KissPeptin-10

Abstract

Glioblastoma multiforme (GB) is the most aggressive and lethal primary brain tumor, with limited biomarkers for diagnosis and therapeutic targeting. This study aimed to investigate the regulatory effects of Kisspeptin-10 on epithelial-mesenchymal transition (EMT) and apoptosis in GB by integrating transcriptomic profiling, network analysis, and in-vitro validation. Kisspeptin-10, a metastasis-suppressor peptide known to modulate EMT and apoptotic pathways in several cancers, has not been previously explored in GB. Differentially expressed genes (DEGs) were identified from publicly available GEO datasets using limma, followed by STRING-based protein-protein interaction (PPI) analysis, cytoHubba-based hub gene ranking, and construction of miRNA-mRNA regulatory networks. A total of 1401 DEGs were identified, including 859 upregulated and 542 downregulated genes, enriched in pathways associated with EMT regulation, cell-cycle progression, extracellular matrix remodeling, and apoptosis. Hub genes such as CDK1, CDC20, JUN, and FABP5 were identified, while miR-200, miR-345, and miR-577 emerged as key regulatory miRNAs linked to EMT and apoptotic signaling. In-vitro validation further supported the modulatory effects of Kisspeptin-10 on EMT and apoptosis markers in GB cells. These findings highlight the diagnostic and therapeutic relevance of Kisspeptin-10-associated molecular regulation in GB. This is the first study to integrate transcriptomics, miRNA-mRNA network analysis, and experimental validation to elucidate Kisspeptin-10-mediated modulation of GB progression.

Abstract

Microglial NLRP3 inflammasome activation plays a central role in the neuroinflammatory cascade that contributes to the pathogenesis of various neurodegenerative diseases. Activation of the canonical inflammasome pathway leads to caspase-1 activation, gasdermin D (GSDMD) cleavage, and pyroptotic cell death, along with the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Kisspeptin-10 (KP-10), a bioactive neuropeptide of the kisspeptin family, has been shown to exert regulatory effects on immune function; however, its role in neuroinflammation process remains unclear. In this study, we investigated the effects of KP-10 on LPS + ATP-induced NLRP3 inflammasome activation and pyroptotic signaling in murine microglial cells.

Abstract

Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide, with metabolic syndrome emerging as a major risk factor. However, the molecular mechanisms underlying the association between metabolic syndrome and hepatocellular carcinoma progression are not fully understood. Here, we investigated the role of kisspeptin signaling in hepatocellular carcinoma progression under metabolic dysregulation. High-fat diet feeding significantly decreased hepatic kisspeptin receptor expression in mice. Integrated transcriptomic and metabolomic analyses revealed that kisspeptin primarily regulated glycolysis-related pathways. In a N-Nitrosodiethylamine-induced hepatocellular carcinoma mouse model, high-fat diet accelerated tumor progression accompanied by kisspeptin receptor downregulation. Treatment with kisspeptin-10 attenuated high-fat diet-promoted hepatocellular carcinoma progression and decreased the expression of key glycolytic enzymes HK, PFKM, and PKM2. In vitro studies using HepG2 cells further confirmed that kisspeptin-10 inhibited these glycolytic enzymes in a dose-dependent manner. The integration of transcriptomic and metabolomic data demonstrated that kisspeptin exerts broad inhibitory effects on metabolism, particularly glucose metabolism, also suggesting potential antitumor effect. Our results suggest kisspeptin as a potential therapeutic target for hepatocellular carcinoma in patients with metabolic syndrome.

Abstract

Kisspeptin is a neuropeptide recognised for a pivotal role within the reproductive system, but potentially important endocrine metabolic effects are less well understood. We examined effects of twice-daily intraperitoneal administration of saline vehicle or kisspeptin-10 (25 nmol/kg), for 21 days, on glucose homeostasis, energy balance, circulating hormones as well as the morphology-function of enteroendocrine and islet cells in high-fat diet (HFD) fed female mice, with normal diet (ND) mice as an additional control group. Kisspeptin-10 decreased body weight, blood glucose and energy intake to ND levels. HFD increased circulating follicle-stimulating hormone (FSH) levels, which were further enhanced by kisspeptin-10 along with luteinising hormone (LH) concentrations. Neither HFD nor kisspeptin-10 affected progesterone or corticosterone. In the ileum, kisspeptin-10 decreased crypt depth and restored villi length to ND control levels, as well as increasing the proportion of glucose-dependent insulinotropic polypeptide (GIP) positive cells when compared to HFD mice and glucagon-like peptide-1 (GLP-1) positive cells compared to ND mice. Peptide YY (PYY) immunoreactivity was unaltered by HFD or kisspeptin-10. Plasma GIP was unchanged but circulating GLP-1 and PYY were reduced to ND levels. Within the pancreas, total islet, beta- and alpha-cell areas were similar in all mice, but kisspeptin-10 intervention restored relative insulin area to ND levels. Glucagon radius, an indicator of peripherally located alpha-cells, was reduced in HFD mice but normalised by kisspeptin-10 alongside elevated glucagon-islet area. Notably, beta-cell proliferation was increased by kisspeptin-10 with no alteration in beta-cell apoptosis. Overall, we reveal a previously uncharacterised diverse metabolic role for kisspeptin in directly modulating the gut-pancreatic axis.

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

Gestational diabetes mellitus (GDM) is a common pregnancy complication that leads to insulin resistance (IR) and adversely affects both maternal and fetal health. Kisspeptin-10 (Kp-10), a peptide acting via G Protein-Coupled Receptor 54 (Gpr54), has shown potential in modulating insulin secretion, but its role in GDM remains unclear. This study explores Kp-10's therapeutic effects on GDM by targeting IR in placental tissues. We used GDM rat models (induced by a high-fat diet and streptozotocin) and high-glucose-treated HTR8/SVneo trophoblast cells to investigate Kp-10's effects on glucose metabolism, insulin signaling, and the cAMP/PKA pathway. Our results show that Gpr54 expression was significantly downregulated in the placental tissues of GDM rats, which was associated with impaired glucose uptake and IR. Kp-10 treatment improved fasting blood glucose (FBG) levels, insulin sensitivity, and fetal outcomes, including increased fetal weight and decreased fetal blood glucose. Moreover, Kp-10 restored the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway and enhanced glucose uptake by upregulating Glut-4, Insr, and Irs1 expression in both placental tissues and HTR8/SVneo cells. The effects of Kp-10 were reversed by the cAMP inhibitor SQ22536, confirming the involvement of the cAMP/PKA pathway in its anti-IR effects. Our findings suggest that Kp-10 has the potential as a therapeutic agent for alleviating IR in GDM and improving maternal-fetal outcomes.

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

Mammalian reproductive function is regulated by hypothalamic neurons that secrete Kisspeptin (Kp), a neuropeptide that stimulates gonadotropin-releasing hormone (GnRH) secretion, triggering pituitary gonadotrophins (LH and FSH) and gonadal steroids. This study evaluated the effect of Kisspeptin-10 (Kp10) on ovulation induction in rabbits, comparing its efficacy with that of the GnRH analogue gonadorelin. Multiparous New Zealand White × California does were assigned to three groups: control group (0.5 % saline solution, i.v.), GnRH group (20 μg gonadorelin, i.m.), and Kp10 group (250 μg Kp10, i.v.). Kp10 induced ovulation in 87.5 % of does, matching the response observed in the GnRH group, with a comparable number of corpora lutea (CL) per ovulated doe (12.9 ± 1.4 vs 14.6 ± 1.4 CL/doe, respectively). On day 7, plasma progesterone (P4) was significantly higher in ovulated GnRH-treated does than in Kp10-treated ones (25.12 ± 4.17 vs 9.47 ± 4.17 ng/mL; p < 0.0211), while non-ovulated controls exhibited minimal P4 concentrations (0.86 ± 0.12 ng/mL). Plasma estradiol (E2) levels showed no significant differences across days or groups, with mean values of 32.74 ± 4.33 pg/mL on day 0 and 37.27 ± 5.49 pg/mL on day 7, respectively. Histological analysis confirmed that Kp10 promoted preovulatory follicle development and CL formation, mirroring GnRH effects. Additionally, Kp10 enhanced angiogenesis, indicated by increased vascular endothelial growth factor (VEGF) expression in more developed follicles and CL. These results suggest that Kp10 could be an alternative to GnRH for ovulation induction in rabbits, although further studies are needed to explore optimal analogues, doses, and administration routes.

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

In Osteoarthritis (OA), the senescence of chondrocytes plays a pivotal role, contributing to cartilage degradation and impairing tissue repair mechanisms. (Kp-10), a peptide hormone, exerts diverse biological functions across multiple cell types and tissues via its receptor Gpr54. However, its role in chondrocytes and OA has been understudied. This study investigates the role of Kp-10 in mitigating TNF-α- induced senescence in primary chondrocytes, a hallmark of OA pathogenesis. Gpr54 expression was confirmed in both primary chondrocytes and the ATDC5 chondrogenic cell line, with TNF-α treatment leading to a dose-dependent decrease in Gpr54 expression. Kp-10 treatment at concentrations of 50 and 100 nM effectively ameliorated TNF-α-induced senescence, as evidenced by diminished senescence-associated β-galactosidase staining and enhanced telomerase activity. Moreover, Kisspeptin-10 modulated the expression of key regulators involved in cellular aging, including hTERT and TERF2, and suppressed the activation of the p53/p21 pathway. Notably, Kp-10 restored SIRT1 expression, which was downregulated by TNF-α. Silencing SIRT1 abolished the protective effects of Kp-10, highlighting the essential role of SIRT1 in its anti-senescence action. These findings suggest that Kp-10 may be a promising therapeutic strategy for OA by mitigating chondrocyte senescence and improving cellular function by modulating the SIRT1 and p53/p21 pathways.

Abstract

Cerebral aneurysms (CAs) are a prevalent brain condition with poorly understood pathological features. The Kisspeptin-10 (KP-10)/G protein-coupled receptor 54 (GPR54) system is a vital neuroendocrine pathway primarily implicated in the regulation of reproductive functions and energy metabolism. This research explores the role of the KP-10/GPR54 system in CAs.

Abstract

Neurogenesis is considered the most robust form of plasticity in the adult brain. To better decipher this process, we evaluated the potential crosstalk of Kisspeptin and Endocannabinoid Systems (KPS and ECS, respectively) on hippocampal neurogenesis. Male adolescent rats were exposed to kisspeptin-10 (KP10) and the endocannabinoid anandamide (AEA) administered alone or in combination with the type 1 cannabinoid receptor (CB1R) antagonist SR141716A. The expression of Kiss1 and Kisspeptin receptor (Kiss1R) has been characterized for the first time in rat hippocampus together with the expression of the CB1R and the Transient Receptor Potential Vanilloid 1 ion channel receptor (TRPV1). Results show that both systems inhibit neurogenesis by reducing the extracellular signal-regulated kinase (ERK) signaling. Despite little differences in the expression of Kiss1R and CB1R, TRPV1 is enhanced by both KP10 and AEA treatments, suggesting TRPV1 as a common thread. KP10 administration reduces CB1R expression in the dentate gyrus, while AEA does not. KPS, unlike ECS, promotes the expression of estrogen receptor α (ER-α) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), also upregulating sirtuin 1 (SIRT1), brain-derived-neurotrophic factor (BDNF), and c-Jun. These findings suggest that the interaction between ECS and KPS could be involved in the fine-tuning of neurogenesis, highlighting a novel role for KPS.

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

Esophageal cancer (EC) treatment remains challenging due to the disease's aggressive nature, frequent late-stage diagnosis, and the need for effective multimodal therapies with minimal side effects. Kisspeptin-10, a naturally occurring neuropeptide and known GPR54 agonist, has been shown to significantly influence tumor growth and progression. However, its specific role in EC remains poorly understood. To address this knowledge gap, we designed this study to investigate the role of Kisspeptin-10 (KP-10) and its receptor GPR54 in EC. We first assessed KP-10 expression in esophageal carcinoma tissues and cell lines using immunohistochemistry, real-time PCR, and western blot analysis. Through lentivirus transduction, we manipulated KP-10 expression and evaluated its effects on cell viability, apoptosis, migration, stemness, epithelial-mesenchymal transition (EMT), and the SIX1/Wnt/β-catenin signaling pathway. These evaluations were performed using CCK-8 assay, TUNEL assay, Transwell assay, mammosphere formation assay, and western blot analysis. Our results demonstrated significantly reduced expression of both KP-10 and GPR54 in EC samples and cell lines compared to healthy tissues. Following KP-10 overexpression in KYSE150 EC cells, we observed inhibited cell growth, promoted apoptosis, decreased cell migration, reduced cancer stem cell properties, and suppressed EMT. Furthermore, KP-10 overexpression inhibited the Wnt/β-catenin signaling pathway, an effect that was reversed by SIX1 overexpression, suggesting that KP-10's impact on this pathway is mediated through SIX1. These findings indicate that KP-10 plays a crucial role in suppressing EC progression and represents a promising therapeutic target for clinical treatment. However, more comprehensive studies are needed to fully elucidate the underlying mechanisms and explore the clinical potential of KP-10 in EC therapy.

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

The aim of the present study was to understand the involved factors in follicular cysts in dairy cows. The study consisted of an in vivo and in vitro approach. The in vivo part, hormonal evaluation (Kisspeptin-10 [Kp-10], Gonadotropin inhibiting hormone [GnIH], Luteinizing hormone [LH], Oestrogens [E2] and cortisol) was performed in sera of both healthy (H) and cows with follicular cysts (FC). The in vitro part was concentrated on estimating the distribution of GPR54 (Kp-10 receptor) and GPR147 (GnIH receptor) on cystic and preovulatory follicles. Serum concentrations of Kp-10, GnIH, LH, E2 and cortisol were significantly higher in Group FC compared with Group H. Gene expression analysis showed a reduction in GPR54 mRNA levels in FC compared to preovulatory follicles, while no expression of the GPR147 receptor was detected. The lower presence of GPR54 in FC compared to the preovulatory follicle can be determined by a down-receptor regulation induced by elevated serum concentrations of Kp-10 in cows with ovarian FC. Endocrine imbalances of the hypothalamic-pituitary-ovarian axis, characterising FC, may reflect altered patterns of Kp-10 and GnIH secretion.

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.