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Biomedicines Jan 2024Endometriosis is characterized by a condition where endometrial tissue grows outside the uterine cavity. The mechanisms of endometrium growth during endometriosis might...
Endometriosis is characterized by a condition where endometrial tissue grows outside the uterine cavity. The mechanisms of endometrium growth during endometriosis might be similar to the development of a tumor. The kisspeptin (KISS1) gene was initially discovered as a suppressor of metastasis. Matrix metalloproteinases (MMPs) and their inhibitors are described as factors in the early stages of endometriosis and tumor growth progression. We applied the quantitative polymerase chain reaction and the immunofluorescence method to investigate KISS1, its receptor (KISS1R), MMP-2, and MMP-9 in the eutopic and ectopic endometrium in women with and without endometriosis. We presume that the dysregulation of KISS1 and MMPs might contribute to endometriosis pathogenesis. Samples for the immunofluorescence study were collected from patients with a confirmed diagnosis of endometriosis in stages I-IV, aged 23 to 38 years old ( = 40). The cell line was derived from the endometrium of patients with extragenital endometriosis ( = 7). KISS1 and KISS1R expression are present in the ectopic endometrium of patients with extragenital endometriosis, as opposed to the control group where these proteins were not expressed. There is a decrease in KISS1 and KISS1R values at all stages of endometriosis. MMP-2 and MMP-9 genes express statistically significant increases in stages II, III, and IV of extragenital endometriosis. MMP synthesis increased in the last stages of endometriosis. We suppose that the KISS1/KISS1R system can be used in the future as a suppressive complex to reduce MMP-2 and MMP-9 expression and prevent endometrial cells from invading.
PubMed: 38255200
DOI: 10.3390/biomedicines12010094 -
Hormones and Behavior Mar 2024Early life adversity in the form of childhood maltreatment in humans or as modeled by maternal separation (MS) in rodents is often associated with an earlier emergence...
Early life adversity in the form of childhood maltreatment in humans or as modeled by maternal separation (MS) in rodents is often associated with an earlier emergence of puberty in females. Earlier pubertal initiation is an example of accelerated biological aging and predicts later risk for anxiety in women, especially in populations exposed to early life trauma. Here we investigated external pubertal markers as well as hypothalamic gene expression of pubertal regulators kisspeptin and gonadotropin-releasing hormone, to determine a biological substrate for MS-induced accelerated puberty. We further investigated a mechanism by which developmental stress might regulate pubertal timing. As kisspeptin and gonadotropin-releasing hormone secretion are typically inhibited by corticotropin releasing hormone at its receptor CRH-R1, we hypothesized that MS induces a downregulation of Crhr1 gene transcription in a cell-specific manner. Finally, we explored the association between pubertal timing and anxiety-like behavior in an acoustic startle paradigm, to drive future preclinical research linking accelerated puberty and anxiety. We replicated previous findings that MS leads to earlier puberty in females but not males, and found expression of kisspeptin and gonadotropin-releasing hormone mRNA to be prematurely increased in MS females. RNAscope confirmed increased expression of these genes, and further revealed that kisspeptin-expressing neurons in females were less likely to express Crhr1 after MS. Early puberty was associated with higher acoustic startle magnitude in females. Taken together, these findings indicate precocial maturation of central pubertal timing mechanisms after MS, as well as a potential role of CRH-R1 in these effects and an association with a translational measure of anxiety.
Topics: Humans; Rats; Female; Animals; Kisspeptins; Adverse Childhood Experiences; Maternal Deprivation; Hypothalamus; Gonadotropin-Releasing Hormone; Sexual Maturation
PubMed: 38241961
DOI: 10.1016/j.yhbeh.2024.105478 -
Reproductive Toxicology (Elmsford, N.Y.) Mar 2024As the incidence of precocious puberty has risen in recent years and the age at puberty onset is younger, children may be at increased risk for health consequences...
As the incidence of precocious puberty has risen in recent years and the age at puberty onset is younger, children may be at increased risk for health consequences associated with the early onset of puberty. Bisphenol A (BPA) is recognized as an endocrine disruptor chemical that is reported to induce precocious puberty. The effect of BPA exposure modes, times, and doses (especially low dose) were controversial. In the present study, we evaluated the potential effects of maternal exposure to low-dose BPA on the hypothalamus, particularly on the arcuate (ARC) nucleus and anteroventral periventricular (AVPV) nucleus during peri-puberty in offspring of BPA-treated rats. Pregnant rats were exposed to corn oil vehicle, 0.05 mg·kg·day BPA, or 5 mg·kg·day from gestation day 1 (GD1) to postnatal day 21 (PND21) by daily gavage. Body weight (BW), vaginal opening (VO), ovarian follicular luteinization, and relevant hormone concentrations were measured; hypothalamic Kiss1 and GnRH1 levels by western immunoblot analysis were also assessed as indices of puberty onset. During or after exposure, low-dose BPA restricted BW after birth (at PND1 and PND5), and subsequently accelerated puberty onset by promoting the expression of prepubertal Kiss1 and GnRH1 in the AVPV nucleus on PND30, leading to advanced VO, an elevation in LH and FSH concentrations (on PND30). We also noted increased BW on PND30 and PND35. Maternal oral exposure to low-dose BPA altered the BW curve during the neonatal and peripubertal periods, and subsequently accelerated puberty onset by promoting prepubertal Kiss1 expression in the AVPV nucleus.
Topics: Pregnancy; Child; Rats; Female; Animals; Humans; Maternal Exposure; Puberty, Precocious; Kisspeptins; Puberty; Benzhydryl Compounds; Phenols
PubMed: 38232916
DOI: 10.1016/j.reprotox.2024.108543 -
Journal of Traditional Chinese Medicine... Feb 2024To elucidate the mechanism of the nourishing and purging fire Chinese herbal mixture (NYPF) in delaying light-induced premature puberty in rats.
OBJECTIVE
To elucidate the mechanism of the nourishing and purging fire Chinese herbal mixture (NYPF) in delaying light-induced premature puberty in rats.
METHODS
Twenty-one days old female Sprague-Dawley rats were randomly assigned to normal group (N), long light exposure group (L), NYPF and normal saline group (NS). Rats in the L, NYPF and NS groups were exposed to 16 h: 350 lux light/8 h: dark, while rats in the N group were exposed to 12 h: 50 lux light/12 h: dark. NYPF and normal saline was administered to the rats in the NYPF group or NS group, respectively, from day 21. Five rats in every group were sacrificed at 9 p.m. on day 28 (P28), on the day when rat's vulva opened in the L group (L-VO), on the day when the first estrous interphase occurred in rats of L group (L-E1), and on the day when the second estrous interphase occurred in rats of L group (L-E2), respectively.
RESULITS
On day 34, all rats in the L group, 80% of rats in the NS group, 40% of rats in the N group, and 20% of rats in the NYPF group showed complete opening of the vulva. At P28, mRNA level of hypothalamic kisspeptin (Kiss-1) in the L group was significantly higher than that in the N group ( 0.05). The rats in the L and NS groups had significantly lower hypothalamic arginine-phenylalanine-amide (RFamide)-related peptide 3 (RFRP-3) mRNA levels than those in the N group ( 0.05), whereas RFRP-3 mRNA level was significantly higher in the NYPF group than that in the L group ( 0.05). At L-VO, the ovarian index of the L and NS groups was significantly higher than that of the N group ( 0.05) and estradiol (E2) level of the NYPF group was significantly lower than that of the N and NS groups ( 0.05); hypothalamic Kiss-1 mRNA level in the L and NS groups was significantly higher than that in the N and NYPF groups ( 0.05), whereas hypothalamic RFRP-3 mRNA level in the L, NYPF, and NS groups was significantly lower than that in the N group ( 0.05). At L-E1, E2 level of the L and NS groups was significantly higher than that of the N group ( 0.01), whereas it was significantly lower in the NYPF group than that of the N, L, and NS groups ( 0.01), and serum luteinizing hormone level of the L and NS groups was significantly higher than that of the N group ( 0.05); levels of serum melatonin and ovarian melatonin receptor 1 (MT-1) mRNA in the L, NYPF, and NS groups were significantly lower than those in the N group ( 0.05). At L-E2, the uterine organ index of the NYPF group was significantly lower than that of the L group ( 0.05); and ovarian MT-1 mRNA level of the L and NS groups was significantly lower than that in the N group ( 0.05).
CONCLUSIONS
NYPF can delay puberty onset in rats exposed to strong light for a prolonged duration, and regulation of the gene expression of Kiss-1 and RFRP-3 in the hypothalamus has been suggested as one of the mechanisms.
Topics: Rats; Animals; Female; Rats, Sprague-Dawley; Kisspeptins; Saline Solution; Sexual Maturation; Hypothalamus; RNA, Messenger
PubMed: 38213244
DOI: 10.19852/j.cnki.jtcm.20230814.001 -
Frontiers in Endocrinology 2023The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level...
The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice.
BACKGROUND
The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN. SCN VIP neurons are known to regulate circadian rhythms and reproductive function.
METHODS
To specifically study SCN VIP neurons, we generated a novel knock out mouse line by conditionally deleting the SCN enriched transcription factor, Ventral Anterior Homeobox 1 (Vax1), in VIP neurons (Vax1; Vax1:Vip).
RESULTS
We found that Vax1 females presented with lengthened estrous cycles, reduced circulating estrogen, and increased depressive-like behavior. Further, Vax1 males and females presented with a shortened circadian period in locomotor activity and SCN circadian period. On a molecular level, the shortening of the SCN period was driven, at least partially, by a direct regulatory role of VAX1 on the circadian clock genes and . Interestingly, Vax1 females presented with increased expression of arginine vasopressin () in the paraventricular nucleus, which resulted in increased circulating corticosterone. SCN VIP and AVP neurons regulate the reproductive gonadotropin-releasing hormone (GnRH) and kisspeptin neurons. To determine how the reproductive neuroendocrine network was impacted in Vax1 mice, we assessed GnRH sensitivity to a kisspeptin challenge . We found that GnRH neurons in Vax1 females, but not males, had an increased sensitivity to kisspeptin, leading to increased luteinizing hormone release. Interestingly, Vax1 males showed a small, but significant increase in total sperm and a modest delay in pubertal onset. Both male and female Vax1 mice were fertile and generated litters comparable in size and frequency to controls.
CONCLUSION
Together, these data identify VAX1 in SCN VIP neurons as a neurological overlap between circadian timekeeping, female reproduction, and depressive-like symptoms in mice, and provide novel insight into the role of SCN VIP neurons.
Topics: Male; Female; Animals; Mice; Transcription Factors; Vasoactive Intestinal Peptide; Kisspeptins; Semen; Suprachiasmatic Nucleus; Reproduction; Neurons; Circadian Rhythm; Gonadotropin-Releasing Hormone; Neuropeptides; Homeodomain Proteins
PubMed: 38205198
DOI: 10.3389/fendo.2023.1269672 -
Endocrinology Dec 2023There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin,... (Review)
Review
There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy cells) is crucial for the generation of gonadotrophin-releasing hormone (GnRH) pulses in mammals. The initial "KNDy hypothesis" proposed that pulsatile GnRH secretion is elicited by episodic kisspeptin release from KNDy cells following synchronized activation and termination of the population by NKB and dynorphin, respectively. Since then, the role of KNDy cells as a critical component of the pulse generator has been further supported by studies at the single-cell level, demonstrating that the population is both necessary and sufficient for pulsatility. In addition, there have been considerable modifications and expansion of the original hypothesis, including work demonstrating the critical role of glutamate in synchronization of the KNDy cell network, functional interactions with other ARC subpopulations, and the existence of species differences in the role of dynorphin in pulse generation. Here we review these recent changes and discuss how the translation of these findings has led to the development of new therapies for disorders related to pulse generation. We also outline critical gaps in knowledge that are currently limiting the application of KNDy research in the clinic, particularly regarding the role of dynorphin in pulse generation in primates.
Topics: Animals; Gonadotropin-Releasing Hormone; Dynorphins; Kisspeptins; Hypothalamus; Arcuate Nucleus of Hypothalamus; Neurokinin B; Neurons; Mammals
PubMed: 38170643
DOI: 10.1210/endocr/bqad194 -
Autoimmunity Dec 2024Recurrent spontaneous abortions (RSA) affect reproductive health and increase the risk of subsequent abortions. To investigate the role of KISS-1/GPR-54 signaling in RSA...
Recurrent spontaneous abortions (RSA) affect reproductive health and increase the risk of subsequent abortions. To investigate the role of KISS-1/GPR-54 signaling in RSA progression. Villus tissue was collected from RSA patients, and human trophoblastic HTR-8/SVneo cells were used. KISS-1 and GRP54 levels were detected using RT-qPCR and immunohistochemistry. Western blotting was performed to analyze ZO-1 and ZEB1 levels. Cell proliferation was determined CCK-8 and cell clone formation assays. Transwell assays were performed to assess cell migration and invasion abilities. KISS-1 was down-regulated in the villus tissues of RSA patients. KISS-1 overexpression dramatically inhibited trophoblast proliferation, migration, and invasion. Mechanistically, ZEB1 expression was down-regulated, whereas ZO-1 expression was up-regulated, after KISS-1 overexpression. GPR54 silencing neutralized the effect of KISS-1 in HTR-8/SVneo cells. Additionally, KISS-1 overexpression inactivated the PI3K/AKT signaling pathway through GRP54. The KISS-1/GPR-54 signaling axis regulates RSA progression by regulating the PI3K/AKT signaling pathway.
Topics: Female; Humans; Pregnancy; Cell Movement; Cell Proliferation; Kisspeptins; Phosphatidylinositol 3-Kinases; Pre-Eclampsia; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 38155490
DOI: 10.1080/08916934.2023.2297564 -
Neuroendocrinology 2024Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown neuroprotective effects in obese mice. However, whether SGLT2i can ameliorate high-fat diet (HFD)-related...
INTRODUCTION
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown neuroprotective effects in obese mice. However, whether SGLT2i can ameliorate high-fat diet (HFD)-related ovulation disorders remains unknown. The aim of this research was to investigate whether dapagliflozin improves HFD-induced ovulatory dysfunction by attenuating microglia-mediated hypothalamic inflammation.
METHODS
C57BL/6J female mice fed HFD were treated with dapagliflozin (1 mg/kg) for 22 weeks. Plasma insulin, leptin, luteinizing hormone (LH), estradiol (E2), and IL-1β levels were also tested. Microglial morphology, cell numbers, and SGLT2 expression were evaluated using immunofluorescence. The expression of IL-1β, NLRP3, kisspeptin, gonadotropin-releasing hormone (GnRH), SGLT2, insulin, and leptin receptors in the hypothalamus was determined using immunohistochemical staining. We also examined the effects of dapagliflozin on glucose metabolism and the release of inflammatory factor in palmitic acid (PA)-treated HMC3 cells.
RESULTS
As expected, dapagliflozin improved HFD-induced metabolic disturbances, peripheral versus central insulin and leptin resistance and also restored the regular estrous cycle. Furthermore, dapagliflozin blunted microglia activation, NLRP3 inflammasome priming, hypothalamic inflammation, and increased the expression of GnRH and kisspeptin at proestrus in the hypothalamus. Additionally, dapagliflozin markedly reduced IL-6 and NO release and fat accumulation, decreased lactic acid production and glucose consumption, and inhibited mammalian target of rapamycin (mTOR) and hexokinase 2 (HK2) expression in PA-treated HMC3 cells. These effects suggest that dapagliflozin reduced the mTOR/HK2-mediated aerobic glycolysis.
CONCLUSIONS
Dapagliflozin improved HFD-related ovulation disorders by regulating glucose metabolism through mTOR/HK2 signaling and attenuating microglia-mediated hypothalamic inflammation. These results validate the novel role for the neuroprotection of SGLT2i in HFD-induced obesity and ovulation disorders.
Topics: Mice; Female; Animals; Diet, High-Fat; Leptin; Sodium-Glucose Transporter 2; NLR Family, Pyrin Domain-Containing 3 Protein; Kisspeptins; Microglia; Mice, Inbred C57BL; Inflammation; TOR Serine-Threonine Kinases; Hypothalamus; Insulin; Glucose; Gonadotropin-Releasing Hormone; Ovulation; Mammals; Benzhydryl Compounds; Glucosides
PubMed: 38147832
DOI: 10.1159/000535420 -
Endocrine Regulations Jan 2023Hypothalamic-pituitary gonadal (HPG) axis is responsible for the development and regulation of the female reproductive system. In polycystic ovary syndrome (PCOS), there... (Review)
Review
Hypothalamic-pituitary gonadal (HPG) axis is responsible for the development and regulation of the female reproductive system. In polycystic ovary syndrome (PCOS), there is a disturbance in the HPG axis. Kisspeptin, a neuropeptide produced by the KISS1 gene, plays a vital role in the regulation of HPG axis by binding with its receptors KISS1R/GPR54, and stimulates gonadotropin secretion from the hypothalamus into pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Polymorphisms or mutations in the KISS1 gene can cause disturbance in the kisspeptin signaling pathway and is thought to disrupt HPG axis. Altered signaling of kisspeptin can cause abnormal secretion of GnRH pulse, which leads to increased LH/FSH ratio, thereby affecting androgen levels and ovulation. The increased levels of androgen worsen the symptoms of PCOS. In the present article, we review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS. The goal of this review article is to provide an overview and metabolic profile of kisspeptin in PCOS patients and the expression of kisspeptin in PCOS animal models. In the present article, we also review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS.
Topics: Animals; Female; Humans; Polycystic Ovary Syndrome; Kisspeptins; Androgens; Luteinizing Hormone; Follicle Stimulating Hormone
PubMed: 38127687
DOI: 10.2478/enr-2023-0032 -
ELife Dec 2023Evidence suggests that estradiol-sensing preoptic area GABA neurons are involved in the preovulatory surge mechanism necessary for ovulation. In vivo CRISPR-Cas9 editing...
Evidence suggests that estradiol-sensing preoptic area GABA neurons are involved in the preovulatory surge mechanism necessary for ovulation. In vivo CRISPR-Cas9 editing was used to achieve a 60-70% knockdown in estrogen receptor alpha (ESR1) expression by GABA neurons located within the regions of the rostral periventricular area of the third ventricle (RP3V) and medial preoptic nuclei (MPN) in adult female mice. Mice exhibited variable reproductive phenotypes with the only significant finding being mice with bilateral ESR1 deletion in RP3V GABA neurons having reduced cFos expression in gonadotropin-releasing hormone (GnRH) neurons at the time of the surge. One sub-population of RP3V GABA neurons expresses kisspeptin. Re-grouping ESR1-edited mice on the basis of their RP3V kisspeptin expression revealed a highly consistent phenotype; mice with a near-complete loss of kisspeptin immunoreactivity displayed constant estrus and failed to exhibit surge activation but retained pulsatile luteinizing hormone (LH) secretion. These observations demonstrate that ESR1-expressing GABA-kisspeptin neurons in the RP3V are essential for the murine preovulatory LH surge mechanism.
Topics: Mice; Female; Animals; Kisspeptins; CRISPR-Cas Systems; Gonadotropin-Releasing Hormone; GABAergic Neurons; Estrous Cycle; gamma-Aminobutyric Acid
PubMed: 38126277
DOI: 10.7554/eLife.90959