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BMC Women's Health Jan 2023The development of polycystic ovary syndrome (PCOS) is closely correlated with apoptosis and oxidative stress in ovarian granulosa cells. Kisspeptin plays an important...
BACKGROUND
The development of polycystic ovary syndrome (PCOS) is closely correlated with apoptosis and oxidative stress in ovarian granulosa cells. Kisspeptin plays an important role in reproductive organ function. This study aimed to explore the role of kisspeptin in PCOS and oxidative stress-triggered apoptosis of ovarian granular cells.
METHODS
A PCOS rat model was established by injecting dehydroepiandrosterone (DHEA) and feeding the rats a high-fat diet. The RNA and protein levels of kisspeptin were analysed by quantitative PCR, western blotting, and histological staining. Tissue damage was evaluated using haematoxylin and eosin (H&E) staining. The viability and proliferation of human granulosa cell KGN were measured using the cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and apoptosis were analysed by flow cytometry. Oxidative stress was analysed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels.
RESULTS
Kisspeptin was downregulated in the ovarian granulosa cells of PCOS rats compared to those of control rats. Kisspeptin overexpression enhanced KGN cell proliferation and inhibited apoptosis. ROS generation was suppressed by kisspeptin, along with decreased levels of MDA and increased levels of the antioxidants GSH, SOD, and CAT. Kisspeptin activates PI3K/AKT and ERK signalling, and inactivation of ERK1/2 suppresses the protective role of kisspeptin in ovarian granulosa cells.
CONCLUSION
Kisspeptin improves proliferation and alleviates apoptosis and oxidative stress in ovarian granulosa cells by activating PI3K/AKT and ERK signalling.
Topics: Female; Rats; Humans; Animals; Polycystic Ovary Syndrome; Proto-Oncogene Proteins c-akt; Kisspeptins; Phosphatidylinositol 3-Kinases; Reactive Oxygen Species; Apoptosis; Cell Proliferation; Granulosa Cells; Superoxide Dismutase
PubMed: 36627631
DOI: 10.1186/s12905-022-02154-6 -
The Lancet. Diabetes & Endocrinology Mar 2023Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues.... (Review)
Review
Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.
Topics: Male; Female; Humans; Puberty; Kisspeptins; Puberty, Precocious
PubMed: 36620967
DOI: 10.1016/S2213-8587(22)00339-4 -
Scientific Reports Jan 2023Simultaneous knockout of the neuroendocrine marker genes Ptprn and Ptprn2, which encode the protein tyrosine phosphatase receptors N and N2, causes infertility in female...
Simultaneous knockout of the neuroendocrine marker genes Ptprn and Ptprn2, which encode the protein tyrosine phosphatase receptors N and N2, causes infertility in female mice while males are fertile. To elucidate the mechanism of the sex-specific roles of Ptprn and Ptprn2 in mouse reproduction, we analyzed the effects of their double knockout (DKO) on the hypothalamic-pituitary-gonadal axis. In DKO females, delayed puberty and lack of ovulation were observed, complemented by changes in ovarian gene expression and steroidogenesis. In contrast, testicular gene expression, steroidogenesis, and reproductive organs development were not significantly affected in DKO males. However, in both sexes, pituitary luteinizing hormone (LH) beta gene expression and LH levels were reduced, as well as follicle-stimulating hormone beta gene and gonadotropin-releasing hormone (GnRH) gene, while the calcium-mobilizing and LH secretory actions of GnRH were preserved. Hypothalamic Gnrh1 and Kiss1 gene expression was also reduced in DKO females and males. In parallel, a significant decrease in the density of immunoreactive GnRH and kisspeptin fibers was detected in the hypothalamic arcuate nucleus of DKO females and males. The female-specific kisspeptin immunoreactivity in the rostral periventricular region of the third ventricle was also reduced in DKO females, but not in DKO males. These data indicate a critical role of Ptprn and Ptprn2 in kisspeptin-GnRH neuronal function and sexual dimorphism in the threshold levels of GnRH required to preserve reproductive functions.
Topics: Male; Female; Mice; Animals; Kisspeptins; Gonadotropin-Releasing Hormone; Reproduction; Hypothalamus; Protein Tyrosine Phosphatases
PubMed: 36611058
DOI: 10.1038/s41598-023-27497-4 -
Molecules and Cells Dec 2022Liver cancer has a high prevalence, with majority of the cases presenting as hepatocellular carcinoma (HCC). The prognosis of metastatic HCC has hardly improved over the...
Liver cancer has a high prevalence, with majority of the cases presenting as hepatocellular carcinoma (HCC). The prognosis of metastatic HCC has hardly improved over the past decade, highlighting the necessity for liver cancer research. Studies have reported the ability of the gene to inhibit the growth or metastasis of liver cancer, but contradictory research results are also emerging. We, therefore, sought to investigate the effects of on growth and migration in human HCC cells. HepG2 human HCC cells were infected with lentivirus particles containing . The overexpression of resulted in an increased proliferation rate of HCC cells. Quantitative polymerase chain reaction and immunoblotting revealed increased Akt activity, and downregulation of the G1/S phase cell cycle inhibitors. A significant increase in tumor spheroid formation with upregulation of β-catenin and CD133 was also observed. overexpression promoted the migratory, invasive ability, and metastatic capacity of the hepatocarcinoma cell line, and these effects were associated with changes in the expressions of epithelial mesenchymal transition (EMT)-related genes such as E-cadherin, N-cadherin, and slug. overexpression also resulted in dramatically increased tumor growth in the xenograft mouse model, and upregulation of proliferating cell nuclear antigen (PCNA) and Ki-67 in the HCC tumors. Furthermore, increased the angiogenic capacity by upregulation of the vascular endothelial growth factor A (VEGF-A) and CD31. Based on these observations, we infer that not only induces HCC proliferation, but also increases the metastatic potential by increasing the migratory ability and angiogenic capacity.
Topics: Animals; Humans; Mice; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Kisspeptins; Liver Neoplasms; Vascular Endothelial Growth Factor A
PubMed: 36572562
DOI: 10.14348/molcells.2022.0105 -
Frontiers in Endocrinology 2022The intestinal microbiota and its derived short-chain fatty acids (SCFAs) can reverse obesity and obesity-related metabolic diseases, but whether it has an effect on...
The intestinal microbiota and its derived short-chain fatty acids (SCFAs) can reverse obesity and obesity-related metabolic diseases, but whether it has an effect on obesity complicated by precocious puberty and its potential mechanism need to be further understood. The purpose of this study was to investigate the effect of the gut microbiota and its derived short-chain fatty acids (SCFAs) on obesity-induced precocious puberty rats and their regulatory mechanisms. We constructed obesity-induced precocious puberty rats using a high-fat diet (HFD) had notable similarity to precocious puberty caused by obesity due to overeating in children. We then added acetate, propionate, butyrate or their mixture to the HFD, and investigated the effect of intestinal microbiota and its derived SCFAs on the hypothalamic-pituitary-gonadal axis (HPGA) in rats with obesity-induced precocious puberty. We found that obesity-induced precocious puberty rats had an early first estrous cycle, increased hypothalamic mRNA expression of Kiss1, GPR54 and GnRH, and early gonadal maturation. Meanwhile, the intestinal microbiota imbalance and the main SCFAs production decreased in the colon. The addition of acetate, propionate, butyrate or their mixture to the HFD could significantly reverse the precocious puberty of rats, reduce GnRH release from the hypothalamus and delay the development of the gonadal axis through the Kiss1-GPR54-PKC-ERK1/2 pathway. Our findings suggest that gut microbiota-derived SCFAs are promising therapeutic means for the prevention of obesity-induced precocious puberty and provide new therapeutic strategies with clinical value.
Topics: Rats; Animals; Female; Gastrointestinal Microbiome; Kisspeptins; Propionates; Obesity; Fatty Acids, Volatile; Gonadotropin-Releasing Hormone; Butyrates
PubMed: 36568086
DOI: 10.3389/fendo.2022.1051797 -
BMC Endocrine Disorders Dec 2022Non-alcoholic fatty liver disease (NAFLD) adversely affects reproduction. We aimed to study the effect of a high-fat diet (HFD), supplemented with apple vinegar, on...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) adversely affects reproduction. We aimed to study the effect of a high-fat diet (HFD), supplemented with apple vinegar, on folliculogenesis in a rat model of NAFLD.
METHODS
Female rats were randomly divided into four groups (N = 28): Standard diet (SD), SD + vinegar, HFD, and HFD + vinegar groups. At the end of the study, biochemical tests were assessed in serum. HOMA-IR (Homeostatic model assessment-Insulin resistance) was calculated. Sex hormones were determined using an ELISA kit; ovary follicle counts were studied using histological methods. The proliferation index of granulosa cells was determined using immunohistochemistry. Kisspeptin expression in the ovary was detected using RT-PCR.
RESULTS
The HFD induced steatohepatitis and NAFLD. The ovaries in the rat model of NAFLD were atrophied. The ovaries had less count of developing follicles and corpus luteum, and more degenerated and cystic follicles in comparison with the SD group. Vinegar + HFD consumption decreased ALT, compared to the HFD group (P = 0.004). Steatohepatitis was reduced in the Vinegar + HFD group (P = 0.001). Vinegar + HFD considerably reduced HOMA-IR (p = 0.01). The HFD + vinegar diet could increase estradiol (P = 0.001), without significantly affecting progesterone or testosterone. In addition, an increase of primordial follicles as an ovarian reserve and also primary follicles were determined in the HFD + vinegar group. There were no statistical differences in the granulosa cell proliferation index in various follicle types between groups. HFD + vinegar significantly enhanced ovarian kisspeptin expression (p = 0.04).
CONCLUSIONS
The vinegar diet in a rat model of NAFLD raises estradiol, primordial, and small primary follicles, and increases ovarian kisspeptin expression indirectly. Insulin resistance and obesity were improved by apple vinegar, and anti-glycemic and anti-lipidemic effects were also determined. The supplementation of apple vinegar in NAFLD might be useful for ovary. However, it requires further investigation.
Topics: Rats; Animals; Female; Non-alcoholic Fatty Liver Disease; Ovary; Acetic Acid; Kisspeptins; Malus; Insulin Resistance; Diet, High-Fat; Estradiol; Liver
PubMed: 36564752
DOI: 10.1186/s12902-022-01205-1 -
Physiology & Behavior Mar 2023This study investigated the possible relationships between the expression of the Kiss1 and Gpr54 gene expressions and the pituitary-gonadal hormones with the female...
Prenatal restraint stress downregulates the hypothalamic kisspeptidergic system transcripts genes, reduces the estrogen plasma levels, delayed the onset of puberty, and reduced the sexual behavior intensity in female rats.
AIMS
This study investigated the possible relationships between the expression of the Kiss1 and Gpr54 gene expressions and the pituitary-gonadal hormones with the female onset of puberty and sexual behavior. The Kiss1 and Gpr54 gene expressions were examined because they are critical to controlling the hypothalamic activation of GnRH neurons and, in turn, the pituitary-gonadal hormones related to the early onset of puberty and sexual behavior. Further, it was evaluated that the pituitary and gonadal hormones involved in the vaginal opening and the expression of sexual behavior.
METHODS
Pregnant rats exposed to PRS from gestation days 17 to 20 were evaluated for maternal and open-field behaviors. The maternal behavior was analyzed because it may alter brain sexual organization affecting the pups development. It was observed in female pups the physical and development and, in adult age, the open-field behavior, the anxiety-like behavior, the estrous cycle, the sexual behavior, the serum FSH, LH, estrogen, progesterone, and testosterone levels, and the gene expression of kisspeptin protein (Kiss1) and Gpr54 in the hypothalamus.
RESULTS
the maternal and open-field behaviors were unaffected. In the F1 generation, PRS reduced weight at weaning, delayed the day of the vaginal opening and reduced the intensity of lordosis, the estrogen levels, and the Kiss1 and Gpr54 gene expression. These effects were attributed to hypothalamic kisspeptidergic system downregulation of transcripts genes and the reduced estrogen levels affected by the PRS.
Topics: Pregnancy; Rats; Animals; Female; Kisspeptins; Sexual Maturation; Hypothalamus; Estrogens
PubMed: 36563733
DOI: 10.1016/j.physbeh.2022.114055 -
Maedica Sep 2022Endometriosis is defined by the presence of endometrial tissue outside the uterus, therefore leading to a chronic inflammatory reaction, adhesions development, scar...
Endometriosis is defined by the presence of endometrial tissue outside the uterus, therefore leading to a chronic inflammatory reaction, adhesions development, scar tissue and a distorted pelvic female anatomy, most of the times leading to female infertility. Kisspeptin represents a neuropeptide thought to have an essential role in the reproductive functions of both female and male patients. Recently, positive correlations with kisspeptins were noticed in patients diagnosed with endometriosis. Our study was performed between January 2021-March 2022 in "Elena Doamna" Clinical Hospital of Obstetrics and Gynecology Iasi, Romania. It was a prospective case-control study and included two groups of patients. Both groups consisted in female patients aged between 18 and 45 years, with a body mass index (BMI) between 18,5-30 kg/m2 and similar medical data. Patients in the study group had primary or secondary infertility and endometriosis, while the control group consisted of women with no reproductive issues who had healthy regular menstruations and at least one child. All patients agreed to participate in our study and signed the consent form. Clinical examination, pelvic ultrasound and hormonal dosages were performed. We tested the levels of LH, FSH, kisspeptin, estradiol, prolactin, testosterone, insulin and the glycemic levels in both groups during the follicular phase of their menstrual cycle. We managed to enroll eight patients with endometriosis in the study group and an equal number of patients in the control group. There were significant differences between serum kisspeptin levels, but not also between other hormonal dosages. All patients in the study group had medical evidences of endometriomas but none of them had been subjected to laparoscopy. When considering our study, we regarded the first attribution given to kisspeptin, the one of a metastasis suppressor, and concluded that the high serum values of kisspeptin in patients with endometriosis represented a compensatory-adaptive mechanism needed to constrain future spread of endometriomas in early stages of this pathology.
PubMed: 36540601
DOI: 10.26574/maedica.2022.17.3.557 -
Scientific Reports Dec 2022Kisspeptin (kp) is a key regulator of reproduction, which stimulates sexual maturation and gametogenesis in mammals, amphibians, and teleosts. In the present study, to...
Kisspeptin (kp) is a key regulator of reproduction, which stimulates sexual maturation and gametogenesis in mammals, amphibians, and teleosts. In the present study, to enhance the biological activity of kp10, a novel analog (referred to as M-kp10) was designed based on the endogenous goldfish variant, in which phenylalanine 6 was substituted by tryptophan and the N-terminus was acetylated. Compared with the native kp-10 and salmon gonadotropin-releasing hormone (GnRH3), the effect of M-kp10 on sexual hormones and reproductive indices as well as the expression of kiss1, cyp19a1, and kiss1ra genes in goldfish (Carassius auratus) was investigated. In practice, peptides were synthesized based on the standard Fmoc-solid-phase peptide synthesis and purified by employing RP-HPLC, followed by approving their structure using ESI-MS. The results showed that M-kp10 increased significantly 17,20β-DHP, LH, FSH and E2 as well as fecundity, hatching and fertilization percentages than the other peptides. Histological studies revealed that M-kp10 led to the faster growth of ovarian follicles compared to the kp-10 and GnRH3. The genes of cyp19a1, kiss1ra, and kiss1 were remarkably more expressed after treatment with M-kp10. In conclusion, the results indicated the superiority of M-kp10 over kp-10 in inducing sexual maturation and accelerating the percentage of fecundity, suggesting that M-kp10 could be a promising candidate for application in the artificial breeding of fish.
Topics: Animals; Female; Kisspeptins; Goldfish; Gonadotropin-Releasing Hormone; Reproduction; Mammals
PubMed: 36536005
DOI: 10.1038/s41598-022-25950-4 -
Frontiers in Endocrinology 2022One of the main health concerns of diabetes is testicular dysfunction and impairment of reproductive function and sperm quality which can cause male infertility....
One of the main health concerns of diabetes is testicular dysfunction and impairment of reproductive function and sperm quality which can cause male infertility. kisspeptin is a hypothalamic neuropeptide hormone that is involved in the regulation of energy metabolism, gonadotrophin-releasing hormone (GnRH), and reproductive function. In the present study, the therapeutic effects of empagliflozin (sodium-glucose co-transporter 2 inhibitors) on kisspeptin expression along with reproductive function were investigated in diabetic male Wistar rats. Diabetes was induced by a single dose injection of 60 mg/kg streptozotocin. Empagliflozin in doses of 10 and 25 mg/kg body weight was used for 8 weeks. Serum samples, testis, epididymis, and pancreas tissues were collected at the end of the experiments. Lipid profiles, oxidative stress markers, blood hormones, expression of kisspeptin along with pathological alterations of the testis were assayed using real-time PCR, biochemical, and histological technics. Data have shown that empagliflozin improved hyperglycemia, reproductive impairment, oxidative stress condition, and histopathological alterations of pancreatic and testis tissues in diabetic animals. It improved the serum levels of sex hormones, insulin, leptin, and the expression of kisspeptin in the testes tissues. Spermatogenesis is also improved in treated animals. Data indicated that the administration of empagliflozin can ameliorate symptoms of diabetes. It probably has promising antidiabetic potential and may improve the male infertility of diabetic subjects. To our knowledge, this is the first experimental evidence for the potential impact of empagliflozin on kisspeptin expression in diabetic male rats.
Topics: Animals; Male; Rats; Infertility, Male; Kisspeptins; Rats, Wistar; Semen; Streptozocin; Diabetes Mellitus, Experimental; Sodium-Glucose Transporter 2 Inhibitors; Genitalia, Male
PubMed: 36479221
DOI: 10.3389/fendo.2022.1059942