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GeroScience Apr 2024The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of...
The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction's echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13's influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.
Topics: Humans; Rats; Animals; Male; Aged; Kisspeptins; Receptors, Kisspeptin-1; Rats, Wistar; Renal Insufficiency, Chronic; Cardiomyopathies; Hypertension; Fibrosis
PubMed: 37987885
DOI: 10.1007/s11357-023-01017-8 -
Endocrinology Nov 2023The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive...
The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive pulsatile hormone secretion remains unclear in females. In order to study spontaneous synchronization within the ARNKISS neuron network, acute brain slices were prepared from adult female Kiss1-GCaMP6 mice. Analysis of both spontaneous synchronizations and those driven by high frequency stimulation of individual ARNKISS neurons revealed that the network exhibits semi-random emergent excitation dependent upon glutamate signaling through AMPA receptors. No role for NMDA receptors was identified. In contrast to male mice, ongoing tachykinin receptor tone within the slice operated to promote spontaneous synchronizations in females. As previously observed in males, we found that ongoing dynorphin transmission in the slice did not contribute to synchronization events. These observations indicate that a very similar AMPA receptor-dependent mechanism underlies ARNKISS neuron synchronizations in the female mouse supporting the "glutamate two-transition" model for kisspeptin neuron synchronization. However, a potentially important sex difference appears to exist with a more prominent facilitatory role for tachykinin transmission in the female.
Topics: Mice; Female; Male; Animals; Kisspeptins; Dynorphins; Arcuate Nucleus of Hypothalamus; Neurokinin B; Brain; Neurons; Glutamates; Gonadotropin-Releasing Hormone
PubMed: 37936337
DOI: 10.1210/endocr/bqad167 -
Fertility and Sterility Jan 2024Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce... (Randomized Controlled Trial)
Randomized Controlled Trial
Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from 2 randomized, placebo-controlled clinical tricals.
BACKGROUND
Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce oocyte maturation during in vitro fertilization treatment, including in women who are at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported.
OBJECTIVE
To determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (phase-2a trial).
DESIGN
Two randomized, placebo-controlled, parallel-group, dose-finding trials.
SETTING
Clinical trials unit.
PATIENTS
Healthy women aged 18-35 years, either without (phase-1; n = 24), or with ovarian stimulation (phase-2a; n = 75).
INTERVENTIONS
Phase-1: single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 μg) or placebo, (n = 6 per dose). Phase-2a: single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 μg; n = 16-17 per dose), triptorelin 0.2 mg (n = 5; active comparator), or placebo (n = 5).
MAIN OUTCOME MEASURES
Phase-1: safety/tolerability; pharmacokinetics; and pharmacodynamics (luteinizing hormone [LH] and other reproductive hormones). Phase-2a: safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); and time to ovulation assessed by transvaginal ultrasound.
RESULTS
In both the trials, MVT-602 was safe and well tolerated across the entire dose range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours. In the phase-2a trial, LH concentrations increased dose dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3 μg MVT-602 and remained >15 IU/L for 33 hours. Time to ovulation after drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 μg), 88% (1 μg), 82% (0.3 μg), and 75% (0.1 μg), of women after MVT-602, 100% after triptorelin and 60% after placebo.
CONCLUSIONS
MVT-602 induces LH concentrations of similar amplitude and duration as the physiological midcycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR.
CLINICAL TRIAL REGISTRATION NUMBER
EUDRA-CT: 2017-003812-38, 2018-001379-20.
Topics: Female; Humans; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Kisspeptins; Luteinizing Hormone; Ovulation Induction; Triptorelin Pamoate; Adolescent; Young Adult; Adult
PubMed: 37925096
DOI: 10.1016/j.fertnstert.2023.10.031 -
Frontiers in Endocrinology 2023Male reproduction is under the control of the hypothalamus-pituitary-gonadal (HPG) axis. The endocannabinoid system (ECS) and the kisspeptin system (KS) are two major...
INTRODUCTION
Male reproduction is under the control of the hypothalamus-pituitary-gonadal (HPG) axis. The endocannabinoid system (ECS) and the kisspeptin system (KS) are two major signaling systems in the central and peripheral control of reproduction, but their possible interaction has been poorly investigated in mammals. This manuscript analyzes their possible reciprocal modulation in the control of the HPG axis.
MATERIALS AND METHODS
Adolescent male rats were treated with kisspeptin-10 (Kp10) and endocannabinoid anandamide (AEA), the latter alone or in combination with the type 1 cannabinoid receptor (CB1) antagonist rimonabant (SR141716A). The hypothalamic KS system and GnRH expression, circulating sex steroids and kisspeptin (Kiss1) levels, and intratesticular KS and ECS were evaluated by immunohistochemical and molecular methods. Non-coding RNAs (i.e., , , , ) were also considered.
RESULTS
Circulating hormonal values were not significantly affected by Kp10 or AEA; in the hypothalamus, Kp10 significantly increased mRNA and aromatase Cyp19, Kiss1, and Kiss1 receptor (Kiss1R) proteins. By contrast, AEA treatment affected the hypothalamic KS at the protein levels, with opposite effects on the ligand and receptor, and SR141716A was capable of attenuating the AEA effects. Among the considered non-coding RNA, only the expression of miR145-5p was positively affected by AEA but not by Kp10 treatment. Localization of Kiss1+/Kiss1R+ neurons in the arcuate nucleus revealed an increase of Kiss1R-expressing neurons in Kp10- and AEA-treated animals associated with enlargement of the lateral ventricles in Kp10-treated animals. In the brain and testis, the selected non-coding RNA was differently modulated by Kp10 or AEA. Lastly, in the testis, AEA treatment affected the KS at the protein levels, whereas Kp10 affected the intragonadal levels of CB1 and FAAH, the main modulator of the AEA tone. Changes in pubertal transition-related miRNAs and the intratesticular distribution of Kiss1, Kiss1R, CB1, and CB2 following KP and AEA treatment corroborate the KS-ECS crosstalk also showing that the CB1 receptor is involved in this interplay.
CONCLUSION
For the first time in mammals, we report the modulation of the KS in both the hypothalamus and testis by AEA and revealed the KP-dependent modulation of CB1 and FAAH in the testis. KP involvement in the progression of spermatogenesis is also suggested.
Topics: Male; Rats; Animals; Kisspeptins; Receptors, Kisspeptin-1; Endocannabinoids; Rimonabant; Hypothalamus; Gonadotropin-Releasing Hormone; Mammals; Reproduction; RNA, Untranslated; MicroRNAs
PubMed: 37900144
DOI: 10.3389/fendo.2023.1269334 -
Frontiers in Endocrinology 2023The neuroendocrine control of ovulation is orchestrated by neuronal circuits that ultimately drive the release of gonadotropin-releasing hormone (GnRH) from the...
BACKGROUND
The neuroendocrine control of ovulation is orchestrated by neuronal circuits that ultimately drive the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus to trigger the preovulatory surge in luteinizing hormone (LH) secretion. While estrogen feedback signals are determinant in triggering activation of GnRH neurons, through stimulation of afferent kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V neurons), many neuropeptidergic and classical neurotransmitter systems have been shown to regulate the LH surge. Among these, several lines of evidence indicate that the monoamine neurotransmitter serotonin (5-HT) has an excitatory, permissive, influence over the generation of the surge, activation of type 2 5-HT (5-HT) receptors. The mechanisms through which this occurs, however, are not well understood. We hypothesized that 5-HT exerts its influence on the surge by stimulating RP3V neurons in a 5-HT receptor-dependent manner.
METHODS
We tested this using kisspeptin neuron-specific calcium imaging and electrophysiology in brain slices obtained from male and female mice.
RESULTS
We show that exogenous 5-HT reversibly increases the activity of the majority of RP3V neurons. This effect is more prominent in females than in males, is likely mediated directly at RP3V neurons and requires activation of 5-HT receptors. The functional impact of 5-HT on RP3V neurons, however, does not significantly vary during the estrous cycle.
CONCLUSION
Taken together, these data suggest that 5-HT receptor-mediated stimulation of RP3V neuron activity might be involved in mediating the influence of 5-HT on the preovulatory LH surge.
Topics: Mice; Female; Male; Animals; Preoptic Area; Kisspeptins; Serotonin; Neurons; Gonadotropin-Releasing Hormone; Receptors, Serotonin; Neurotransmitter Agents
PubMed: 37900129
DOI: 10.3389/fendo.2023.1212854 -
Scientific Reports Oct 2023We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with...
We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals were treated with Kp10. Hypothyroidism reduced testicular and sex gland mass, decreased the proliferation of the seminiferous epithelium, and compromised sperm morphology, motility, and vigor. A decrease in plasma LH and testosterone levels and an increase in prolactin secretion were observed in the hypothyroid rats. Hypothyroidism reduced Kiss1 and Kiss1r protein and gene expression and Star and Cyp11a1 mRNA levels in the testis. Furthermore, it reduced Lhb, Prl, and Drd2 and increased Tshb and Gnrhr expression in the pituitary. In the hypothalamus, hypothyroidism increased Pdyn and Kiss1r while reducing Gnrh1. Kp10 treatment in hypothyroid rats restored testicular and seminal vesicle morphology, improved sperm morphology and motility, reversed high prolactin levels, and increased LH and testosterone levels. In addition, Kp10 increased testicular expression of Kiss1, Kiss1r, Fshr, and Nr5a1 and pituitary Kiss1 expression. Our findings describe the inhibitory effects of hypothyroidism on the male gonadal axis and sperm quality and demonstrate that Kp10 treatment reverses high prolactin levels and improves gonadal function and sperm quality in hypothyroid rats.
Topics: Rats; Animals; Male; Kisspeptins; Prolactin; Luteinizing Hormone; Receptors, Kisspeptin-1; Semen; Hypothyroidism; Testis; Testosterone
PubMed: 37798396
DOI: 10.1038/s41598-023-44056-z -
Frontiers in Oncology 2023Metastatic dissemination is still one of the major causes of death of melanoma's patients. KiSS1 is a metastasis suppressor originally identified in melanoma cells,...
Metastatic dissemination is still one of the major causes of death of melanoma's patients. KiSS1 is a metastasis suppressor originally identified in melanoma cells, known to play an important physiological role in mammals' development and puberty. It has been previously shown that expression of KiSS1 could be increased in lung cancer cells using epigenetic agents, and that KiSS1 could have a pro-apoptotic action in combination with cisplatin. Thus, the aim of the present study was to examine in human melanoma vemurafenib sensitive- and -resistant BRAF mutant cells characterized by different mutational profiles and KiSS1, KiSS1 receptor and KiSS1 drug-induced release, if peptides derived from KiSS1 cleavage, i.e., kisspeptin 54, could increase the sensitivity to vemurafenib of human melanoma, using cellular, molecular and biochemical approaches. We found that kisspeptin 54 increases vemurafenib pro-apoptotic activity in a statistically significant manner, also in drug resistant cellular models. The efficacy of the combination appears to reflect the intrinsic susceptibility of each cell line to PLX4032-induced apoptosis, together with the different mutational profile as well as perturbation of proteins regulating the apoptotic pathway, The results presented here highlight the possibility to exploit KiSS1 to modulate the apoptotic response to therapeutically relevant agents, suggesting a multitasking function of this metastasis suppressor.
PubMed: 37790750
DOI: 10.3389/fonc.2023.1182853 -
The Journal of International Medical... Sep 2023To identify the effects of metformin and kisspeptin structural polymorphism on the risk of polycystic ovary syndrome (PCOS) in Iraqi women.
OBJECTIVE
To identify the effects of metformin and kisspeptin structural polymorphism on the risk of polycystic ovary syndrome (PCOS) in Iraqi women.
METHODS
Samples were collected at the family planning center of Al-Hassan Teaching Hospital (infertility clinic), Iraq. Hormonal and hematological parameters were measured. Kisspeptin structural polymorphisms were analyzed by polymerase chain reaction using a conventional thermal cycler and Phyre2 predictions. Kisspeptin concentrations were assessed by an enzyme-linked immunosorbent assay.
RESULTS
Follicle-stimulating hormone (FSH) was the only sex hormone that changed in women with PCOS after metformin treatment. FSH concentrations were significantly increased after therapy compared with before therapy (9.39 ± 2.1 vs 5.13 ± 1.53 IU/L). We found that a single nucleotide polymorphism substituting G to C was related to PCOS. The kisspeptin structural polymorphism showed that the C allele was related to low FSH concentrations after treatment (6.92 ± 2.2 IU/L to 5.34 ± 1.58 IU/L). Kisspeptin concentrations were significantly lower after metformin treatment than before metformin treatment (395.44 ± 67.83 vs 273.18 ± 42.98 ng/mL).
CONCLUSION
A variation in the gene or its protein structure may be involved in the development of PCOS. The response to metformin may be used as an indicator and could contribute to the early diagnosis and medical therapy of PCOS.
Topics: Humans; Female; Kisspeptins; Iraq; Polycystic Ovary Syndrome; Follicle Stimulating Hormone, Human; Polymorphism, Single Nucleotide; Metformin
PubMed: 37702549
DOI: 10.1177/03000605231196837 -
Biology of Reproduction Nov 2023Kisspeptin (KP, encoded by Kiss1, binding to the Gpr54 receptor) is a neuropeptide conveying information on the metabolic status to the hypothalamic-pituitary-gonadal...
Maternal cafeteria diet influences kisspeptin (Kiss1), kisspeptin receptor(Gpr54), and sirtuin (Sirt1) genes, hormonal and metabolic profiles, and reproductive functions in rat offspring in a sex-specific manner†.
Kisspeptin (KP, encoded by Kiss1, binding to the Gpr54 receptor) is a neuropeptide conveying information on the metabolic status to the hypothalamic-pituitary-gonadal axis. KP acts together with dynorphin A (encoded by Pdyn) and neurokinin B (encoded by Tac2) to regulate reproduction. KP is crucial for the onset of puberty and is under the control of sirtuin (encoded by Sirt1). We hypothesize that the maternal cafeteria (CAF) diet has adverse effects on the offspring's hormonal, metabolic, and reproductive functions due to sex-specific alterations in the expression of Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 in the hypothalamus, and Kiss1, Gpr54, and Sirt1 in the liver. Rats were fed a CAF diet before pregnancy, during pregnancy, and during lactation. The vaginal opening was monitored. Offspring were sacrificed in three age points: PND 30, PND 35, and PND 60 (females) and PND 40, PND 45, and PND 60 (males). Their metabolic and hormonal status was assessed. mRNA for Kiss1, Gpr54, Pdyn, Tac2, and Sirt1 were measured by real-time PCR in the hypothalamus and/or livers. We found that CAF offspring had lower weight and altered body composition; increased cholesterol and triglyceride levels, sex-specific changes in glucose and insulin levels; sex-dependent changes in Sirt1/Kiss1 mRNA ratio in the hypothalamus; sex-specific alterations in Kiss1 and Sirt1 mRNA in the liver with more diversity in males; and a delayed puberty onset in females. We concluded that the mother's CAF diet leads to sex-specific alterations in metabolic and reproductive outcomes via Kiss1/Gpr54 and Sirt1 systems in offspring.
Topics: Pregnancy; Female; Male; Rats; Animals; Kisspeptins; Sirtuin 1; Sexual Maturation; Receptors, Kisspeptin-1; Diet; Metabolome; RNA, Messenger
PubMed: 37665248
DOI: 10.1093/biolre/ioad101 -
In Vivo (Athens, Greece) 2023To investigate the possible association of kisspeptin levels with the ovarian reserves of women of reproductive age.
BACKGROUND/AIM
To investigate the possible association of kisspeptin levels with the ovarian reserves of women of reproductive age.
PATIENTS AND METHODS
Eighty women aged 19-40 participated after signing an informed consent. Of these, 74 were finally included as in 6 women the blood samples were considered inappropriate due to hemolysis. They were divided into three main groups according to their ovarian reserve patterns: women with adequate ovarian reserves (Group A - AOR) (n=30), women with increased ovarian reserves (Group B - PCOS) (n=31), and women with diminished ovarian reserves (Group C - DOR) (n=13).
RESULTS
Women with diminished ovarian reserves had statistically significantly increased age and FSH compared to the other two groups. No statistically significant difference was found between the three groups for estradiol and thyroid stimulating hormone. Moreover, body mass index, luteinizing hormone, total testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone, anti-Mullerian hormone (AMH), and antral follicle count (AFC) were increased in group B compared to the other two groups. AMH and AFC were decreased in women with diminished ovarian reserves compared to the other two groups, as expected. The comparison of kisspeptin levels between the three groups showed that kisspeptin levels were increased in women with diminished ovarian reserves, compared to the other two groups, but without a statistically significant difference. However, kisspeptin levels in group C were statistically significantly higher than those in group A.
CONCLUSION
There are no strong indications that kisspeptin levels are associated with the ovarian reserve in women of reproductive age.
Topics: Female; Humans; Ovarian Reserve; Kisspeptins; Testosterone; Anti-Mullerian Hormone; Estradiol
PubMed: 37652519
DOI: 10.21873/invivo.13322