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Background: Nesfatin-1 is a neuropeptide that regulates the hypothalamic-pituitary-gonadal axis and may play a role in uterus function. It is co-expressed with other peptides, such as phoenixin, which can influence sex hormone secretion. Our previous research has confirmed that phoenixin-14 is involved in the development of cystic endometrial hyperplasia (CEH) and pyometra in dogs. Therefore, based on the similarities and interactions between these neuropeptides, we hypothesized that nesfatin-1 might also regulate the reproductive system in dogs. This study aimed to determine the expression of nesfatin-1 and its interaction with phoenixin-14 in dogs with CEH or pyometra compared to healthy females, and concerning animals' body condition score (BCS 4–5/9 vs. BCS > 5/9). Results: The analysis of nesfatin-1 in the uterus of bitches consisted of qPCR, western blot and immunofluorescence assays, and ELISAs. The results showed significantly higher nesfatin-1 encoding gene, nucleobindin-2 mRNA (Nucb2) and nesfatin-1 protein expression in overweight females and those suffering from CEH or pyometra compared to healthy animals. The immunoreactivity of nesfatin-1 was elevated in the uteri of bitches with higher BCS > 5/9. Moreover, nesfatin-1 blood concentrations increased in all examined overweight bitches. In the case of phoenixin signals, we found opposite results, regardless of the female body condition score. Conclusion: The etiology of CEH and pyometra are not fully known, although we have expanded the level of knowledge with respect to the possible interaction of nesfatin-1 and phoenixin in female dogs' uteri. They interact oppositely. With increasing female body weight, the expression of nesfatin-1 in the uterus and its peripheral blood concentration increased. However, for female dogs affected by CEH and pyometra, a decreased level of phoenixin-14, irrespective of their body condition score is characteristic. This knowledge could be crucial in the development of biomarkers for these conditions, which may lead to earlier recognition. [ABSTRACT FROM AUTHOR]

Phoenixin (PNX) is a conserved secreted peptide that was identified 10 years ago with numerous studies published on its pleiotropic functions. PNX is associated with estrous cycle length, protection from a high‐fat diet, and reduction of anxiety behavior. However, no study had yet evaluated the impact of deleting PNX in the whole animal. We sought to evaluate a mouse model lacking the PNX parent gene, small integral membrane protein 20 (Smim20), and the resulting effect on reproduction, energy homeostasis, and anxiety. We found that the Smim20 knockout mice had normal fertility and estrous cycle lengths. Consistent with normal fertility, the hypothalamii of the knockout mice showed no changes in the levels of reproduction‐related genes, but the male mice had some changes in energy homeostasis‐related genes, such as melanocortin receptor 4 (Mc4r). When placed on a high‐fat diet, the wildtype and knockout mice responded similarly, but the male heterozygous mice gained slightly less weight. When placed in an open field test box, the female knockout mice traveled less distance in the outer zone, indicating alterations in anxiety or locomotor behavior. In summary, the homozygous knockout of PNX did not alter fertility and modestly alters a few neuroendocrine genes in response to a high‐fat diet, especially in the female mice. However, it altered the behavior of mice in an open field test. PNX therefore may not be crucial for reproductive function or weight, however, we cannot rule out possible compensatory mechanisms in the knockout model. Understanding the role of PNX in physiology may ultimately lead to an enhanced understanding of neuroendocrine mechanisms involving this enigmatic peptide. [ABSTRACT FROM AUTHOR]

Abstract Background Nesfatin-1 is a neuropeptide that regulates the hypothalamic-pituitary-gonadal axis and may play a role in uterus function. It is co-expressed with other peptides, such as phoenixin, which can influence sex hormone secretion. Our previous research has confirmed that phoenixin-14 is involved in the development of cystic endometrial hyperplasia (CEH) and pyometra in dogs. Therefore, based on the similarities and interactions between these neuropeptides, we hypothesized that nesfatin-1 might also regulate the reproductive system in dogs. This study aimed to determine the expression of nesfatin-1 and its interaction with phoenixin-14 in dogs with CEH or pyometra compared to healthy females, and concerning animals’ body condition score (BCS 4–5/9 vs. BCS > 5/9). Results The analysis of nesfatin-1 in the uterus of bitches consisted of qPCR, western blot and immunofluorescence assays, and ELISAs. The results showed significantly higher nesfatin-1 encoding gene, nucleobindin-2 mRNA (Nucb2) and nesfatin-1 protein expression in overweight females and those suffering from CEH or pyometra compared to healthy animals. The immunoreactivity of nesfatin-1 was elevated in the uteri of bitches with higher BCS > 5/9. Moreover, nesfatin-1 blood concentrations increased in all examined overweight bitches. In the case of phoenixin signals, we found opposite results, regardless of the female body condition score. Conclusion The etiology of CEH and pyometra are not fully known, although we have expanded the level of knowledge with respect to the possible interaction of nesfatin-1 and phoenixin in female dogs’ uteri. They interact oppositely. With increasing female body weight, the expression of nesfatin-1 in the uterus and its peripheral blood concentration increased. However, for female dogs affected by CEH and pyometra, a decreased level of phoenixin-14, irrespective of their body condition score is characteristic. This knowledge could be crucial in the development of biomarkers for these conditions, which may lead to earlier recognition.

Multiple factors, such as stress, excessive deviations in body weight (obesity and cachexia), eating disorders, including anorexia nervosa, energy-deficient conditions and insulin resistance affect women's reproductive health due to dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis and the following ovulatory dysfunction, categorized as hypothalamic hypogonadism, that may present with menstrual cycle disturbances and/ or infertility. The kisspeptinergic system is the one that links stress, nutrition and reproductive signals and plays a key role in maintaining normal pulsatility of gonadotropin-releasing hormone (GnRH) and ovulation. In addition to leptin and insulin, elevated corticotropin-releasing hormone (CRH) and the activation of hypothalamic-pituitary-adrenal (HPA) axis are thought to be key modulators of ovulatory dysfunction. Neuroendocrine regulation of the reproductive processes is a subject of intense research, having in mind the global increase in the incidence of infertility. The purpose of this review is to present the effector elements of the HPG and HPA axis, to gather the available information about the markers and regulators, that are known to date - kiss-peptins, adipocytokines, appetite modulators, as well as to present some newly discovered neuro-peptides (spexin and phoenixin), that are involved in the modulation of reproductive functions, with the potential to reveal new mechanisms in the pathogenesis and to discover new possibilities for the treatment of ovulatory dysfunctions. [ABSTRACT FROM AUTHOR]

Aim. The aim of the study was to assess concentrations of the following neuropeptides: phoenixin, spexin and kisspeptin in venous blood serum of children and adolescents suffering from bipolar disorder, and by this their predictive efficiency in this disorder. Material. The study included 75 individuals with a mean age of 15.26 years (95% CI: 14.86-15.67), of which the study group comprised 57 individuals diagnosed with bipolar affective disorder and the control group - 18 individuals with no psychiatric diagnosis and no pharmacological treatment. Method. Phoenixin, spexin and kisspeptin levels were determined in the peripheral venous blood serum. Neuropeptide concentrations were measured with the enzyme-linked immunosorbent assay (ELISA). Results. The mean phoenixin concentration in the studied group equalled 1.57 ng/ml (95% CI: 1.35-1.79), while in the control group - 2.69 ng/ml (95% CI: 2.38-3; U Mann-Whitney test p-value < 0.05). For spexin, these results were 639.65 pg/ml (95% CI: 558.86-720.44) in the studied group, and 354.28 pg/ml (95% CI: 310.33-398.22; U Mann-Whitney test p-value < 0.05) in the control group. The observed differences were statistically significant. The mean concentration of kisspeptin levels in the studied group was 126.02 pg/ml (95% CI: 39.82-212.23; median: 59.85), while in the control group - 54.83 pg/ml (95% CI: 39.23-70.43; median: 51.3; U Mann-Whitney test p-value = 0.29), and the observed difference was not statistically significant. Conclusions. The occurrence of bipolar disorder symptoms is statistically significantly linked with a decreased phoenixin concentration and to a small degree - with an increased spexin concentration in blood serum of patients. However, it is not linked with the kisspeptin concentration. [ABSTRACT FROM AUTHOR]

There are some initial suggestions in the literature that phoenixin, spexin, nesfatin-1 and kisspeptin may play a role in the pathogenesis of affective disorders. Therefore, they may also be cautiously considered as potential diagnostic or predictive biomarkers of BD. This study aimed to evaluate the levels of the aforementioned neuropeptides in the peripheral blood of children and adolescents with bipolar. This study included 122 individuals: 67 persons with diagnosed bipolar disorder types I and II constituted the study group, and 55 healthy persons were included in the control group. Statistically significant differences in the concentrations of neuropeptides between the control and study groups were noted in relation to nesfatin-1 and spexin (although spexin lost statistical significance after introducing the Bonferroni correction). In a logistic regression analysis, an increased risk of bipolar disorder was noted for a decrease in nesfatin-1 concentration. Lower levels of nesfatin-1 seemed to be a significant risk factor for the development of bipolar disorder types I and II. Furthermore, the occurrence of bipolar disorder was associated with significantly elevated levels of spexin. None of the analyzed neuropeptides was significantly correlated with the number of symptoms of bipolar disorder. [ABSTRACT FROM AUTHOR]

Purpose: Acute central serous chorioretinopathy (ACSCR) is a condition characterized by decreased visual acuity, macular thickening, and edema under the retinal layer. Although the underlying mechanisms of the disease are not fully understood, oxidative stress is considered to be a critical risk factor. The aim of this study was to shed light on the pathophysiology of ACSCR by investigating the levels of circulating trimethylamine N-oxide (TMAO), phoenixin (PNX), alarin (ALA), and spexin (SPX) molecules in ACSCR patients. Methods: The study included 30 ACSCR patients and 30 healthy individuals as controls. ACSCR was diagnosed using optical coherence tomography (OCT) imaging. Five mL blood samples were collected from all participants following overnight fasting. The levels of TMAO, PNX, ALA, and SPX in the blood samples were measured using the ELISA method. Results: Visual acuity was found to be significantly reduced in ACSCR patients compared to the control group (<0.05), while macular thickness was increased (<0.05). Furthermore, TMAO, PNX, and ALA levels were significantly higher in ACSCR patients (<0.05), while SPX levels were significantly lower compared to the control group (<0.05). In ACSCR patients, there was a positive correlation between macular thickness and TMAO, PNX, and ALA; there was, however, a negative correlation with SPX. Additionally, visual acuity was negatively correlated with TMAO, PNX, and ALA, while SPX levels decreased as visual acuity decreased. Conclusions: These results demonstrate a correlation between the TMAO, PNX, ALA, and SPX levels of ACSCR patients and their visual acuity and macular thickness. Given the role of these molecules in ACSCR's pathophysiology, they hold promise as potential diagnostic, therapeutic, and follow-up markers in the future. [ABSTRACT FROM AUTHOR]

Introduction: Heart failure (HF) nowadays in western countries is an immense problem largely due to its social impact as well as an economic burden. A widely accepted biomarker-based strategy to establish prognosis and predict re-hospitalization events in HF is lacking. Currently, besides natriuretic peptides and cardiac troponins, a variety of molecules are being studied. Phoenixin (PNX) is a neuropeptide mainly involved in the regulation of gonadotropin secretion. Recently, a significant cardioprotective effect of PNX was reported. Aim : The aim of this study was to measure PNX plasma concentration in a group of HF with reduced ejection fraction (HFrEF) patients and to compare it to levels found in HF-negative participants. Material and methods: A group of 74 HFrEF patients and a control group consisting of 40 participants without systolic or diastolic myocardial dysfunction were studied. Each individual underwent anthropometric measurements, laboratory testing, clinical and echocardiographic examination. To evaluate PNX plasma concentration, an immunoenzymatic assay (ELISA) was performed. Results and discussion: PNX plasma concentration in the HFrEF group was not statistically different than in the control group. No significant correlation between PNX level and age, sex, BMI, HF etiology, diabetes or atrial fibrillation presence was found. PNX concentration correlated positively with total and LDL cholesterol blood levels in HFrEF patients. A negative correlation was found with creatinine in HFrEF, uric acid and triglycerides levels as well as AlAT activity in the control group. Conclusions: There is no significant difference in PNX plasma concentration between HF and non-HF individuals. PNX role in cardiovascular disease requires further investigation. [ABSTRACT FROM AUTHOR]

There are some initial suggestions in the literature that phoenixin, spexin, nesfatin-1 and kisspeptin may play a role in the pathogenesis of affective disorders. Therefore, they may also be cautiously considered as potential diagnostic or predictive biomarkers of BD. This study aimed to evaluate the levels of the aforementioned neuropeptides in the peripheral blood of children and adolescents with bipolar. This study included 122 individuals: 67 persons with diagnosed bipolar disorder types I and II constituted the study group, and 55 healthy persons were included in the control group. Statistically significant differences in the concentrations of neuropeptides between the control and study groups were noted in relation to nesfatin-1 and spexin (although spexin lost statistical significance after introducing the Bonferroni correction). In a logistic regression analysis, an increased risk of bipolar disorder was noted for a decrease in nesfatin-1 concentration. Lower levels of nesfatin-1 seemed to be a significant risk factor for the development of bipolar disorder types I and II. Furthermore, the occurrence of bipolar disorder was associated with significantly elevated levels of spexin. None of the analyzed neuropeptides was significantly correlated with the number of symptoms of bipolar disorder.

Endometriosis is one of the most common gynecologic diseases in women of reproductive age. The pathophysiology of endometriosis is still not fully understood. Phoenixin (PNX-14) is a newly discovered neuropeptide that regulates the hypothalamo – pituitary – gonadal (HPG) axis and reproductive functions. Recently, we reported that PNX-14, its precursor protein and receptor were expressed in human endometrium. Moreover, PNX-14 serum levels in endometriosis were reduced. This study aimed to evaluate the in vitro biological functions of physiological PNX-14 concentrations on the ectopic endometrium Z12 cells. The proliferation and migration of Z12 cells were assessed using the xCELLigence® RTCA DP system following 72 h of stimulation with 0.05 and 0.2 nM of PNX-14. GPR173 and small integral membrane protein 20 (SMIM20) gene expression was evaluated using quantitative polymerase chain reaction (qPCR) and the protein levels of GPR173 were analyzed using Western blot analysis. PNX-14 at the concentration observed in the serum of patients with endometriosis (0.05 nM) reduced GPR173 and increased SMIM20 expression, while protein levels of GPR173 remained unchanged. Cell proliferation was increased by the 0.02 nM PNX-14— the concentration found in healthy subjects. The 0.2 nM of PNX-14 decreased SMIM20 expression with no change to GPR173 expression and reduced ectopic epithelial cell proliferation during the first 5 h after stimulation. However, at 72 h, the proliferation increased. This study shows that PNX-14 at endometriosis specific concentration desensitized ectopic epithelium to PNX-14, and increased the expression of SMIM20 to restore the physiological levels of PNX-14. • Phenixin-14 at endometriosis-specific concentration increases Z12 cells migration. • Phenixin-14 at endometriosis-specific concentration decreases GPR173 expression. • Phenixin-14 at endometriosis-specific concentration increases SMIM20 expression. • Phenixin-14 at healthy women-specific concentration increases Z12 proliferation. • Phenixin-14 at healthy women-specific concentration decreases SMIM20 expression. [ABSTRACT FROM AUTHOR]

Phoenixin is a pleiotropic peptide, whose known functions have broadened significantly over the last decade. Initially first described as a reproductive peptide in 2013, phoenixin is now recognized as being implicated in hypertension, neuroinflammation, pruritus, food intake, anxiety as well as stress. Due to its wide field of involvement, an interaction with physiological as well as psychological control loops has been speculated. It has shown to be both able to actively reduce anxiety as well as being influenced by external stressors. Initial rodent models have shown that central administration of phoenixin alters the behavior of the subjects when confronted with stress-inducing situations, proposing an interaction with the perception and processing of stress and anxiety. Although the research on phoenixin is still in its infancy, there are several promising insights into its functionality, which might prove to be of value in the pharmacological treatment of several psychiatric and psychosomatic illnesses such as anorexia nervosa, post-traumatic stress disorder as well as the increasingly prevalent stress-related illnesses of burnout and depression. In this review, we aim to provide an overview of the current state of knowledge of phoenixin, its interactions with physiological processes as well as focus on the recent developments in stress response and the possible novel treatment options this might entail. [ABSTRACT FROM AUTHOR]

It is known that phoenixin-14 (PNX-14) has a mediatory role in reproduction; however, there is no report on the role of the PNX-14 on epilepsy. Therefore, this study aimed to investigate the antiepileptic effects of the PNX-14 on the pentylenetetrazol (PTZ)-induced epilepsy in the stages of the estrous cycle among rats. A total of 168 adult female Wistar rats were randomly divided into seven groups, including control (intracerebroventricular injection was performed with saline), PNX-14 (5 µg), PNX-14 (10 µg), bicuculline (competitive antagonist of GABAA receptors; 5 nmol)+PNX-14 (5 µg), bicuculline (BIC) (5 nmol)+PNX-14 (10 µg), saclofen (competitive antagonist of GABAB receptors; 2.5 µg)+PNX-14 (5 µg), and saclofen (2.5 µg)+PNX-14 (10 µg) in proestrus, estrus, metestrus, and diestrus. Afterward, the control and treatment groups were followed by intraperitoneal administration of 80 mg/kg PTZ. Initiation time of myoclonic seizures (ITMS), initiation time of tonic-clonic seizures (ITTS), seizure duration (SD), and mortality rate (MR) were monitored and recorded for 30 min. According to the results, PNX-14 alone significantly reduced the SD and seizure mortality in all phases of estrus (P

Chronic stress caused by prolonged emotional pressure can lead to various physiological issues, including reproductive dysfunction. Although reproductive problems can also induce chronic stress, the impact of chronic stress-induced reproductive dysfunction remains contentious. This study investigates the effects of chronic unpredictable stress (CUS) on reproductive neuropeptides, sperm quality, and testicular morphology. Sixteen twelve-week-old Sprague Dawley rats were divided into two groups: a non-stress control group and a CUS-induced group. The CUS regimen involved various stressors over 28 days, with both groups undergoing behavioural assessments through sucrose-preference and forced-swim tests. Hypothalamic gene expression levels of CRH, PNX, GPR173, kisspeptin, GnRH, GnIH , and spexin neuropeptides were measured via qPCR, while plasma cortisol, luteinizing hormone (LH), and testosterone concentrations were quantified using ELISA. Seminal fluid and testis samples were collected for sperm analysis and histopathological evaluation, respectively. Results showed altered behaviours in CUS-induced rats, reflecting stress impacts. Hypothalamic corticotropin-releasing hormone (CRH) expression and plasma cortisol levels were significantly higher in CUS-induced rats compared to controls (p < 0.05). Conversely, phoenixin (PNX) expression decreased in the CUS group (p < 0.05), while kisspeptin, spexin , and gonadotropin-inhibitory hormone (GnIH) levels showed no significant differences between groups. Despite a significant increase in GnRH expression (p < 0.05), plasma LH and testosterone concentrations were significantly lower (p < 0.05) in CUS-induced rats. Histopathological analysis revealed abnormal testis morphology in CUS-induced rats, including disrupted architecture, visible interstitial spaces between seminiferous tubules, and absence of spermatogenesis. In conclusion, CUS affects reproductive function by modulating PNX and GnRH expression, influencing cortisol levels, and subsequently reducing plasma LH and testosterone concentrations. This study highlights the complex interplay between chronic stress and reproductive health, emphasizing the significant impact of stress on reproductive functions. • Chronic stress has recently associated with decreasing of reproductive health quality among males. • Chronic stress significantly reduced reproductive neuropeptides gene expression, phoenixin levels and reproductive hormones. • CUS influences reproductive function by modulating phoenixin and GnRH expression. • Testis and sperm morphology are severely affected by the CUS induced. [ABSTRACT FROM AUTHOR]

Purpose: Acute central serous chorioretinopathy (ACSCR) is a condition characterized by decreased visual acuity, macular thickening, and edema under the retinal layer. Although the underlying mechanisms of the disease are not fully understood, oxidative stress is considered to be a critical risk factor. The aim of this study was to shed light on the pathophysiology of ACSCR by investigating the levels of circulating trimethylamine N-oxide (TMAO), phoenixin (PNX), alarin (ALA), and spexin (SPX) molecules in ACSCR patients. Methods: The study included 30 ACSCR patients and 30 healthy individuals as controls. ACSCR was diagnosed using optical coherence tomography (OCT) imaging. Five mL blood samples were collected from all participants following overnight fasting. The levels of TMAO, PNX, ALA, and SPX in the blood samples were measured using the ELISA method. Results: Visual acuity was found to be significantly reduced in ACSCR patients compared to the control group (

Phoenixin is a pleiotropic peptide, whose known functions have broadened significantly over the last decade. Initially first described as a reproductive peptide in 2013, phoenixin is now recognized as being implicated in hypertension, neuroinflammation, pruritus, food intake, anxiety as well as stress. Due to its wide field of involvement, an interaction with physiological as well as psychological control loops has been speculated. It has shown to be both able to actively reduce anxiety as well as being influenced by external stressors. Initial rodent models have shown that central administration of phoenixin alters the behavior of the subjects when confronted with stress-inducing situations, proposing an interaction with the perception and processing of stress and anxiety. Although the research on phoenixin is still in its infancy, there are several promising insights into its functionality, which might prove to be of value in the pharmacological treatment of several psychiatric and psychosomatic illnesses such as anorexia nervosa, post-traumatic stress disorder as well as the increasingly prevalent stress-related illnesses of burnout and depression. In this review, we aim to provide an overview of the current state of knowledge of phoenixin, its interactions with physiological processes as well as focus on the recent developments in stress response and the possible novel treatment options this might entail.

Obesity is linked to reproductive disorders. Novel neuropeptide phoenixin demonstrated many therapeutic actions. In this study, we aim to evaluate phoenixin's potential effect in obesity-induced infertility through modulating mitochondrial dynamics. Ninety adult female rats were divided to 4 groups: (I), fed with normal pellet diet; (II), given phoenixin; (III), fed with high-fat diet. Rats that developed obesity and infertility were divided to 2 groups: (III-A), received no further treatment; (III-B), given phoenixin. Our results showed that phoenixin treatment in obese infertile rats significantly decreased serum levels of insulin and testosterone and ovarian levels of dynamin-related protein1(Drp1),reactive oxygen species ROS, TNF-α, MDA, and caspase-3. Phoenixin treatment also significantly increased serum estrogen progesterone, LH, and FSH together with ovarian levels of GnRH receptor (GnRHR), mitofusin2(Mfn2), mitochondrial transmembrane potential (ΔΨm), and electron transport chain (ETC) complex-I significantly when compared with obese group. Ovarian histopathological changes were similarly improved by phoenixin. Our data demonstrate phoenixin's role in improving obesity-induced infertility. [ABSTRACT FROM AUTHOR]

Background: Polycystic Ovary Syndrome (PCOS), the ubiquitous reproductive disorder, has been documented as highly prevalent (6-9%) in India. 10% of women globally are predicted to have the disease. The highly mutable endocrinopathy, with differential clinical criteria for each diagnosis of PCOS, can mask the severity of the syndrome by influencing the incidence and occurrence of PCOS., Area Covered: When there is a solid theoretical hypothesis between the neuroendocrine origin and ovarian origin of PCOS, recent evidence supports the neuroendocrine derivation of the pathology. It is considered of neuroendocrine basis - as it controls the ovarian axis and acts as a delicate target because it possesses receptors for various gonadal hormones, neurotransmitters & neuropeptides. Can these neuroendocrine alterations, variations in central brain circuits, and neuropeptide dysregulation be the tie that would link the pathophysiology of the disorder, the occurrence of all the 1˚ and 2˚ symptoms like polycystic ovaries, hyperandrogenism, obesity, insulin resistance, etc., in PCOS?, Conclusion: This review anticipates providing a comprehensive overview of how neuropeptides such as Kisspeptin, Neurokinin B, Dynorphin A, β-Endorphin, Nesfatin, Neuropeptide Y, Phoenixin, Leptin, Ghrelin, Orexin, and Neudesin influence PCOS, the understanding of which may help to establish potential drug candidates against precise targets in these central circuits., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Phoenixin is a newly discovered neuropeptide generated from small integral membrane protein 20. Phoenixin is a ligand for the G protein-coupled receptor 173 (GPR173) and has been detected in central and peripheral tissues of human, rats, mice, bovine, and zebrafish. It was initially involved in regulating reproductive function by stimulating the luteinizing hormone release from pituitary cells by increasing the level of gonadotropin-releasing hormone. Recently, many functions of phoenixin have been generalized, including regulation of food intake, memory, Alzheimer’s disease, anxiety, inflammation, neuronal and microglial activity, energy metabolism and body fluid balance, cardiovascular function, and endocrine activity. In addition, the interaction between phoenixin and nesfatin-1 have been revealed. The present article summarized the latest research progress on physiological function of phoenixin, suggesting that it is a potential target for novel drug development and clinical application.

Neuropeptides are a diverse class of signaling molecules in metazoans. They occur in all animals with a nervous system and also in neuron-less placozoans. However, their origin has remained unclear because no neuropeptide shows deep homology across lineages, and none have been found in sponges. Here, we identify two neuropeptide precursors, phoenixin (PNX) and nesfatin, with broad evolutionary conservation. By database searches, sequence alignments, and gene-structure comparisons, we show that both precursors are present in bilaterians, cnidarians, ctenophores, and sponges. We also found PNX and a secreted nesfatin precursor homolog in the choanoflagellate Salpingoeca rosetta. PNX, in particular, is highly conserved, including its cleavage sites, suggesting that prohormone processing occurs also in choanoflagellates. In addition, based on phyletic patterns and negative pharmacological assays, we question the originally proposed GPR-173 (SREB3) as a PNX receptor. Our findings revealed that secreted neuropeptide homologs derived from longer precursors have premetazoan origins and thus evolved before neurons. [ABSTRACT FROM AUTHOR]

It is known that phoenixin-14 (PNX-14) has a mediatory role in reproduction; however, there is no report on the role of the PNX-14 on epilepsy. Therefore, this study aimed to investigate the antiepileptic effects of the PNX-14 on the pentylenetetrazol (PTZ)-induced epilepsy in the stages of the estrous cycle among rats. A total of 168 adult female Wistar rats were randomly divided into seven groups, including control (intracerebroventricular injection was performed with saline), PNX-14 (5 µg), PNX-14 (10 µg), bicuculline (competitive antagonist of GABAA receptors; 5 nmol)+PNX-14 (5 µg), bicuculline (BIC) (5 nmol)+PNX-14 (10 µg), saclofen (competitive antagonist of GABAB receptors; 2.5 µg)+PNX-14 (5 µg), and saclofen (2.5 µg)+PNX-14 (10 µg) in proestrus, estrus, metestrus, and diestrus. Afterward, the control and treatment groups were followed by intraperitoneal administration of 80 mg/kg PTZ. Initiation time of myoclonic seizures (ITMS), initiation time of tonic-clonic seizures (ITTS), seizure duration (SD), and mortality rate (MR) were monitored and recorded for 30 min. According to the results, PNX-14 alone significantly reduced the SD and seizure mortality in all phases of estrus (P<0.05). The injection of PNX-14 with BIC significantly reduced SD and seizure mortality in all estrus phases (P<0.05). PNX-14 alone increased both ITMS and ITTS in all phases of estrus (P<0.05). Furthermore, the injection of PNX-14 with BIC significantly reduced the effects of the PNX-14 on ITMS and ITTS in all estrus stages (P<0.05). These results showed that the antiepileptic activity of PNX-14 was probably mediated by GABAA receptors, and this effect was more prominent during the luteal phase than the follicular phase. [ABSTRACT FROM AUTHOR]

The phoenixin (PNX) peptide is linked to the control of reproduction, food intake, stress, and inflammation. However, little is known about what regulates its gene and protein expression, information that is critical to understand the physiological role of PNX. In this review, we summarize what is known about the transcriptional control of Pnx and its receptor Gpr173. A main function of PNX is as a positive regulator of the hypothalamic-pituitary-gonadal axis, but there is a lack of research on its control by reproductive hormones and peptides. PNX is also associated with food intake, and its expression is linked to feeding status, fatty acids, and glucose. It is influenced by environmental and hormonal-induced stress. The regulation of Pnx in most contexts remains an enigma, in part due to conflicting and negative results. An extensive analysis of the response of the Pnx gene to factors related to reproduction, metabolism, stress, and inflammation is required. Analysis of the Pnx promoter and epigenetic regulation must be considered to understand how this level of control contributes to its pleiotropic effects. PNX is now linked to a broad range of functions, but more research on its gene regulation is required to understand its place in overall physiology and therapeutic potential. [ABSTRACT FROM AUTHOR]

It is hypothesized that novel neuropeptides such as phoenixin (PNX), spexin (SPX), and kisspeptin (KISS) are involved in the pathogenesis of eating disorders. The study presented here analyzed neuropeptide concentrations during the course of anorexia nervosa (AN) and aimed to correlate those values with anthropometric and psychometric measurements. A longitudinal study was carried outin 30 AN adolescent patients and 15 age-matched healthy female controls. Selected neuroprotein serum levels were analyzed in malnourished patients (accAN) and following partial weight recovery (norAN), and these values were compared with the control group. In accAN patients, decreased serum PNX levels were detected while SPX serum concentrations were lower in the accAN and norAN patients. No differences were observed in KISS concentrations in all studied groups. In malnourished adolescent inpatients with AN, serum PNX and SPX level were decreased. The partial weight recovery normalized PNX concentrations but failed to normalize SPX levels. Therefore these two neuropeptides might be crucial for the etiology and course of the AN. The KISS levels did not change in the course of AN. The PNX levels were associated with some symptoms of eating disorders which may indicate its potential contribution in the regulation of emotions and behaviors in AN. [ABSTRACT FROM AUTHOR]

Phoenixin-14 (PNX-14) has a wide bioactivity in the central nervous system. Its role in the hypothalamus has been investigated, and it has been reported that it is involved in the regulation of excitability in hypothalamic neurons. However, its role in the regulation of excitability in entorhinal cortex and the hippocampus is unknown. In this study, we investigated whether i. PNX-14 induces any synchronous discharges or epileptiform activity and ii. PNX-14 has any effect on already initiated epileptiform discharges. We used 350 µm thick acute horizontal hippocampal–entorhinal cortex slices obtained from 30- to 35-day-old mice. Extracellular field potential recordings were evaluated in the entorhinal cortex and hippocampus CA1 region. Bath application of PNX-14 did not initiate any epileptiform activity or abnormal discharges. 4-Aminopyridine was applied to induce epileptiform activity in the slices. We found that 200 nM PNX-14 reduced the frequency of interictal-like events in both the entorhinal cortex and hippocampus CA1 region which was induced by 4-aminopyridine. Furthermore, PNX-14 led to a similar suppression in the total power of local field potentials of 1–120 Hz. The frequency or the duration of the ictal events was not affected. These results exhibited for the first time that PNX-14 has a modulatory effect on synchronized neuronal discharges which should be considered in future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Neuropeptides are involved in numerous brain activities and are responsible for a wide spectrum of higher mental functions. The main purpose of this outline structural qualitative study was to identify the possible immunoreactivity of classical neuropeptides, as well as novel ones such as nesfatin-1, phoenixin (PNX), spexin (SPX), neuromedin U (NMU) and respective receptors within the rat claustrum for the first time. The study shows the novel identification of peptidergic neurotransmission in the rat claustrum which potentially implicates a contribution of this neuropeptide to numerous central neurosecretory mechanisms. • Nesfatin-1, spexin and phoenixin- expressing neurons are present in the rat claustrum. • Majority of neurons in the rat claustrum exhibit expression of NPY and Y1 receptor. • Claustral neurons can probably be regulated by orexin, melanocortin and NMU signaling. • Neuropeptide signalling may contribute to the functions of rat claustrum. [ABSTRACT FROM AUTHOR]

There are examples of physiological conditions under which thirst is inappropriately exaggerated, and the mechanisms for these paradoxical ingestive behaviors remain unknown. We are interested in thirst mechanisms across the female life cycle and have identified a novel mechanism through which ingestive behavior may be activated. We discovered a previously unrecognized endogenous hypothalamic peptide, phoenixin (PNX), identified physiologically relevant actions of the peptide in brain and pituitary gland to control reproductive hormone secretion in female rodents, and in the process identified the previously orphaned G protein-coupled receptor Gpr173 to be a potential receptor for the peptide. Labeled PNX binding distribution in brain parallels areas known to be important in ingestive behaviors as well in areas where gonadal steroids feedback to control estrous cyclicity (Stein LM, Tullock CW, Mathews SK, Garcia-Galiano D, Elias CF, Samson WK, Yosten GLC, Am J Physiol Regul Integr Comp Physiol 311: R489-R496, 2016). We have demonstrated upregulation of Gpr173 during puberty, fluctuations across the estrous cycle, and, importantly, upregulation during the last third of gestation. It is during this hypervolemic, hyponatremic state that both vasopressin secretion and thirst are inappropriately elevated in humans. Here, we show that central administration of PNX stimulated water drinking in both males and females under ad libitum conditions, increased water drinking after overnight fluid deprivation, and increased both water and 1.5% NaCl ingestion under fed and hydrated conditions. Importantly, losartan pretreatment blocked the effect of PNX on water drinking, and knockdown of Gpr173 by use of short interfering RNA constructs significantly attenuated water drinking in response to overnight fluid deprivation. These actions, together with the stimulatory action of PNX on vasopressin secretion, suggest that this recently discovered neuropeptide may impact the recruitment of critically important neural circuits through which ingestive behaviors and endocrine mechanisms that maintain fluid and electrolyte homeostasis are regulated. [ABSTRACT FROM AUTHOR]

Phoenixin (PNX) is a neuropeptide shown to play roles in the control of reproduction. The nucleus of the solitary tract (NTS), a critical autonomic integrating centre in the hindbrain, is one of many areas with dense expression of PNX. Using coronal NTS slices obtained from male Sprague‐Dawley rats, the present study characterised the effects of PNX on both spike frequency and membrane potential of NTS neurones. Extracellular recordings demonstrated that bath‐applied 10 nmol L‐1 PNX increased the firing frequency in 32% of NTS neurones, effects which were confirmed with patch‐clamp recordings showing that 50% of NTS neurones tested depolarised in response to application of the peptide. Surprisingly, the responsiveness to PNX in NTS neurones then declined suddenly to 9% (P < 0.001). This effect was subsequently attributed to stress associated with construction in our animal care facility because PNX responsiveness was again observed in slices from rats delivered and maintained in a construction‐free facility. We then examined whether this loss of PNX responsiveness could be replicated in rats placed on a chronic stress regimen involving ongoing corticosterone (CORT) treatment in the construction‐free facility. Slices from animals treated in this way showed a similar lack of neuronal responsiveness to PNX (9.1 ± 3.9%) within 2 weeks of CORT treatment. These effects were specific to PNX responsiveness because CORT treatment had no effect on the responsiveness of NTS neurones to angiotensin II. These results are the first to implicate PNX with respect to directly controlling the excitability of NTS neurones and also provide intriguing data showing the plasticity of these effects associated with environmental and glucocorticoid stress levels of the animal. [ABSTRACT FROM AUTHOR]

Phoenixin is a 20-amino acid peptide (PNX-20) cleaved from the small integral membrane protein 20 (SMIM20), with multiple biological roles in mammals. However, its role in nonmammalian vertebrates is poorly understood. This research aimed to determine whether PNX-20 influences feeding and metabolism in zebrafish. The mRNAs encoding SMIM20 and its putative receptor, super conserved receptor expressed in brain 3 (SREB3), are present in both central and peripheral tissues of zebrafish. Immunohistochemical analysis confirmed the presence of PNX-like immunoreactivity in the gut and in zebrafish liver (ZFL) cell line. We also found that short-term fasting (7 days) significantly decreased smim20 mRNA expression in the brain, gut, liver, gonads, and muscle, which suggests a role for PNX-20 in food intake regulation. Indeed, single intraperitoneal injection of 1,000 ng/g body wt PNX-20 reduced feeding in both male and female zebrafish, likely in part by enhancing hypothalamic cart and reducing hypothalamic/gut preproghrelin mRNAs. Furthermore, the present results demonstrated that PNX-20 modulates the expression of genes involved in glucose transport and metabolism in ZFL cells. In general terms, such PNX-induced modulation of gene expression was characterized by the upregulation of glycolytic genes and the downregulation of gluconeogenic genes. A kinetic study of the ATP production rate from both glycolytic and mitochondrial pathways demonstrated that PNX-20-treated ZFL cells exhibited significantly higher ATP production rate associated with glycolysis than control cells. This confirms a positive role for PNX-20 on glycolysis. Together, these results indicate that PNX-20 is an anorexigen with important metabolic roles in zebrafish. [ABSTRACT FROM AUTHOR]

Anxiety disorders are the most common mental health conditions and currently constitute a significant social and pharmacological issue. The neurochemical aetiology of anxiety has not been fully explained yet, and it has been the subject of numerous basic research studies. In this context, the recently identified highly multifunctional regulatory neurohormones -- phoenixin and nesfatin-1 seem to be of special interest. Phoenixin, a neuropeptide of hypothalamic-pituitary-gonadal axis, has potent anxiolytic properties in the animal model. Newly identified hypothalamic and brainstem neuropeptide nesfatin-1 is considered to play an important role in the mechanisms underlying generation of anxiety symptoms in animals. Clinical studies showing decreased serum levels of nesfatin-1 in patients with generalised anxiety disorder are sparse. On the other hand, elevated nesfatin-1 expression was noted in the brainstem of male suicide victims. The neurophysiological effects of both nesfatin-1 and phoenixin seem to be distinctly sex-related. The aim of this review article is to summarise recent reports regarding the postulated involvement of these neuropeptides in the functioning of neuronal pathways involved in the pathophysiology of anxiety responses. [ABSTRACT FROM AUTHOR]

Recent studies have shown a rise in precocious puberty, especially in girls. At the same time, childhood obesity due to overnutrition and energy imbalance is rising too. Nutrition and fertility are currently facing major challenges in our societies, and are interconnected. Studies have shown that high-fat and/or high-glycaemic-index diet can cause hypothalamic inflammation and microglial activation. Molecular and animal studies reveal that microglial activation seems to produce and activate prostaglandins, neurotrophic factors activating GnRH (gonadotropin-releasing hormone expressing neurons), thus initiating precocious puberty. GnRH neurons’ mechanisms of excitability are not well understood. In this review, we study the phenomenon of the rise of precocious puberty, we examine the physiology of GnRH neurons, and we review the recent literature regarding the pathophysiological mechanisms that connect diet-induced hypothalamic inflammation and diet-induced phoenixin regulation with precocious puberty.

The novel peptide phoenixin was shown to be involved in several physiological processes ranging from reproduction to food intake. Interest in this protein has steadily increased over the last few years and its known implications have become much broader, playing a role in glucose homeostasis, anxiety, nociception, and pruritus. Phoenixin is expressed in a multitude of organs such as the small intestine, pancreas, and in the hypothalamus, as well as several other brain nuclei influencing numerous physiological functions. Its highly conserved amino-acid sequence amongst species leads to the assumption, that phoenixin might be involved in essential physiological functions. Its co-expression and opposing functionality to the extensively studied peptide nesfatin-1 has given rise to the idea of a possible counterbalancing role. Several recent publications focused on phoenixin’s role in stress reactions, namely restraint stress and lipopolysaccharide-induced inflammation response, in which also nesfatin-1 is known to be altered. This review provides an overview on the phoenixins and nesfatin-1 properties and putative effects, and especially highlights the recent developments on their role and interaction in the response to response.

Phoenixin is a neuropeptide with a well-established role in the central regulation of reproductive processes; however, knowledge regarding its role in the ovary is limited. One of the main active phoenixin isoforms is phoenixin-14, which acts through G protein-coupled receptor 173. Our research hypothesis was that phoenixin-14 is expressed in porcine corpus luteum and exerts luteotropic action by affecting the endocrine function of luteal cells through G protein-coupled receptor 173 and protein kinase signaling. Luteal cells were cultured to investigate the effect of phoenixin-14 (1-1000 nM) on endocrine function. We showed that phoenixin-14 and G protein-coupled receptor 173 are produced locally in porcine corpus luteum and their levels change during the estrous cycle. We detected phoenixin-14 immunostaining in the cytoplasm and G protein-coupled receptor 173 in the cell membrane. Plasma phoenixin levels were highest during the early luteal phase. Interestingly, insulin, luteinizing hormone, progesterone, and prostaglandins decreased phoenixin-14 levels in luteal cells. Phoenixin-14 increased progesterone, estradiol, and prostaglandin E2 secretion, but decreased prostaglandin F2α, upregulated the expression of steroidogenic enzymes, and downregulated receptors for luteinizing hormone and prostaglandin. Also, phoenixin-14 increased the expression of G protein-coupled receptor 173 and the phosphorylation of extracellular signal-regulated kinase 1/2, protein kinase B, inhibited the phosphorylation of protein kinase A, and had mixed effect on AMP-activated protein kinase alpha and protein kinase C. G protein-coupled receptor 173 and extracellular signal-regulated kinase 1/2 mediated the effect of phoenixin-14 on endocrine function of luteal cells. Our results suggest that phoenixin is produced by porcine luteal cells and can be a new regulator of their function., (© The Author(s) 2023. Published by Oxford University Press behalf of Society for the Study of Reproduction.)

There are some initial suggestions in the literature that phoenixin, spexin, nesfatin-1 and kisspeptin may play a role in the pathogenesis of affective disorders. Therefore, they may also be cautiously considered as potential diagnostic or predictive biomarkers of BD. This study aimed to evaluate the levels of the aforementioned neuropeptides in the peripheral blood of children and adolescents with bipolar. This study included 122 individuals: 67 persons with diagnosed bipolar disorder types I and II constituted the study group, and 55 healthy persons were included in the control group. Statistically significant differences in the concentrations of neuropeptides between the control and study groups were noted in relation to nesfatin-1 and spexin (although spexin lost statistical significance after introducing the Bonferroni correction). In a logistic regression analysis, an increased risk of bipolar disorder was noted for a decrease in nesfatin-1 concentration. Lower levels of nesfatin-1 seemed to be a significant risk factor for the development of bipolar disorder types I and II. Furthermore, the occurrence of bipolar disorder was associated with significantly elevated levels of spexin. None of the analyzed neuropeptides was significantly correlated with the number of symptoms of bipolar disorder.

• Phoenixin activates several nesfatin-1 immunoreactive nuclei in the rat brain. • This correlates to changes in feeding behavior and locomotion. • This activation may play a role in the modulation of food intake signaling. Phoenixin is a novel neuropeptide initially associated with reproductive functions, but subsequently also with feeding behavior. Nesfatin-1 is also involved in the regulation of food intake and has been shown to largely colocalize with phoenixin in the rat brain; however, a functional link is missing so far. The current study investigated whether phoenixin activates nesfatin-1 immunoreactive nuclei in the rat brain. Male Sprague Dawley rats chronically equipped with an intracerebroventricular cannula were injected with vehicle (5 µl ddH 2 O) or phoenixin (1.7 nmol in 5 µl ddH 2 O, n = 5–6 group). Behavior was assessed manually and c-Fos as well as nesfatin-1 immunoreactivity using immunohistochemistry. Phoenixin significantly increased feeding and drinking behavior as well as locomotor activity compared to vehicle (p < 0.01). Moreover, phoenixin injected intracerebroventricularly (icv) activated several nuclei throughout the rat brain as assessed using c-Fos; the number of c-Fos/nesfatin-1 immunoreactive neurons was increased in the lateral septal nucleus (4-fold), supraoptic nucleus (107-fold), paraventricular nucleus (6-fold) and the nucleus of the solitary tract (18-fold) compared to vehicle (p < 0.05). In summary, phoenixin activates several nesfatin-1 immunoreactive nuclei in the rat brain. This activation may play a role in the modulation of food intake. [ABSTRACT FROM AUTHOR]

Phoenixin is novel neuropeptide, recently identified following the description of a peptide sequence highly conserved across several animal species, including humans, cows, and pigs. Expressed both centrally in the hypothalamus and arcuate nucleus and peripherally in cardiac and gastrointestinal tissue, it appears to modulate reproductive hormone secretion in a gonadotrophin-releasing hormone–dependent manner and may also influence anxiety and memory. While there remains much to be described regarding its signaling, this review assesses the currently available literature in both animal and human studies to summarize our understanding of the physiological role of this novel neuropeptide, and its function in reproductive hormone release. [ABSTRACT FROM AUTHOR]

Summary: The recently discovered peptide phoenixin (PNX) and its receptor GPR173 are novel factors that exhibit a large spectrum of regulatory activity, especially when considered as a central modulator of GnRH‐related hormonal control of reproductive processes. It has been already proven that GnRH agonists and antagonists can modulate peptidergic signalling in the HPG axis. Despite these findings, there is so far no information regarding the influence of treatment with GnRH analogues on SMIM20/phoenixin signalling in the hypothalamic–pituitary–gonadal axis. In the current study, SMIM20/phoenixin and GPR173 mRNA levels were measured in the hypothalamus, pituitary and ovaries of female rats in the dioestrus phase following treatment with GnRH‐R agonist (buserelin) and antagonist (cetrorelix) using quantitative real‐time PCR. The serum PNX concentrations were also estimated with ELISA technique. The hypothalamic, hypophyseal and especially ovarian levels of SMIM20 mRNA were increased after both buserelin and cetrorelix administration. The GPR173 expressions were in turn decreased in the hypothalamus and pituitary. Treatment with the GnRH analogues led to the modulation of SMIM20/phoenixin and GPR173 mRNA expression in the female rat hypothalamic–pituitary–gonadal axis. By identifying buserelin and cetrorelix as novel modulators of phoenixin signalling in the animal HPG axis, these results cast new light on the GnRH analogues mode of action and contribute to a better understanding of the mechanisms responsible for the hormonal control of reproduction. [ABSTRACT FROM AUTHOR]

Abstract Phoenixin-14 (PNX) is a newly discovered peptide produced by proteolytic cleavage of the small integral membrane protein 20 (Smim20). Previous studies showed that PNX is involved in controlling reproduction, pain, anxiety and memory. Furthermore, in humans, PNX positively correlates with BMI suggesting a potential role of PNX in controlling fat accumulation in obesity. Since the influence of PNX on adipose tissue formation has not been so far demonstrated, we investigated the effects of PNX on proliferation and differentiation of preadipocytes using 3T3-L1 and rat primary preadipocytes. We detected Smim20 and Gpr173 mRNA in 3T3-L1 preadipocytes as well as in rat primary preadipocytes. Furthermore, we found that PNX peptide is produced and secreted from 3T3-L1 and rat primary adipocytes. PNX increased 3T3-L1 preadipocytes proliferation and viability. PNX stimulated the expression of adipogenic genes (Pparγ , C/ebpβ and Fabp4) in 3T3-L1 adipocytes. 3T3-L1 preadipocytes differentiated in the presence of PNX had increased lipid content. Stimulation of cell proliferation and differentiation by PNX was also confirmed in rat preadipocytes. PNX failed to induce AKT phosphorylation, however, PNX increased cAMP levels in 3T3-L1 cells. Suppression of Epac signalling attenuated PNX-induced Pparγ expression without affecting cell proliferation. Our data show that PNX stimulates differentiation of 3T3-L1 and rat primary preadipocytes into mature adipocytes via cAMP/Epac-dependent pathway. In conclusion our data shows that phoenixin promotes white adipogenesis, thereby may be involved in controlling body mass regulation. Highlights • Gpr173 and Smim20 are expressed in 3T3-L1 and rat primary preadipocytes. • PNX-14 peptide is produced in rat and 3T3-L1 adipocytes. • PNX-14 stimulates 3T3-L1 and rat primary preadipocytes proliferation. • PNX-14 promotes differentiation of 3T3-L1 and rat primary preadipocytes. • PNX-14 stimulates 3T3-L1 preadipocytes differentiation via cAMP/Epac signalling. [ABSTRACT FROM AUTHOR]

The SREB (Super-conserved Receptors Expressed in Brain) family of orphan G protein-coupled receptors is highly conserved in vertebrates and consists of three members: SREB1 (orphan designation GPR27), SREB2 (GPR85), and SREB3 (GPR173). SREBs are associated with processes ranging from neuronal plasticity to reproductive control. Relatively little is known about similarities across the entire family, or how mammalian gene expression patterns compare to non-mammalian vertebrates. In fish, this system may be particularly complex, as some species have gained a fourth member (SREB3B) while others have lost genes. To better understand the system, the present study aimed to: 1) use qPCR to characterize sreb and related gene expression patterns in the brains of three fish species with different systems, and 2) identify possible differences in transcriptional regulation among the receptors, using upstream transcription factor binding sites across 70 ray-finned fish genomes. Overall, regional patterns of sreb expression were abundant in forebrain-related areas. However, some species-specific patterns were detected, such as abundant expression of receptors in zebrafish (Danio rerio) hypothalamic-containing sections, and divergence between sreb3a and sreb3b in pufferfish (Dichotomyctere nigroviridis). In addition, a gene possibly related to the system (dkk3a) was spatially correlated with the receptors in all three species. Genomic regions upstream of sreb2 and sreb3b , but largely not sreb1 or sreb3a , contained many highly conserved transcription factor binding sites. These results provide novel information about expression differences and transcriptional regulation across fish that may inform future research to better understand these receptors. [Display omitted] • Sreb gene expression was abundant in forebrain-related regions in fish. • Sreb3a and sreb3b exhibited different expression patterns in a pufferfish species. • Sreb2 and sreb3b genomic regions exhibited unique and conserved transcription factor binding sites. • Expression patterns for dkk3a exhibited similarity to sreb receptors in all species studied. [ABSTRACT FROM AUTHOR]

Phoenixin (PNX) neuropeptide is a cleaved product of the Smim20 protein. Its most common isoforms are the 14- and 20-amino acid peptides. The biological functions of PNX are mediated via the activation of the GPR173 receptor. PNX plays an important role in the central nervous system (CNS) and in the female reproductive system where it potentiates LH secretion and controls the estrus cycle. Moreover, it stimulates oocyte maturation and increases the number of ovulated oocytes. Nevertheless, PNX not only regulates the reproduction system but also exerts anxiolytic, anti-inflammatory, and cell-protective effects. Furthermore, it is involved in behavior, food intake, sensory perception, memory, and energy metabolism. Outside the CNS, PNX exerts its effects on the heart, ovaries, adipose tissue, and pancreatic islets. This review presents all the currently available studies demonstrating the pleiotropic effects of PNX.

Phoenixin (PNX) is a newly identified reproductive peptide required for the estrous cycle. It is most highly expressed in the hypothalamus, where it is a positive regulator of gonadotropin-releasing hormone (GnRH) and kisspeptin. However, it is unknown what signals lie upstream of Pnx to coordinate its effects on GnRH and kisspeptin. We investigated the effects of the hormones, estrogen and leptin; the fatty acids, palmitate, docosahexaenoic acid (DHA), oleate and palmitoleate; and the endocrine disrupting chemical BPA on Pnx mRNA levels. We also examined whether the signaling pathways of nitric oxide, lipopolysaccharide, cAMP and protein kinase C could alter Pnx expression. Immortalized hypothalamic neurons were treated from 2 to 24 h with these compounds and Pnx mRNA levels were measured with RT-qPCR. Unexpectedly, only BPA as well as the fatty acids, palmitate, DHA and oleate, could alter Pnx expression; therefore suggesting that Pnx may fulfill a nutrient-sensing role in the hypothalamus. Our study is the first to delineate potential regulators of this novel neuropeptide, and our findings provide some insight into the functional role of PNX in the hypothalamus.

Phoenixin (PNX) is a newly identified reproductive peptide required for the estrous cycle. It is most highly expressed in the hypothalamus, where it is a positive regulator of gonadotropin-releasing hormone (GnRH) and kisspeptin. However, it is unknown what signals lie upstream of Pnx to coordinate its effects on GnRH and kisspeptin. We investigated the effects of the hormones, estrogen and leptin; the fatty acids, palmitate, docosahexaenoic acid (DHA), oleate and palmitoleate; and the endocrine disrupting chemical BPA on Pnx mRNA levels. We also examined whether the signaling pathways of nitric oxide, lipopolysaccharide, cAMP and protein kinase C could alter Pnx expression. Immortalized hypothalamic neurons were treated from 2 to 24 h with these compounds and Pnx mRNA levels were measured with RT-qPCR. Unexpectedly, only BPA as well as the fatty acids, palmitate, DHA and oleate, could alter Pnx expression; therefore suggesting that Pnx may fulfill a nutrient-sensing role in the hypothalamus. Our study is the first to delineate potential regulators of this novel neuropeptide, and our findings provide some insight into the functional role of PNX in the hypothalamus. [ABSTRACT FROM AUTHOR]

Using a series of classical protein purification techniques, coupled with more modern molecular approaches, a family of neuropeptides, the Phoenixins, was identified to be produced in brain and heart, and to bind selectively in pituitary gland, ovary and brain. These same binding sites were revealed, using a novel receptor identification strategy, to express the orphan G protein-coupled receptor, GPR173, the expression of which was required for the actions of phoenixin both in vivo and in vitro . In fact, studies using small interfering RNA molecules to compromise GPR173 expression revealed the physiologic relevance of the initially reported pharmacologic actions of the peptides. Those include not only the reproductive actions of the peptides in brain and pituitary gland, but also a CNS site of action in the maintenance of fluid and electrolyte homeostasis. Additional pharmacologic actions of the phoenixins have been described and the race is on to establish the physiologic relevance of those actions as well as the therapeutic potential of phoenixin analogs. [ABSTRACT FROM AUTHOR]

Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa. [ABSTRACT FROM AUTHOR]

Phoenixin-14 (PNX-14) is a regulatory neuropeptide encoded by the SMIM20 gene, which has been implicated in the reproductive cycle by modulating the hypothalamic-pituitary-gonadal (HPG) axis. Recently, we showed that PNX-14 is downregulated in bitches with cystic endometrial hyperplasia and pyometra. The objective of this study was to determine the expression of Smim20 , PNX-14, and its putative receptor GRP173 in the canine ovary (both healthy and those with ovarian cysts), periovarian adipose tissue (PAT) and in the endometrium during the oestrous cycle. The expression was analysed by RT-qPCR and Western blot. In tissue sections, peptides were localised by immunofluorescent assays, and blood plasma concentrations of PNX-14 were detected by EIA. The results demonstrated increased levels of PNX in bitches in the anestrus groups compared to diestrus animals. The expression of GPR173 increased in PAT during the diestrus phase and endometrial tissue in late diestrus bitches. In the ovary, strong signals of PNX-14 and GPR173 were detected in the luteal and follicular cells. Furthermore, bitches with cystic ovaries were characterised by elevated circulating PNX levels and a significantly higher expression of PNX and GPR173 in gonadal tissues, when compared with healthy animals. Moreover, a positive correlation between PNX and progesterone in the blood of healthy bitches was noted, which changed to a negative correlation in females affected by cystic ovaries. These studies expand the knowledge regarding the expression and localization of the PNX/GRP173 system in canine reproductive organs during physiological and pathological conditions. • Phoenixin-14 may regulate the reproductive functions of canines. • The expression of phoenixin-14 and GRP173 increase in cases of cystic ovarian disorders. • The expression of GRP173 increase in periovarian adipose tissue in the diestrus phase. [ABSTRACT FROM AUTHOR]

Background: Alteration in energy expenditure or metabolism is the most accused risk issue for the onset and for the course of neurodegenerative cognitive disorders. Neuropeptides are suggested to be related with learning and memory. Phoenixin (PNX) is the most recently reported neuropeptide and we aimed to compare the plasma level in people with subjective memory complaints, patients with mild cognitive impairment, and mild Alzheimer's disease (AD).Methods: Ninety two participants enrolled in the study. After screening tests, all participants were assessed with a neuropsychological battery for further cognitive evaluations. We used ELISA kit to assay the level of Human PNX.Results: Patients with AD were significantly older than people in subjective memory complaint group (p = 0.02). There was no significant difference between groups according to gender (p = 0.435). Mean plasma PNX level was not significantly different between groups (p = 0.279). Mean plasma PNX level in MCI group was positively correlated with BMI (r = 0.402 and p = 0.028), serum HDL level (r = 0.454 and p = 0.012), blood systolic pressure (r = 0.428 and p = 0.018) and negatively correlated with logical memory (r=-0.335 and p=0.031). The mean plasma PNX level was positively correlated with immediate recall in subjective memory complaint group (r = 0.417 and p = 0.034).Conclusion: This study is the first studying the association of plasma PNX level and cognitive complaints or decline. The knowledge about the role, interaction, and physiological functions of PNX is lacking. Lower plasma PNX level might be important in prodromal stages as MCI and the predictive role of PNX should be investigated in further studies. [ABSTRACT FROM AUTHOR]

Background Polycystic ovary syndrome (PCOS) is commonly characterized by obesity, insulin resistance (IR), hyperandrogenemia and hirsutism. Following the reported relationship between phoenixin-14 and gonadotropin production in rat hypothalamic-pituitary-gonadal axis, the present study was designed to investigate the circulating concentrations of phoenixin-14 and their associations with the concentrations of sex hormones including luteinizing hormone (LH), follicular stimulating hormone (FSH), estradiol (E 2 ), progesterone (P 4 ) and total testosterone (TT) in PCOS patients. Methods A total of 41 women with diagnosed PCOS using Rotterdam criteria and 37 healthy individuals were enrolled in the study. Results Serum phoenixin-14 concentration in PCOS patients ( n = 41) was 0.515 ± 0.044 ng/ml, significantly higher than that in healthy controls (0.289 ± 0.046 ng/ml, n = 37). PCOS patients had higher serum LH, dehydroepiandrosterone and fasting blood glucose concentrations, and higher index of homeostasis model of assessment-IR than those in healthy women. Correlation analysis showed significantly positive correlations of phoenixin-14 with LH, FSH, TT, P 4 , BMI and nesfatin-1 concentrations, and significantly negative correlations with E 2 and serum insulin (FSI) concentrations, respectively. Conclusions Compared to control women, PCOS patients had significantly increased serum phoenixin-14, LH and androgen concentrations. The positive correlations of phoenixin-14 concentrations with LH and TT concentrations suggest a possible role of phoenixin-14 in the development of PCOS. [ABSTRACT FROM AUTHOR]