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JCI Insight Dec 2023Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive...
Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-β1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen-treated IER-SftpcI73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr-null (FPr-/-) line showed attenuated weight loss and gene dosage-dependent rescue of mortality compared with FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.
Topics: Mice; Animals; Dinoprost; Fibroblasts; Idiopathic Pulmonary Fibrosis; Fibrosis; Population Dynamics
PubMed: 37934604
DOI: 10.1172/jci.insight.172977 -
The Journal of Endocrinology Jul 2024Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1 million US women experience menopause annually, but despite the... (Review)
Review
Menopause marks the cessation of fertility and the transition to post-reproductive years. Nearly 1 million US women experience menopause annually, but despite the significant impact it has on their physical and mental health, menopause has been insufficiently studied. Oxytocin is a neurohormone that regulates emotionality, social behaviors, and fundamental physiological systems. Localization of oxytocin receptors in the brain, reproductive tissues, bone, and heart support their role in mental health and potentially sleep, along with reproductive and cardiovascular functions. While experimental data linking oxytocin to behavior and physiology in animals are largely consistent, human data are correlative and inconclusive. As women transition into menopause, oxytocin levels decrease while their susceptibility to mood disorders, poor sleep, osteoporosis, and cardiovascular diseases increases. These concurrent changes highlight oxytocin as a potential influence on the health and mood of women along their reproductive life span. Here, we summarize experimental rodent and non-human primate studies that link oxytocin to reproductive aging and metabolic health and highlight the inconclusive findings in studies of women. Most human studies relied on a single oxytocin assessment in plasma or on intranasal oxytocin administration. The pulsatile release and short half-life of plasma oxytocin limit the validity of these methods. We discuss the need for oxytocin assessments in stable bio-samples, such as urine, and to use valid assays for assessment of associations between changing oxytocin levels and well-being across the reproductive life span. This work has the potential to guide therapeutic strategies that will one day alleviate adverse health outcomes for many women.
Topics: Oxytocin; Humans; Female; Animals; Menopause; Women's Health; Aging; Receptors, Oxytocin; Middle Aged
PubMed: 38670161
DOI: 10.1530/JOE-23-0396 -
Trends in Biochemical Sciences Apr 2024Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and... (Review)
Review
Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT/VP signaling system in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development.
Topics: Animals; Humans; Oxytocin; Vasopressins; Receptors, Vasopressin
PubMed: 38418338
DOI: 10.1016/j.tibs.2024.01.010 -
Journal of Medicinal Chemistry Nov 2023Oxytocin (OT) and vasopressin (VP) are related neuropeptides that regulate many biological processes. In humans, OT and VP act via four G protein-coupled receptors, OTR,...
Oxytocin (OT) and vasopressin (VP) are related neuropeptides that regulate many biological processes. In humans, OT and VP act via four G protein-coupled receptors, OTR, VR, VR, and VR (VPRs), which are associated with several disorders. To investigate the therapeutic potential of these receptors, particularly in the receptor-dense areas of the brain, molecular probes with a high temporal and spatial resolution are required. Such a spatiotemporal resolution can be achieved by incorporating photochromic moieties into OT and VP. Here, we report the design, synthesis, and (photo)pharmacological characterization of 12 OT- and VP-derived photoprobes using different modification strategies. Despite OT's and VP's sensitivity toward structural changes, we identified two photoprobes with good potency and photoswitch window for investigating the OTR and VR. These photoprobes should be of high value for producing cutting-edge photocontrollable peptide probes for the study of dynamic and kinetic receptor activation processes in specific regions of the brain.
Topics: Humans; Oxytocin; Receptors, Oxytocin; Vasopressins; Receptors, G-Protein-Coupled; Neuropeptides
PubMed: 37857356
DOI: 10.1021/acs.jmedchem.3c01415 -
Journal of Medicinal Chemistry Jul 2023Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling... (Review)
Review
Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E (PGE) triggers several physiological and pathological conditions. It mediates signaling through four G-protein coupled receptors, EP1, EP2, EP3, and EP4. Among these, EP2 is expressed throughout the body including the brain and uterus. The functional role of EP2 has been extensively studied using EP2 gene knockout mice, cellular models, and selective small molecule agonists and antagonists for this receptor. The efficacy data from in vitro and in vivo animal models indicate that EP2 receptor is a major proinflammatory mediator with deleterious functions in a variety of diseases suggesting a path forward for EP2 inhibitors as the next generation of selective anti-inflammatory and antiproliferative agents. Interestingly in certain diseases, EP2 action is beneficial; therefore, EP2 agonists seem to be clinically useful. Here, we highlight the strengths, weaknesses, opportunities, and potential threats (SWOT analysis) for targeting EP2 receptor for therapeutic development for a variety of unmet clinical needs.
Topics: Animals; Mice; Receptors, Prostaglandin E; Dinoprostone; Cyclooxygenase 2; Drug Discovery; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 37458373
DOI: 10.1021/acs.jmedchem.3c00655 -
Digestion 2024Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal symptoms, but its pathogenesis is not fully understood. (Review)
Review
BACKGROUND
Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal symptoms, but its pathogenesis is not fully understood.
SUMMARY
We have recently shown in rats that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve the intestinal barrier dysfunction, which is a major pathophysiology of IBS. We have additionally shown that the neuropeptides injected intracisternally induced a visceral antinociceptive action against colonic distension. Since it has been known that intestinal barrier dysfunction causes visceral hypersensitivity, the other main pathophysiology of IBS, the neuropeptides act centrally to reduce leaky gut, followed by improvement of visceral sensation, leading to therapeutic action on IBS. It has been recently reported that there is a bidirectional relationship between neuroinflammation in the brain and the pathophysiology of IBS. For example, activation of microglia in the brain causes visceral hypersensitivity. Accumulating evidence has suggested that orexin, ghrelin, or oxytocin could improve neuroinflammation in the CNS. All these results suggest that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve intestinal barrier function and visceral sensation and also induce a protective action against neuroinflammation in the brain.
KEY MESSAGES
We therefore speculated that orexin, ghrelin, or oxytocin in the brain possess dual actions, improvement of visceral sensation/leaky gut in the gut, and reduction of neuroinflammation in the brain, thereby inducing a therapeutic effect on IBS in a convergent manner.
Topics: Rats; Animals; Irritable Bowel Syndrome; Orexins; Ghrelin; Oxytocin; Neuroinflammatory Diseases; Neuropeptides; Brain
PubMed: 37673052
DOI: 10.1159/000533275 -
BMC Veterinary Research Jul 2023Oxytocin has traditionally been known for its physiological effects on muscle contraction associated with birth and lactation, but in the last years is widely used as a... (Review)
Review
Oxytocin has traditionally been known for its physiological effects on muscle contraction associated with birth and lactation, but in the last years is widely used as a biomarker of "positive experiences" in psychology and behavior. Different types of samples have been used for oxytocin measurements with saliva samples having the particular advantage of an easy and non-stressful collection. However, the low concentration of oxytocin in saliva can represent a limitation for its use. For this reason, sensitive assays and even a previous sample treatment in some cases are required for saliva oxytocin quantification. In addition, the lack of standardized and generally agreed-upon approach to peripheral oxytocin measurement leads to large discrepancies between different laboratories, that use different sample treatment protocols and different assays. The main objectives of this review are to describe the current status of the use of saliva for oxytocin measurement, provide details of the different sample processing techniques that can be applied and inform about the analytical techniques and assays available in different animal species, and also in humans for comparative purposes. It is expected that this information can contribute to an increase in the knowledge about the measurements of oxytocin in saliva and to its wider use in the future.
Topics: Pregnancy; Female; Humans; Animals; Oxytocin; Saliva; Parturition; Lactation; Biomarkers
PubMed: 37507690
DOI: 10.1186/s12917-023-03661-w -
NEJM Evidence Jun 2024AbstractWith recent severe restrictions to abortion accessibility in the United States and a pending Supreme Court case challenging the Food and Drug Administration's... (Review)
Review
AbstractWith recent severe restrictions to abortion accessibility in the United States and a pending Supreme Court case challenging the Food and Drug Administration's approval of mifepristone, evidence-based strategies to protect and expand access to abortion care are needed. Two safe and effective regimens for medication abortion are widely used globally - misoprostol-only and misoprostol in combination with mifepristone. However, misoprostol-only regimens are rarely used in the United States. In 2023, the National Abortion Federation and the Society of Family Planning updated their recommended protocol for misoprostol-only for medication abortion to 800 μg of misoprostol administered buccally, sublingually, or vaginally every 3 hours for three or more doses. To characterize the data supporting this specific regimen, this article reviews the relevant literature to address the question of how effective misoprostol-only is for medication abortion. The authors conclude that the updated misoprostol regimen is highly effective and a potential strategy for expanding access to abortion.
Topics: Misoprostol; Humans; Female; Abortion, Induced; Pregnancy; Abortifacient Agents, Nonsteroidal; Mifepristone; United States
PubMed: 38804786
DOI: 10.1056/EVIDccon2300129 -
Neuropeptides Dec 2023Oxytocin (OXT) is a hypothalamic peptide that plays a number of roles in the body, being involved in labor and lactation, as well as cognitive-emotional processes and... (Review)
Review
Oxytocin (OXT) is a hypothalamic peptide that plays a number of roles in the body, being involved in labor and lactation, as well as cognitive-emotional processes and social behavior. In recent years, knowledge of the physiology of OXT has been repeatedly used to explore its potential role in the treatment of numerous diseases, identifying a significant role for OXT in appetite regulation, eating behavior, weight regulation, and food-related beliefs. In this review we provide an overview of publications on this topic, but due to the wealth of research, we have limited our focus to studies based on the use of intranasal OXT in psychiatric diseases, with a particular focus on the role of oxytocin in eating disorders and obesity. Accumulating evidence that OXT intranasal supplementation may provide some therapeutic benefit seems promising. In individuals with autistic spectrum disorders (ASD) and schizophrenia, OXT may affect core deficits, improving social cognition and reducing symptom severity in schizophrenia. Dysregulation of serum and CSF OXT levels, as well as polymorphisms of its genes, may affect emotion perception in patients with eating disorders and correlate with co-occurring depressive and anxiety disorders. Nevertheless, there are still many critical questions regarding the pharmacokinetics and pharmacodynamics of intranasal OXT that can only be answered in larger randomized controlled trials.
Topics: Female; Humans; Oxytocin; Feeding and Eating Disorders; Administration, Intranasal; Schizophrenia; Obesity
PubMed: 37837804
DOI: 10.1016/j.npep.2023.102387 -
Reproductive Health Aug 2023Most treatments for postpartum haemorrhage (PPH) lack evidence of effectiveness. New innovations are ubiquitous but have not been synthesized for ready access. (Review)
Review
BACKGROUND
Most treatments for postpartum haemorrhage (PPH) lack evidence of effectiveness. New innovations are ubiquitous but have not been synthesized for ready access.
NARRATIVE REVIEW
Pubmed 2020 to 2021 was searched on 'postpartum haemorrhage treatment', and novel reports among 755 citations were catalogued. New health care strategies included early diagnosis with a bundled first response and home-based treatment of PPH. A calibrated postpartum blood monitoring tray has been described. Oxytocin is more effective than misoprostol; addition of misoprostol to oxytocin does not improve treatment. Heat stable carbetocin has not been assessed for treatment. A thermostable microneedle oxytocin patch has been developed. Intravenous tranexamic acid reduces mortality but deaths have been reported from inadvertent intrathecal injection. New transvaginal uterine artery clamps have been described. Novel approaches to uterine balloon tamponade include improvised and purpose-designed free-flow (as opposed to fixed volume) devices and vaginal balloon tamponade. Uterine suction tamponade methods include purpose-designed and improvised devices. Restrictive fluid resuscitation, massive transfusion protocols, fibrinogen use, early cryopreciptate transfusion and point-of-care viscoelastic haemostatic assay-guided blood product transfusion have been reported. Pelvic artery embolization and endovascular balloon occlusion of the aorta and pelvic arteries are used where available. External aortic compression and direct compression of the aorta during laparotomy or aortic clamping (such as with the Paily clamp) are alternatives. Transvaginal haemostatic ligation and compression sutures, placental site sutures and a variety of novel compression sutures have been reported. These include Esike's technique, three vertical compression sutures, vertical plus horizontal compression sutures, parallel loop binding compression sutures, uterine isthmus vertical compression sutures, isthmic circumferential suture, circumferential compression sutures with intrauterine balloon, King's combined uterine suture and removable retropubic uterine compression suture. Innovative measures for placenta accreta spectrum include a lower uterine folding suture, a modified cervical inversion technique, bilateral uterine artery ligation with myometrial excision of the adherent placenta and cervico-isthmic sutures or a T-shaped lower segment repair. Technological advances include cell salvage, high frequency focussed ultrasound for placenta increta and extra-corporeal membrane oxygenation.
CONCLUSIONS
Knowledge of innovative methods can equip clinicians with last-resort options when faced with haemorrhage unresponsive to conventional methods.
Topics: Female; Pregnancy; Humans; Postpartum Hemorrhage; Oxytocin; Misoprostol; Placenta; Hemostatics
PubMed: 37568196
DOI: 10.1186/s12978-023-01657-1