Kisspeptin-54

Abstract

Arginine-vasopressin (AVP) deficiency (AVP-D) is caused by hypothalamic-pituitary damage of vasopressinergic neurons leading to polyuria and polydipsia. Diagnostic tests for AVP-D are limited by low accuracy and/or tolerability. Kisspeptin (KP) stimulates AVP release in animals, but no study has investigated KP as a provocative test for AVP-D in humans. We investigated circulating AVP levels in response to intravenous (IV) KP in adults. We also explored sex differences in AVP response to KP. Twelve healthy adults (50% female) received an IV KP bolus. Serum AVP was measured pre- and 10, 20, 40, and 60 min post-KP. AVP levels were higher in males at all time points (p = .028) and did not change in response to KP. KP did not stimulate AVP, possibly due to dose, administration route, or cross-species differences in the AVP system. Our study does not support IV KP bolus of 0.24 nmol/kg as a provocative test for AVP-D. CLINICAL TRIAL REGISTRATION: Our study was registered on ClinicalTrials.gov (NCT00914823).

Abstract

KISS1 plays a role in the trophoblast in terms of imbalances in trophoblast-decidua interactions during cesarean scar pregnancy (CSP). However, genes in decidual cells remain poorly understood. To elucidate the role of the KISS1 gene in the invasion process of decidual cells during the progression of CSP, decidual tissue samples were collected from the basal decidua from CSP implantation sites and normal first-trimester intrauterine pregnancies (IUPs). Single-cell RNA sequencing was performed to assess cellular heterogeneity and investigate the functional characteristics of cells at the trophoblast-decidua interface. Immunohistochemistry, qRTPCR and Western blotting were used to detect KISS1 expression in CSP and IUP decidual cells. RNA interference and overexpression experiments were conducted to further validate the function of the KISS1 gene in migration and invasion. The mechanism by which KISS1 activates molecules was validated through RNA-seq combined with luciferase assays. Among all cell types, the decidual stromal cell population exhibited decreased KISS1 expression, which was accompanied by the downregulation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. KISS1 expression levels in decidual cells were significantly lower in the CSP group than in the IUP group (P < 0.001). siKISS1 reduced the invasion and migration of decidual cells, whereas overexpression of KISS1 reversed these effects. siKISS1 decreased p-AKT expression in decidual cells, whereas overexpression of KISS1 significantly increased p-AKT expression levels. KISS1 was significantly upregulated by miR-6809 but downregulated by miR-4768. Our results indicate that the downregulation of KISS1 expression may play a crucial role in the decidualization process of CSP by influencing trophoblast-decidua interactions.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 receptors making it highly clinically challenging subtype pf breast cancer. In this study, we investigated the effect of exogenous Kisspeptin-10 (Kp-10), on MDA-MB-231 and MDA-MB-468 cells. TNBC cells using both in vitro and in silico approaches. Kp-10 treatment significantly reduced cell viability and migration and induced a dose-dependent upregulation of KISS1 mRNA, suggesting a positive feedback loop. Alongside this, Kp-10 modulated key transcription factors-upregulating GATA2, CDX2, and FLI1 while downregulating ZEB1-indicating a shift towards a less aggressive transcriptional state. EMT reversal was evident from increased E-cadherin and β-catenin, and reduced N-cadherin, CD44, and Vimentin. Pro-apoptotic genes CASP3, CASP8, CASP9, and BAX were upregulated, while BCL2 was suppressed, suggesting activation of both apoptotic pathways. Metabolomics profile unveiled the changes in pathways related to apoptosis, anti-angiogenesis, and redox homeostasis. In silico analyses confirmed reduced KISS1 expression in metastatic TNBC tissues and highlighted a correlation between high GATA2/CASP9 levels and improved survival. Kisspeptin-10 reactivates KISS1 and induces anti-tumor effects via transcriptional, apoptotic, and metabolic reprogramming, highlighting its potential as a therapeutic agent in triple-negative breast cancer.

Abstract

Osteoarthritis (OA), characterized by chondrocyte senescence and oxidative stress, affects over 300 million people globally. Kisspeptin-54, a neuropeptide with pleiotropic protective effects, was investigated for its role in chondrocyte senescence and its underlying mechanisms.

Abstract

This study aimed to identify kisspeptin as a new marker for infertility in men with abnormal semen parameters by comparing serum and seminal plasma kisspeptin levels between fertile men and infertile men with normal and abnormal semen parameters.

Abstract

Polycystic ovary syndrome (PCOS) is among the most common endocrine and metabolic disorders. Kisspeptin, a neuropeptide, which has been implicated in enhancing hypothalamic-pituitary-ovarian (HPO) axis activity, might play a role in the pathogenesis of PCOS. However, previous studies have had inconsistent results.

Abstract

We aimed to evaluate the usefulness of serum kisspeptin (KP), measured in the 1st trimester (11-14 weeks), as a new biomarker that can predict antenatal complications.

Abstract

Pterygium is a prevalent ocular surface condition characterized by its extension toward the cornea at the corneoscleral junction. The etiology and development of pterygium are not fully understood. The discovery of new biomarkers may facilitate early intervention and the prevention of postoperative recurrence.

Abstract

Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions. While neuroendocrine-immune system dysfunction plays a crucial role in the development of autoimmune diseases, its involvement in MG remains largely unexplored. Kisspeptin, a neuropeptide hormone and endogenous ligand for GPR54 receptor, has been demonstrated to regulate antitumor immunity, antiviral immunity, and several autoimmune diseases. However, the role and mechanism of kisspeptin in MG remain to be elucidated.

Abstract

Ischemic stroke damages the blood-brain barrier (BBB), worsening neuronal injury. Treatments to protect the BBB are limited. We evaluated the neurovascular protective capacity of Kisspeptin-54 in ischemic stroke using in vivo and in vitro models. In vivo, mice underwent middle cerebral artery occlusion (MCAO), and cerebral infarct volume, neurological function, and blood-brain barrier (BBB) permeability were evaluated. In vitro, human brain microvascular endothelial cells (HBMVECs) were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to assess the effects of Kisspeptin-54 on paracellular flux and transendothelial electrical resistance (TEER). Additionally, GATA-4 was silenced to investigate its role in mediating protection. Our results showed that cortical ischemia downregulated KISS-1 metastasis-suppressor (KISS1, 59% mRNA; 55% protein) and G protein-coupled receptor 54 (GPR54, 54% mRNA; 48% protein), with a 32% decline in circulating Kisspeptin-54. Prophylactic Kisspeptin-54 reduced cerebral infarct volume by 42%, enhanced neurological performance by 49%, and decreased BBB leakage by 26%, with near-complete occludin recovery. In vitro: Kisspeptin-54 treatment reduced paracellular flux by 48% and increased transendothelial resistance by 60%. GATA-4 silencing abolished Kisspeptin-54-induced occludin restoration, increasing permeability by 65% and diminishing barrier resistance by 28%. This study reveals Kisspeptin-54 modulates BBB stability via GATA-4-driven occludin expression, highlighting the KISS1/GPR54 pathway as a potential therapeutic target for ischemic stroke.

Abstract

To summarize the state of knowledge on kisspeptin, a factor that alters the migration properties of some types of cancer cell and also plays an important role in the control of the reproductive axis.

Abstract

The kisspeptin/kisspeptin receptor (KISS1/KISS1R) system has emerged as a vital regulator of various physiological processes, including cancer progression, metabolic function, and reproduction. KISS1R, a member of the G protein-coupled receptor family, is crucial for regulating the hypothalamic/pituitary/gonadal axis. A growing number of KISS1R agonists are currently being investigated in clinical trials, whereas the number of antagonists remains limited. Most existing ligands are synthetic peptides, with only a few small-molecule compounds, such as musk ambrette, having been identified. In this article, we provide an overview of the KISS1/KISS1R system and its involvement in diseases such as reproductive disorders, cancer, diabetes, and cardiovascular disease. We also highlight the various technologies used to identify KISS1R ligands, including radioligand binding assays, calcium flux assays, IP1 formation assays, ERK phosphorylation assays, qRT-PCR, and AI-based virtual screening. Furthermore, we discuss the latest advances in identifying KISS1R agonists and antagonists, highlighting ongoing challenges and future directions in research. These insights lay the groundwork for future research aimed at leveraging this system for developing innovative therapeutic strategies across a range of medical conditions.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has passed; however, its long-term effects are yet to be determined. Pregnant women and their neonates faced a higher risk for complications during this pandemic as COVID-19 was reported to result in oxidative and inflammatory stress and the cytokine storm, which would impact pregnancy, namely the trophoblast invasion and placental development and functioning. Therefore, this study aims to determine the effect of COVID-19 on the placental functioning in South African pregnancies through the analysis of kisspeptin and placental morphology. Immunohistochemical analyses of placental samples were performed to detect the expression of kisspeptin. Histopathological analysis was conducted to identify vascular and inflammatory alterations. This study demonstrated that COVID-19 results in a significantly increased expression of placental kisspeptin in both the central (p = 0.001) and peripheral (p < 0.0001) regions as compared with the placentae from control pregnancies. Upon further analysis, the placentae from COVID-19 pregnancies also presented with severe inflammation and maternal and fetal vascular malperfusion compared with the control placentae. A significantly increased expression of placental kisspeptin was observed in COVID-19 positive pregnancies, implying impaired placental functioning. This was further supported by vascular and inflammatory alterations observed in COVID-19-positive placentae, which may suggest that trophoblast invasion was compromised. To date, there still exists small clusters of COVID-19 outbreaks, and our findings highlight the importance of the future surveillance of these mothers and neonates in COVID-19 pregnancies in South Africa, as neonates from other countries have presented with abnormalities.

Abstract

Kisspeptin administration by intravenous or subcutaneous routes activates hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is being developed to treat reproductive disorders. However, these invasive routes markedly limit patient acceptability and clinical use. Recent rodent data has identified a large GnRH population within the olfactory system communicating directly with hypothalamic GnRH neurons. Intranasal kisspeptin administration may be able to capitalise on this novel pathway and thus offer a potential non-invasive approach to stimulate reproductive hormones. Herein, we examine intranasal kisspeptin using human, pharmaceutical, and rodent studies.

Abstract

The neuropeptide kisspeptin activates the hypothalamic-pituitary-gonadal (HPG) axis and influences neural circuits controlling sexual behavior. Animal studies have determined its sex-specific roles in reproductive behaviors, whereas human research has linked kisspeptin to increased brain activity in regions associated with sexual and emotional processing, making it a potential treatment for disorders of sexual desire. Here I discuss the current evidence on the promise of kisspeptin as a therapy for sexual dysfunction, highlight the challenges currently hindering its application, and advocate future studies focusing on sex-specific effects and interactions within the neuroendocrine system. Understanding its broader physiological roles and improving delivery methods will be key to unlocking kisspeptin's therapeutic potential.

Abstract

Kisspeptin is a critical endogenous activator of the reproductive system, with escalating clinical interest as a novel therapeutic for common reproductive and psychosexual disorders. However, conflicting animal data suggest that kisspeptin can have anxiolytic, neutral, or anxiogenic effects.

Abstract

Per- and polyfluoroalkyl substances (PFAS) exert endocrine disruptive effects on the endocrine-metabolic axis. Emerging knowledge suggests that kisspeptin may play a key role in these effects.

Abstract

A clinically significant oxytocin-deficient state (OXT-D) has been established in adults with arginine vasopressin deficiency, and there is a need to develop diagnostic testing. Kisspeptin (KP) is a candidate for such a test, as KP receptors are found on oxytocinergic neurons, and KP administration increases plasma OXT in animals. We hypothesized that intravenous KP administration would increase peripheral OXT levels post-injection in healthy adults.