased risk of bleeding in T allele carriers (odds ratio [OR]: 3.07, 95% confidence interval [CI]: 1.68-5.63). PROK2 rs3796224 (C>T) variant was most strongly associated with cumulative bleeding events within 6 months (p = 4.57 × 10-4 ) with an increased risk of bleeding in T allele carriers (OR: 2.16, 95% CI: 1.20-3.89). Moreover, HRNR rs6662450 (C>T) variant showed the strongest relation with cumulative bleeding events within 12 months (p = 4.86 × 10-4 ) with a reduced risk of bleeding in T allele carriers (OR: 0.48, 95% CI: 0.24-0.95). CONCLUSION: Fifteen genes, including PROK2, HRNR, and FIG4, were potential biomarkers of high bleeding propensity in East Asian patients with ACS using ticagrelor.
Subject(s)
Acute Coronary Syndrome , Gastrointestinal Hormones , Hemorrhage , Neuropeptides , Ticagrelor , Humans , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/genetics , East Asian People , Flavoproteins/genetics , Gastrointestinal Hormones/genetics , Neuropeptides/genetics , Phosphoric Monoester Hydrolases/genetics , Prospective Studies , Ticagrelor/adverse effects , Hemorrhage/chemically induced , Hemorrhage/genetics , Calcium-Binding Proteins/genetics , Intermediate Filament Proteins/geneticsABSTRACT
Lower-grade glioma (LGG) is a crucial pathological type of glioma. Prokineticins have not been reported in LGG. Prokineticins as a member of the multifunctional chemokine-like peptide family are divided into two ligands: PROK1 and PROK2. We evaluated the role of PROK1 and PROK2 in LGG using TCGA database. We downloaded the datasets of LGG from TCGA and evaluated the influence of prokineticins on LGG survival by survival module. Correlations between clinical information and prokineticins expression were analyzed using logistic regression. Univariable survival and multivariate Cox analysis was used to compare several clinical characteristics with survival. Correlation between prokineticins and cancer immune infiltrates was explored using CIBERSORT and correlation module of GEPIA. We analyzed genes of PROK1 and PROK2 affecting LGG, screened differentially expressed genes (DEGs), interacted protein-protein with DEGs through the STRING website, then imported the results into the Cytospace software, and calculated the hub genes. To analyze whether hub genes and prokineticins are related, the relationship between PROK1 and PROK2 and hub genes was assessed and shown by heat map. In addition, gene set enrichment analysis (GSEA) was performed using the TCGA dataset. The univariate analysis using logistic regression and PROK1 and PROK2 showed opposite expression differences between tumor and normal tissues (p < 0.05). PRO1 and PROK2 expressions showed significant differences in tumor grade, age, Iiscitrate DeHydrogenase (IDH) status, histological type, and 1P/19q codeletion. Multivariate analysis revealed that the up-regulated PROK1 and PROK2 expression is an independent prognostic factor for bad prognosis. Specifically, prokineticin expression level has significant correlations with infiltrating levels of Th1 cells, NK CD 56bright cells, and Mast cells in LGG. We screened 21 DEGs and obtained 5 hub genes (HOXC10, HOXD13, SOX4, GATA4, HOXA9). GSEA-identified FCMR activation, creation of C4 and C2 activators, and CD22-mediated BCR regulation in gene ontology (GO) were differentially enriched in high PROK1 and PROK2 expression phenotype pathway, cytoplasmic ribosomal proteins, and ribosome and were differentially enriched in the low PROK1 and PROK2 expression phenotype pathway. Prokineticins are a prognostic biomarker and the correlation between hub genes and LGG requires further attention.
Subject(s)
Brain Neoplasms , Gastrointestinal Hormones , Glioma , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived , Biomarkers , Brain Neoplasms/pathology , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Gene Ontology , Glioma/pathology , Homeodomain Proteins , Humans , Prognosis , SOXC Transcription Factors , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/genetics , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/metabolismABSTRACT
Atherosclerosis precedes the onset of clinical manifestations of cardiovascular diseases (CVDs). We used carotid intima-media thickness (cIMT) to investigate genetic susceptibility to atherosclerosis in 7894 unrelated adults (3963 women, 3931 men; 40 to 60 years) resident in four sub-Saharan African countries. cIMT was measured by ultrasound and genotyping was performed on the H3Africa SNP Array. Two new African-specific genome-wide significant loci for mean-max cIMT, SIRPA (p = 4.7E-08), and FBXL17 (p = 2.5E-08), were identified. Sex-stratified analysis revealed associations with one male-specific locus, SNX29 (p = 6.3E-09), and two female-specific loci, LARP6 (p = 2.4E-09) and PROK1 (p = 1.0E-08). We replicate previous cIMT associations with different lead SNPs in linkage disequilibrium with SNPs primarily identified in European populations. Our study find significant enrichment for genes involved in oestrogen response from female-specific signals. The genes identified show biological relevance to atherosclerosis and/or CVDs, sex-differences and transferability of signals from non-African studies.
Subject(s)
Atherosclerosis/genetics , Atherosclerosis/pathology , Carotid Intima-Media Thickness/statistics & numerical data , Genetic Predisposition to Disease/genetics , Adult , Africa South of the Sahara , Autoantigens/genetics , Cardiovascular Diseases/genetics , Female , Gastrointestinal Hormones/genetics , Genome/genetics , Histones/genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Ribonucleoproteins/genetics , Sex Factors , Sorting Nexins/genetics , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/genetics , SS-B AntigenABSTRACT
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.
Subject(s)
Drosophila Proteins/metabolism , Eating/physiology , Energy Metabolism/physiology , Gastrointestinal Hormones/metabolism , Homeostasis , Nutrients/metabolism , Somatostatin/metabolism , Animals , Animals, Genetically Modified , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Eating/genetics , Energy Metabolism/genetics , Enteroendocrine Cells/metabolism , Gastrointestinal Hormones/genetics , Gene Knockout Techniques , Humans , Hypoglycemia/genetics , Hypoglycemia/metabolism , Insect Hormones/genetics , Insect Hormones/metabolism , Oligopeptides/genetics , Oligopeptides/metabolism , Pyrrolidonecarboxylic Acid/analogs & derivatives , Pyrrolidonecarboxylic Acid/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Signal Transduction/genetics , Somatostatin/genetics , Survival AnalysisABSTRACT
Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1ß were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1ß. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1ß in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.
Subject(s)
Bortezomib/toxicity , Gastrointestinal Hormones/metabolism , Histone Demethylases/metabolism , Hyperalgesia/pathology , Neuropeptides/metabolism , Pain/pathology , Peripheral Nervous System Diseases/pathology , Spinal Cord/pathology , Animals , Antineoplastic Agents/toxicity , Cytokines/metabolism , Gastrointestinal Hormones/genetics , Histone Demethylases/genetics , Hyperalgesia/chemically induced , Hyperalgesia/genetics , Hyperalgesia/metabolism , Male , Mice , Mice, Inbred C57BL , Neuropeptides/genetics , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Pain/chemically induced , Pain/genetics , Pain/metabolism , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/metabolism , Spinal Cord/metabolismABSTRACT
Evidence accumulated in recent years has revealed that neutrophils are involved in the initial establishment of endometriosis, which is well-known as a chronic inflammatory disease. So far, why and how neutrophils promote the formation of early endometriosis are still unclear. In this study, using a mouse model of endometriosis, we demonstrated that endometriosis mice (EMs mice) had a significantly increased number of neutrophils in peritoneal fluids and lesions, and increased levels of granulocyte colony-stimulating factor (G-CSF) and IL-6 in serum and peritoneal fluids compared to the control group. In the neutrophils and uterine fragments co-injection experiment, neutrophils regulated by G-CSF and IL-6 had a similar effect to neutrophils from EMs mice, increasing the number, area, weight and microvessel density (MVD) of endometriotic lesions. Blocking the effect of G-CSF and IL-6 in EMs mice resulted in a decrease in the number, area and weight of endometriotic lesions. Following the depletion of neutrophils in vivo using a anti-Ly6G antibody, the MVD in the lesions of mice treated with neutrophils from EMs mice and neutrophils from pG/pI6 mice were significantly reduced. Neutrophils from EMs mice and neutrophils from pG/pI6 mice altered the expression levels of Mmp9, Bv8 and Trail genes compared to the neutrophils from PBS-treated mice. IL-6 together with G-CSF induced a higher expression of phospho-STAT3 and STAT3 in neutrophils. These findings suggest that neutrophils modulated by G-CSF and IL-6 through the STAT3 pathway alter the expression levels of the angiogenesis-related genes Mmp9, Bv8 and Trail, and may promote the establishment of early endometriosis.
Subject(s)
Endometriosis/metabolism , Endometrium/blood supply , Endometrium/metabolism , Granulocyte Colony-Stimulating Factor/metabolism , Interleukin-6/metabolism , Neovascularization, Pathologic , Neutrophils/metabolism , Animals , Disease Models, Animal , Endometriosis/immunology , Endometriosis/pathology , Endometrium/immunology , Female , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Granulocyte Colony-Stimulating Factor/genetics , Interleukin-6/genetics , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice, Inbred BALB C , Microvascular Density , Neuropeptides/genetics , Neuropeptides/metabolism , Neutrophils/immunology , Phosphorylation , STAT3 Transcription Factor/metabolism , Signal Transduction , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/metabolismABSTRACT
Malignant glioma is one of the most lethal cancers with rapid progression, high recurrence, and poor prognosis in the central nervous system. Fatty acid-binding protein 6 (FABP6) is a bile acid carrier protein that is overexpressed in colorectal cancer. This study aimed to assess the involvement of FABP6 expression in the progression of malignant glioma. Immunohistochemical analysis revealed that FABP6 expression was higher in glioma than in normal brain tissue. After the knockdown of FABP6, a decrease in the migration and invasion abilities of glioma cells was observed. The phosphorylation of the myosin light chain was inhibited, which may be associated with migration ability. Moreover, expression levels of invasion-related proteins, matrix metalloproteinase-2 (MMP-2) and cathepsin B, were reduced. Furthermore, tube formation was inhibited in the human umbilical vein endothelial cells with a decreased concentration of vascular endothelial growth factor (VEGF) in the conditioned medium after the knockdown of FABP6. The phosphorylation of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p65 were also decreased after FABP6 reduction. Finally, the bioluminescent images and immunostaining of MMP-2, cluster of differentiation 31 (CD31), and the VEGF receptor 1 (VEGFR1) revealed attenuated tumor progression in the combination of the FABP6-knocked-down and temozolomide (TMZ)-treated group in an orthotopic xenograft mouse tumor model. This is the first study that revealed the impact of FABP6 on the invasion, angiogenesis, and progression of glioma. The results of this study show that FABP6 may be a potential therapeutic target combined with TMZ for malignant gliomas.
Subject(s)
Fatty Acid-Binding Proteins/antagonists & inhibitors , Gastrointestinal Hormones/antagonists & inhibitors , Glioblastoma/blood supply , Glioblastoma/metabolism , Matrix Metalloproteinase 2/metabolism , Neovascularization, Pathologic/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Cell Line, Tumor , Cell Movement/genetics , Clone Cells , Disease Progression , Extracellular Matrix/metabolism , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/metabolism , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Gene Expression Regulation, Neoplastic , Glioblastoma/pathology , Humans , Mice, Nude , Neoplasm Invasiveness , Phosphorylation , RNA, Small Interfering/metabolism , Temozolomide/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Circadian rhythms in mammals are governed by the hypothalamic suprachiasmatic nucleus (SCN), in which 20,000 clock cells are connected together into a powerful time-keeping network. In the absence of network-level cellular interactions, the SCN fails as a clock. The topology and specific roles of its distinct cell populations (nodes) that direct network functions are, however, not understood. To characterise its component cells and network structure, we conducted single-cell sequencing of SCN organotypic slices and identified eleven distinct neuronal sub-populations across circadian day and night. We defined neuropeptidergic signalling axes between these nodes, and built neuropeptide-specific network topologies. This revealed their temporal plasticity, being up-regulated in circadian day. Through intersectional genetics and real-time imaging, we interrogated the contribution of the Prok2-ProkR2 neuropeptidergic axis to network-wide time-keeping. We showed that Prok2-ProkR2 signalling acts as a key regulator of SCN period and rhythmicity and contributes to defining the network-level properties that underpin robust circadian co-ordination. These results highlight the diverse and distinct contributions of neuropeptide-modulated communication of temporal information across the SCN.
Subject(s)
Circadian Clocks/genetics , Circadian Rhythm/genetics , Gastrointestinal Hormones/genetics , Neuropeptides/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, Peptide/genetics , Suprachiasmatic Nucleus/metabolism , Transcriptome , Animals , Gastrin-Releasing Peptide/genetics , Gastrin-Releasing Peptide/metabolism , Gastrointestinal Hormones/metabolism , Gene Expression Regulation , Gene Regulatory Networks , Mice , Neurons/cytology , Neurons/metabolism , Neuropeptides/metabolism , Receptors, Bombesin/genetics , Receptors, Bombesin/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Peptide/metabolism , Receptors, Vasopressin/genetics , Receptors, Vasopressin/metabolism , Signal Transduction , Single-Cell Analysis , Suprachiasmatic Nucleus/cytology , Vasoactive Intestinal Peptide/genetics , Vasoactive Intestinal Peptide/metabolism , Vasopressins/genetics , Vasopressins/metabolismABSTRACT
Prokineticin 2 (PK2) is a secreted protein involved in several pathological and physiological processes, including the regulation of inflammation, sickness behaviors, and circadian rhythms. Recently, it was reported that PK2 is associated with the pathogenesis of collagen-induced arthritis in mice. However, the role of PK2 in the pathogenesis of rheumatoid arthritis (RA) or osteoarthritis (OA) remains unknown. In this study, we collected synovial tissue, plasma, synovial fluid, and synovial fibroblasts (SF) from RA and OA patients to analyze the function of PK2 using immunohistochemistry, enzyme-linked immunosorbent assays, and tissue superfusion studies. PK2 and its receptors prokineticin receptor (PKR) 1 and 2 were expressed in RA and OA synovial tissues. PKR1 expression was downregulated in RA synovial tissue compared with OA synovial tissue. The PK2 concentration was higher in RA synovial fluid than in OA synovial fluid but similar between RA and OA plasma. PK2 suppressed the production of IL-6 from TNFα-prestimulated OA-SF, and this effect was attenuated in TNFα-prestimulated RA-SF. This phenomenon was accompanied by the upregulation of PKR1 in OA-SF. This study provides a new model to explain some aspects underlying the chronicity of inflammation in RA.
Subject(s)
Arthritis, Rheumatoid/metabolism , Fibroblasts/metabolism , Gastrointestinal Hormones/metabolism , Neuropeptides/metabolism , Osteoarthritis/metabolism , Aged , Animals , Arthritis, Rheumatoid/etiology , Biomarkers , Disease Models, Animal , Disease Susceptibility , Female , Fibroblasts/pathology , Gastrointestinal Hormones/genetics , Humans , Inflammation Mediators , Male , Mice , Middle Aged , Models, Biological , Neuropeptides/genetics , Osteoarthritis/etiology , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Peptide/genetics , Receptors, Peptide/metabolism , Signal Transduction , Synovial Membrane/metabolism , Synovial Membrane/pathologyABSTRACT
Bone tissue is organized at the molecular level to resist fracture with the minimum of bone material. This implies that several modifications of the extracellular matrix, including enzymatic collagen crosslinking, take place. We previously highlighted the role of several gut hormones in enhancing collagen maturity and bone strength. The present study investigated the effect of proglucagon-derived peptides on osteoblast-mediated collagen post-processing. Briefly, MC3T3-E1 murine osteoblasts were cultured in the presence of glucagon (GCG), [D-Ala²]-glucagon-like peptide-1 ([D-Ala²]-GLP-1), and [Gly²]-glucagon-like peptide-2 ([Gly²]-GLP-2). Gut hormone receptor expression at the mRNA and protein levels were investigated by qPCR and Western blot. Extent of collagen postprocessing was examined by Fourier transform infrared microspectroscopy. GCG and GLP-1 receptors were not evidenced in osteoblast cells at the mRNA and protein levels. However, it is not clear whether the known GLP-2 receptor is expressed. Nevertheless, administration of [Gly²]-GLP-2, but not GCG or [D-Ala²]-GLP-1, led to a dose-dependent increase in collagen maturity and an acceleration of collagen post-processing. This mechanism was dependent on adenylyl cyclase activation. In conclusion, the present study highlighted a direct effect of [Gly²]-GLP-2 to enhance collagen post-processing and crosslinking maturation in murine osteoblast cultures. Whether this effect is translatable to human osteoblasts remains to be elucidated.
Subject(s)
Collagen/metabolism , Glucagon-Like Peptide 2/pharmacology , Osteoblasts/metabolism , Animals , CHO Cells , Cells, Cultured , Collagen/drug effects , Cricetulus , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Gene Expression/drug effects , Glucagon/pharmacology , Glucagon-Like Peptide 1/analogs & derivatives , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide 2/chemistry , Glucagon-Like Peptide-2 Receptor/genetics , Glucagon-Like Peptide-2 Receptor/metabolism , Mice , Osteoblasts/drug effects , Protein Multimerization/drug effectsABSTRACT
Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.
Subject(s)
Brain Injuries, Traumatic/pathology , Cerebral Cortex/pathology , Ferroptosis , Gastrointestinal Hormones/metabolism , Neuropeptides/metabolism , Adult , Aged , Animals , Brain Injuries, Traumatic/surgery , Cells, Cultured , Cerebral Cortex/cytology , Coenzyme A Ligases/metabolism , Disease Models, Animal , F-Box Proteins/genetics , F-Box Proteins/metabolism , Female , Gastrointestinal Hormones/genetics , Gene Knockdown Techniques , Humans , Lipid Peroxidation , Male , Mice , Middle Aged , Mitochondria/pathology , Neurons/cytology , Neurons/pathology , Neuropeptides/genetics , Phospholipids/biosynthesis , Primary Cell Culture , Proteolysis , UbiquitinationABSTRACT
Prokineticins are family of small proteins involved in many important biological processes including food intake and control of energy balance. The prokineticin 2 (PROK2) is expressed in several peripheral tissues and areas in the central nervous system. PROK2 activates G protein-coupled receptors, namely, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). Preclinical models exhibiting disturbances of the PROK2 pathway (at the level of PROK2 or its receptors) are characterized by changes in food intake, feeding behavior and insulin sensitivity related to a dysfunction of the energy balance control. In Humans, mutations of PROK2 and PROKR2 genes are associated to the Kallmann syndrome (KS) that affects both the hormonal reproductive axis and the sense of smell and may also lead to obesity. Moreover, plasma PROK2 concentration has been correlated with various cardiometabolic risk factors and type 2 diabetes (T2D). The present review summarizes knowledge on PROK2 structure, signaling and function focusing on its role in control of food intake and energy homeostasis.
Subject(s)
Diabetes Mellitus, Type 2 , Energy Metabolism , Gastrointestinal Hormones , Kallmann Syndrome , Mutation , Neuropeptides , Receptors, G-Protein-Coupled , Signal Transduction , Animals , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Humans , Kallmann Syndrome/genetics , Kallmann Syndrome/metabolism , Neuropeptides/genetics , Neuropeptides/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolismABSTRACT
Gastrointestinal hormones are peptides, and the gastrointestinal tract is the largest endocrine organ in the body for production of peptide hormones. As a premise for accurate measurement of gastrointestinal hormones, the present review provides first an overview over the complex biology of the hormones: The structures and structural homologies; biogenetic aspects; phenotype variabilities; and cellular expression in- and outside the digestive tract. Second, the different methodological principles for measurement are discussed: Bioassay, radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), mass-spectrometry (LC-MS/MS) and processing-independent analysis (PIA). Third, the variability of secretion patterns for some of the gut hormones is illustrated. Finally, the diagnostic value of gut hormone measurement is discussed. The review concludes that measurement of gastrointestinal peptide hormones is relevant not only for examination of digestive functions and diseases, but also for extra-intestinal functions. Moreover, it concludes that, so far, immunoassay technologies (RIA and ELISA) in modernized forms are still the most feasible for accurate measurements of gastrointestinal hormones in biological fluids. Mass-spectrometry technologies are promising, but still too insensitive and expensive.
Subject(s)
Enzyme-Linked Immunosorbent Assay/methods , Gastrointestinal Hormones/analysis , Mass Spectrometry/methods , Peptide Hormones/analysis , Radioimmunoassay/methods , Alternative Splicing , Animals , Biological Assay/methods , Blood Chemical Analysis/methods , Gastrointestinal Hormones/chemistry , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Gene Expression , Humans , Peptide Hormones/chemistry , Peptide Hormones/genetics , Peptide Hormones/metabolismABSTRACT
[Figure: see text].
Subject(s)
Cardiomegaly/metabolism , Endothelium, Vascular/metabolism , Gastrointestinal Hormones/metabolism , Heart Failure/metabolism , Myocytes, Cardiac/metabolism , Neuropeptides/metabolism , Signal Transduction/physiology , Activins/genetics , Activins/metabolism , Animals , Cardiomegaly/genetics , Cardiomegaly/physiopathology , Endothelium, Vascular/physiopathology , Gastrointestinal Hormones/genetics , Heart Failure/genetics , Heart Failure/physiopathology , Humans , Mice , Mice, Transgenic , Neuropeptides/geneticsABSTRACT
Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic ß-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Insulin-Secreting Cells/drug effects , Insulin/metabolism , Polyphenols/therapeutic use , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Gastrointestinal Hormones/genetics , Glucagon-Like Peptide 1/genetics , Humans , Insulin Secretion/genetics , Insulin-Secreting Cells/pathologyABSTRACT
Hypoxia controls metabolism at several levels, e.g., via mitochondrial ATP production, glucose uptake and glycolysis. Hence it is likely that hypoxia also affects the action and/or production of many peptide hormones linked to food intake and appetite control. Many of those are produced in the gastrointestinal tract, endocrine pancreas, adipose tissue, and selective areas in the brain which modulate and concert their actions. However, the complexity of the hypoxia response and the links to peptides/hormones involved in food intake and appetite control in the different organs are not well known. This review summarizes the role of the hypoxia response and its effects on major peptides linked to appetite regulation, nutrition and metabolism.