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1.
Biomed Khim ; 66(1): 89-94, 2020 Jan.
Artigo em Russo | MEDLINE | ID: mdl-32116231

RESUMO

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.


Assuntos
Neoplasias da Mama/metabolismo , Receptores Androgênicos/metabolismo , Receptores da Prolactina/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Feminino , Humanos , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona
2.
Chemosphere ; 242: 125143, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31675585

RESUMO

Ochratoxin A (OTA), a mycotoxin widely found in foodstuffs, reportedly damages multiple brain regions in developing rodents, but the corresponding mechanisms have not been elucidated. In this study, zebrafish embryos at 6 h post fertilization (hpf) were exposed to various concentrations of OTA and the phenomenon associated with intracerebral hemorrhage was observed at 72 hpf. Exposure of embryos to OTA significantly increased their hemorrhagic rate in a dose-dependent manner. Large numbers of extravagated erythrocytes were observed in the midbrain/hindbrain areas of Tg(fli-1a:EGFP; gata1:DsRed) embryos following exposure to OTA. OTA also disrupted the vascular patterning, especially the arch-shaped central arteries (CtAs), in treated embryos. Histological analysis revealed a cavity-like pattern in their hindbrain ventricles, implying the possibility of cerebral edema. OTA-induced intracerebral hemorrhage and CtA vessel defects were partially reversed by the presence of miR-731 antagomir or the overexpression of prolactin receptor a (prlra); prlra is a downstream target of miR-731. These results suggest that exposure to OTA has a negative effect on cerebral vasculature development by interfering with the miR-731/PRLR axis in zebrafish.


Assuntos
Hemorragia Cerebral/induzido quimicamente , Ocratoxinas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Eritrócitos/efeitos dos fármacos , MicroRNAs , Micotoxinas , Receptores da Prolactina/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/fisiologia
3.
J Dairy Sci ; 103(2): 1982-1992, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31759600

RESUMO

Little is known about the effects of heat stress during the late gestation period on lactation in dairy goats. For this reason, 32 Saanen goats were randomly assigned to 1 of 2 groups, control (CT; n = 16) or heat stress (HS; n = 16), during late gestation. The HS goats were housed in a climatic chamber before parturition and subjected to heat stress for the last 45 d. After parturition, the HS goats were housed in the same conditions as the CT group. Mammary gland biopsies were performed on 7 goats per treatment at -30, -15, 15, and 30 d relative to parturition, so that the expression levels of several genes could be determined. The HS goats produced less milk than the CT goats did during the first half of lactation, but not during the rest of lactation. Before parturition, apoptosis-related transcripts (TP53 and BAX) were higher in the mammary glands of the HS goats than in those of the CT goats. The HS goats also had higher levels of HSPB1 gene expression during gestation and lactation. However, expression of the prolactin receptor gene was lower after parturition in the mammary glands of HS, suggesting downregulation of prolactin signaling. In summary, heat stress during final gestation reduces milk yield in the subsequent lactation. Although the upregulation of apoptosis signaling in the HS goats suggests that heat stress affects mammary cell number, the loss of the effect on milk production is more compatible with an effect on cell activity, which could be due to a downregulation of prolactin signaling.


Assuntos
Regulação da Expressão Gênica , Cabras/fisiologia , Lactação/fisiologia , Leite/metabolismo , Receptores da Prolactina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Cabras/genética , Resposta ao Choque Térmico/fisiologia , Glândulas Mamárias Animais/fisiologia , Parto , Gravidez , Distribuição Aleatória
4.
Biochemistry (Mosc) ; 84(10): 1204-1212, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694516

RESUMO

Cholestasis of pregnancy is a pathology associated with disruptions in the bile flow and dysregulation of salt and water homeostasis. Prolactin is one of the most important regulators of salt and water balance. Changes in the expression of long and short isoforms of the prolactin receptor (PrlR) and mediators of prolactin signaling were studied by immunoblotting and RT-qPCR in the rat kidney cortex and outer medulla in the model of cholestasis of pregnancy. Both PrlR isoforms were shown to participate in the effects of prolactin in cholestasis of pregnancy. Direct impact of prolactin on the kidney has been demonstrated: (i) mRNA expression of both PrlR isoforms in the kidney depended on the physiological conditions and prolactin levels; (ii) expression of pSTAT5, a key mediator of the long PrlR isoform signaling, was increased in animals with cholestasis of pregnancy; (iii) in the case of long PrlR isoform predomination, expression of mRNAs for the prolactin signaling inhibitors SOCS3 and PIAS3 was upregulated (the genes of these regulators contain STAT-responsive elements in their promoters); (iv) expression of the mRNA for galactose-1-phosphate uridyltransferase (GALT), a molecular target of the PrlR short isoform, was decreased in the kidney outer medulla.


Assuntos
Colestase/metabolismo , Modelos Animais de Doenças , Rim/metabolismo , Prolactina/metabolismo , Transdução de Sinais , Animais , Feminino , Gravidez , Isoformas de Proteínas/metabolismo , Ratos , Receptores da Prolactina/metabolismo
5.
Anim Sci J ; 90(11): 1444-1452, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31486226

RESUMO

The aim was to evaluate in female roe deer: (a) PAG mRNA relative abundance in endometrial uterine tissue for determination of the duration of embryonic diapause, (b) mRNA relative abundance of progesterone, estradiol, and prolactin (P4, E2, and PRL) receptors (PGR, ESR, and PRLR) during diapause and after implantation in the endometrium; (c) concentration of P4, E2, and PRL in the blood, and (d) a noninvasive method of hormone detection by measurement of P4 and E2 concentrations in feces. A total of fifteen individuals were obtained post mortem during hunting seasons and divided into three experimental groups (November, December, January). The results did not reveal mRNA relative abundance for PAGs in the endometrium or detectable PAG concentrations in the serum of all examined females. Concentration of PRL and mRNA relative abundance for PRLR long isoform in the endometrium was the highest in January (p < .01). mRNA relative abundance for PGR, P4 concentration in the endometrium, serum, and feces was the highest in January (p < .01). Endometrial origin PRL and P4 may be responsible for the termination of this process and pregnancy development after implantation.


Assuntos
Cervos/metabolismo , Cervos/fisiologia , Implantação do Embrião/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Endométrio/metabolismo , Estradiol/genética , Estradiol/metabolismo , Feminino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Gravidez , Progesterona/genética , Progesterona/metabolismo , RNA Mensageiro/metabolismo , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo
6.
J Agric Food Chem ; 67(34): 9532-9542, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31369265

RESUMO

Murine mammary gland is an ideal model for studying the development and milk synthesis in dairy animals. MicroRNAs play an important role in milk synthesis and mammary gland development; however, the molecular mechanism of miR-142-3p continues to be poorly understood. Here, we knocked down miR-142-3p expression in vitro and vivo, increased the prolactin receptor expression and activated many downstream cellular proteins, such as mammalian target of rapamycin, sterol regulatory element-binding transcription factor 1, cyclin D1, and signal transducer and activator of transcription 5. Additionally, miR-142-3p knockdown in mouse mammary gland epithelial cells increased proliferation but not viability, induced cell cycle progression, decreased apoptosis, and increased the expression of triglycerides and ß-casein. Moreover, miR-142-3p knockdown in murine mammary gland tissue in vivo affected the structure and function of the mammary gland, which showed an increased number of lobules and ducts and was more capable of producing milk. However, overexpression of miR-142-3p had the opposite effects. In summary, these data reveal that miR-142-3p regulates milk synthesis and the structure of murine mammary glands via PRLR-mediated multiple signaling pathways.


Assuntos
Glândulas Mamárias Animais/metabolismo , MicroRNAs/metabolismo , Leite/metabolismo , Receptores da Prolactina/metabolismo , Animais , Caseínas/metabolismo , Células Epiteliais/metabolismo , Feminino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Receptores da Prolactina/genética , Transdução de Sinais , Triglicerídeos/metabolismo
7.
Endocrinology ; 160(11): 2587-2599, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373638

RESUMO

The prolactin receptor (Prlr) mediates not only the multiple effects of prolactin, but also those of the placental lactogens and, in humans, some actions of growth hormone. Although Prlr expression has been reported to be widespread in the body, specific cellular expression patterns within tissues are undefined for many organs. One persisting problem in investigating Prlr function is that the protein is difficult to detect using conventional methods. To allow investigation of Prlr expression with a single cell resolution, we have recently developed a knock-in mouse strain in which Cre recombinase is expressed together with the long isoform of the Prlr using an internal ribosome entry site. When crossed to a Cre-dependent reporter mouse strain, Cre-mediated recombination will genetically label cells that acutely express the Prlr as well as cells that have transiently expressed the Prlr during development. We report here the anatomical distribution of cells which express the fluorescent reporter τ green fluorescent protein in a total of 38 organs prepared from young adult male and female Prlr reporter mice. Our results establish a resource for dissecting the functional role of Prlr in multiple murine tissues.


Assuntos
Receptores da Prolactina/metabolismo , Animais , Glândulas Endócrinas/metabolismo , Glândulas Exócrinas/metabolismo , Feminino , Trato Gastrointestinal/metabolismo , Sistema Linfático/metabolismo , Masculino , Camundongos , Sistema Respiratório/metabolismo , Sistema Urogenital/metabolismo
8.
Exp Parasitol ; 204: 107721, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288023

RESUMO

BACKGROUND: Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan able to infect humans and it is common in pregnant women. During pregnancy and lactation, there are changes in the concentration of 17ß-estradiol (E2), progesterone (Prg), and prolactin (PRL). It is known that a proinflamatory response reduces the susceptibility to be infected, and this response may change according to hormonal impairment. Monocytes and macrophages are the main barrier against many intracellular microorganisms, due to their ability to produce cytokines. The aim of this work was to determine the effect of E2, progesterone, and PRL on the infective capacity of T. gondii, proinflamatory immune response modulation and the expression of hormonal receptors on THP-1 cell stimulated with T. gondii. METHODS: The THP-1 cells were infected with 1500 T. gondii tachyzoites, of RH strain. Stimuli were conducted with recombinant PRL (200 ng/mL), E2 (40 nM) y Prg (40 nM). MTT assays were performed to evaluate cellular viability. Western blot assays were carried out to evaluate the expression of the hormonal receptors (PRLR, ERα, and ERß). Cytokines produced were measured with a magnetic bead kit directed to 17 cytokines. RESULTS: Stimuli with E2 and Prg increased T. gondii infection in monocytes after 48 h; however, no differences in infection were observed in PRL stimulus. The E2 decreased the secretion of IL-12 and IL-1ß and PRL did not modify the production of these cytokines in THP-1 cells stimulated with T. gondii; however, both hormones increased the production of IL-10. Besides, PRL augmented the production of IL-4 and IL-13. In contrast, Prg reduced these cytokines. Our results show that T. gondii induces the expression of ERα and ERß and lowers PRLR. The hormones modify the expression of the receptors of other hormones: Prg decreases PRLR, ERß and increases ERα; E2 diminishes PRLR; and PRL decreases ERα and ERß expression. CONCLUSION: The hormones can increase T. gondii infection and could be mediating an anti-inflammatory response in THP-1 cells. T. gondii induces changes in the expression of hormonal receptors.


Assuntos
Citocinas/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Receptores da Prolactina/metabolismo , Células THP-1/metabolismo , Toxoplasma/fisiologia , Animais , Corantes , Estradiol/metabolismo , Feminino , Humanos , Camundongos , Progesterona/metabolismo , Prolactina/metabolismo , Isoformas de Proteínas/metabolismo , Células THP-1/imunologia , Células THP-1/parasitologia , Sais de Tetrazólio , Tiazóis , Toxoplasma/crescimento & desenvolvimento
9.
Biochemistry (Mosc) ; 84(4): 329-345, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31228925

RESUMO

The review describes functional and structural features of different isoforms of prolactin receptor, mechanisms of signaling pathway activation, and molecular messengers involved in the transmission and termination of signal from the prolactin receptor isoforms. Changes in the ratio between prolactin receptor isoforms, key mediators of prolactin signal transduction and termination in various organs and tissues, are analyzed. Special attention is given to the role of molecular mediators and the ratio between the isoforms in normal physiological functions and pathologies. Approaches for therapeutic correction of prolactin signaling impairments are discussed.


Assuntos
Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Inibidoras de STAT Ativados/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores da Prolactina/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo
10.
PLoS One ; 14(5): e0215831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31063493

RESUMO

Increasing evidence suggests that signaling through the prolactin/prolactin receptor axis is important for stimulation the growth of many cancers including glioblastoma multiforme, breast and ovarian carcinoma. Efficient inhibitors of signaling have previously been developed but their applicability as cancer drugs is limited by the short in vivo half-life. In this study, we show that a fusion protein, consisting of the prolactin receptor antagonist PrlRA and an albumin binding domain for half-life extension can be expressed as inclusion bodies in Escherichia coli and efficiently refolded and purified to homogeneity. The fusion protein was found to have strong affinity for the two intended targets: the prolactin receptor (KD = 2.3±0.2 nM) and mouse serum albumin (KD = 0.38±0.01 nM). Further investigation showed that it could efficiently prevent prolactin mediated phosphorylation of STAT5 at 100 nM concentration and above, similar to the PrlRA itself, suggesting a potential as drug for cancer therapy in the future. Complexion with HSA weakened the affinity for the receptor to 21±3 nM, however the ability to prevent phosphorylation of STAT5 was still prominent. Injection into rats showed a 100-fold higher concentration in blood after 24 h compared to PrlRA itself.


Assuntos
Prolactina/farmacologia , Receptores da Prolactina/antagonistas & inibidores , Fator de Transcrição STAT5/metabolismo , Animais , Linhagem Celular Tumoral , Meia-Vida , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Prolactina/farmacocinética , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/farmacologia , Distribuição Tecidual
11.
Int J Mol Sci ; 20(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30987013

RESUMO

The epithelial-mesenchymal transition (EMT) process is known to play an essential role in tumor progression, metastasis and resistance to therapy. This report evaluated the prognostic value of co-expression of the receptor for prolactin (PRLR), a suppressor of EMT, and the receptors for transforming growth factor ß (TGFßRI and TGFßRII), an inducer of EMT, in association with different clinicopathological parameters using TMA of 102 breast cancer patients and publicly available data on breast cancer patients. Interestingly, the results revealed that malignant tissues had significantly lower levels of concomitant protein expression of these receptors in comparison to normal/benign breast tissue. In addition, a higher level of concomitant expression was also observed in less aggressive breast cancer phenotypes, including low grade tumors, luminal breast cancer subtype, and less advanced stages of the disease (lymph node negative and early stages). Moreover, the results also showed that the expression of a gene signature composed of PRLR/TGFßRI/TGFßRII correlates more with differentiated grade I tumors, and identified a subset of patients showing better survival outcomes evident in luminal B and HER-2 enriched molecular subtypes. Together, these results indicate that loss of the co-expression of PRLR, TGFßRI and TGFßRII is indicative of aggressiveness and poor patient survival outcomes in breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptores da Prolactina/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Neoplasias da Mama/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Gradação de Tumores , Invasividade Neoplásica , Fenótipo , Receptores da Prolactina/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Análise de Sobrevida , Resultado do Tratamento
13.
Endocrinology ; 160(5): 1150-1163, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004482

RESUMO

Pancreatic ß-cells undergo profound hyperplasia during pregnancy to maintain maternal euglycemia. Failure to reprogram ß-cells into a more replicative state has been found to underlie susceptibility to gestational diabetes mellitus (GDM). We recently identified a requirement for prolactin receptor (PRLR) signaling in the metabolic adaptations to pregnancy, where ß-cell-specific PRLR knockout (ßPRLRKO) mice exhibit a metabolic phenotype consistent with GDM. However, the underlying transcriptional program that is responsible for the PRLR-dependent metabolic adaptations during gestation remains incompletely understood. To identify PRLR signaling gene regulatory networks and target genes within ß-cells during pregnancy, we performed a transcriptomic analysis of pancreatic islets isolated from either ßPRLRKO mice or littermate controls in late gestation. Gene set enrichment analysis identified forkhead box protein M1 and polycomb repressor complex 2 subunits, Suz12 and enhancer of zeste homolog 2 (Ezh2), as novel candidate regulators of PRLR-dependent ß-cell adaptation. Gene ontology term pathway enrichment revealed both established and novel PRLR signaling target genes that together promote a state of increased cellular metabolism and/or proliferation. In contrast to the requirement for ß-cell PRLR signaling in maintaining euglycemia during pregnancy, PRLR target genes were not induced following high-fat diet feeding. Collectively, the current study expands our understanding of which transcriptional regulators and networks mediate gene expression required for islet adaptation during pregnancy. The current work also supports the presence of pregnancy-specific adaptive mechanisms distinct from those activated by nutritional stress.


Assuntos
Regulação da Expressão Gênica , Células Secretoras de Insulina/metabolismo , Receptores da Prolactina/genética , Transdução de Sinais/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Diabetes Gestacional/genética , Diabetes Gestacional/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Células Secretoras de Insulina/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Gravidez , Receptores da Prolactina/metabolismo
14.
Horm Metab Res ; 51(4): 215-219, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30840999

RESUMO

Prolactin is a peptide hormone known to have multiple functions. However, the role of prolactin has been extensively studied only in female physiology and its function in male reproduction still remains majorly unexplored. Studies in rodents and humans have demonstrated the presence of prolactin and its receptor in testes, thereby suggesting a possible role during spermatogenesis. Experimental evidences from prolactin and prolactin receptor deficient male rodent models as well as studies done in hypo- and hyper-prolactinemic males hint at neuroendocrine and reproductive abnormalities. Nonetheless, there still remains a lot of ambiguity on the exact role of prolactin and its receptor in male reproduction. This review summarizes in depth on the role of prolactin in spermatogenesis.


Assuntos
Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Reprodução , Animais , Humanos , Masculino , Modelos Animais , Transdução de Sinais , Testículo/metabolismo
15.
Nat Rev Endocrinol ; 15(6): 356-365, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30899100

RESUMO

The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.


Assuntos
Pleiotropia Genética/fisiologia , Nível de Saúde , Hiperprolactinemia/metabolismo , Osteoporose/metabolismo , Prolactina/metabolismo , Animais , Feminino , Homeostase/fisiologia , Humanos , Hiperprolactinemia/genética , Osteoporose/genética , Prolactina/deficiência , Prolactina/genética , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo
16.
Endocrinology ; 160(5): 1323-1332, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901026

RESUMO

Hyperprolactinemia causes infertility, but the specific mechanism is unknown. It is clear that elevated prolactin levels suppress pulsatile release of GnRH from the hypothalamus, with a consequent reduction in pulsatile LH secretion from the pituitary. Only a few GnRH neurons express prolactin receptors (Prlrs), however, and thus prolactin must act indirectly in the underlying neural circuitry. Here, we have tested the hypothesis that prolactin-induced inhibition of LH secretion is mediated by kisspeptin neurons, which provide major excitatory inputs to GnRH neurons. To evaluate pulsatile LH secretion, we collected serial blood samples from diestrous mice and measured LH levels by ultrasensitive ELISA. Acute prolactin administration decreased LH pulses in wild-type mice. Kisspeptin neurons in the arcuate nucleus and in the rostral periventricular area of the third ventricle (RP3V) acutely responded to prolactin, but prolactin-induced signaling in kisspeptin neurons was up to fourfold higher in the arcuate nucleus when compared with the RP3V. Consistent with this, conditional knockout of Prlr specifically in arcuate nucleus kisspeptin neurons prevented prolactin-induced suppression of LH secretion. Our data establish that during hyperprolactinemia, suppression of pulsatile LH secretion is mediated by Prlr on arcuate kisspeptin neurons.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Neurônios/efeitos dos fármacos , Prolactina/farmacologia , Animais , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Hiperprolactinemia/genética , Hiperprolactinemia/metabolismo , Injeções Subcutâneas , Hormônio Luteinizante/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/fisiologia , Prolactina/administração & dosagem , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo
17.
Med Hypotheses ; 125: 137-138, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30902142

RESUMO

Primary acquired nasolacrimal duct obstruction (PANDO) is a syndrome of unknown etiology, predominantly affecting post-menopausal females, characterized by progressive inflammation, fibrosis and subsequent obstruction of the nasolacrimal duct. Numerous factors have been proposed as possible etiologic factors and include anatomical configuration, ocular and nasal infections, peri-lacrimal vascular disorders, hormonal influence, lacrimal drainage lymphoid tissue, gastroesophageal reflux disease, topical medications, swimming pool exposure, smoking, genetic factors, autonomic and lysosomal dysregulation. The authors hypothesize Prolactin (PRL) and Prolactin-inducible protein (PIP) play a role in the etiopathogenesis of primary acquired nasolacrimal duct obstruction.


Assuntos
Proteínas de Transporte/fisiologia , Refluxo Gastroesofágico/fisiopatologia , Glicoproteínas/fisiologia , Ducto Nasolacrimal/fisiopatologia , Prolactina/fisiologia , Animais , Doenças Autoimunes/fisiopatologia , Autofagia , Feminino , Humanos , Inflamação , Masculino , Proteínas de Membrana Transportadoras , Camundongos , Camundongos Knockout , Modelos Teóricos , Pós-Menopausa , Transporte Proteico , Receptores da Prolactina/fisiologia , Fatores de Risco
18.
Mol Divers ; 23(4): 1019-1028, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30740642

RESUMO

The prolactin hormone is involved in several biological functions, although its main role resides on reproduction. As it interferes on fertility changes, studies focused on human health have established a linkage of this hormone to fertility losses. Regarding animal research, there is still a lack of information about the structure of prolactin. In case of horse breeding, prolactin has a particular influence; once there is an individualization of these animals and equines are known for presenting several reproductive disorders. As there is no molecular structure available for the prolactin hormone and receptor, we performed several bioinformatics analyses through prediction and refinement softwares, as well as manual modifications. Aiming to elucidate the first computational structure of both molecules and analyse structural and functional aspects related to these proteins, here we provide the first known equine model for prolactin and prolactin receptor, which obtained high global quality scores in diverse software's for quality assessment. QMEAN overall score obtained for ePrl was (- 4.09) and QMEANbrane for ePrlr was (- 8.45), which proves the structures' reliability. This study will implement another tool in equine genomics in order to give light to interactions of these molecules, structural and functional alterations and therefore help diagnosing fertility problems, contributing in the selection of a high genetic herd.


Assuntos
Cavalos , Modelos Moleculares , Prolactina/química , Receptores da Prolactina/química , Animais , Simulação por Computador , Genômica , Reprodutibilidade dos Testes , Reprodução , Software
19.
FASEB J ; 33(5): 6115-6128, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30735445

RESUMO

There is clear evidence for carrier-mediated transport of prolactin into the brain, and it has been widely assumed that prolactin receptors (PRLRs) in the choroid plexus (ChP) might mediate this transport. Using PRLR knockout mice, we recently showed that PRLRs in ChP are not required for prolactin transport into the brain. Hence, the function of PRLR in the ChP remains unknown. PRLR expression is increased in the ChP during lactation, suggesting a possible role in adaptive function of prolactin at this time. To gain insight into prolactin function in the ChP, we have utilized RNA sequencing and NanoString techniques to characterize transcriptional changes in response to differing levels of prolactin at diestrus, during pregnancy, and in lactation. We have observed opposing transcriptional effects of prolactin on the ChP in different physiologic states, being primarily inhibitory during diestrus but stimulatory in lactation. Insulin-like growth factor 2 (Igf2), a highly expressing transcript found in the ChP, showed a 6-fold increase at lactation that returned to baseline on suppression of prolactin levels. These results indicate that Igf2 may be an important downstream mediator of prolactin-induced signaling in the ChP.-Phillipps, H. R., Rand, C. J., Brown, R. S. E., Kokay, I. C., Stanton, J.-A., Grattan, D. R. Prolactin regulation of insulin-like growth factor 2 gene expression in the adult mouse choroid plexus.


Assuntos
Encéfalo/metabolismo , Fator de Crescimento Insulin-Like II/genética , Lactação/metabolismo , Prolactina/metabolismo , Animais , Estro/metabolismo , Feminino , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Gravidez/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores da Prolactina/metabolismo
20.
G3 (Bethesda) ; 9(4): 1075-1084, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30760540

RESUMO

Parental care is critical for offspring survival in many species. However, parental behaviors have been lost in roughly 1% of avian species known as the obligate brood parasites. To shed light on molecular and neurobiological mechanisms mediating brood parasitic behavior, we compared brain gene expression patterns between two brood parasitic species and one closely related non-parasitic Icterid (blackbird) species. Our analyses focused on gene expression changes specifically in the preoptic area (POA), a brain region known to play a critical role in parental behavior across vertebrates. Using comparative transcriptomic approaches, we identified gene expression patterns associated with brood parasitism. We evaluated three non-mutually exclusive alternatives for the evolution of brood parasitism: (1) retention of juvenile-like (neotenic) gene expression, (2) reduced expression of maternal care-related genes in the POA, and/or (3) increased expression of genes inhibiting maternal care. We find evidence for neotenic expression patterns in both species of parasitic cowbirds as compared to maternal, non-parasites. In addition, we observed differential expression in a number of genes with previously established roles in mediating maternal care. Together, these results provide the first insight into transcriptomic and genetic mechanisms underlying the loss of maternal behavior in avian brood parasites.


Assuntos
Comportamento Animal , Comportamento Materno , Passeriformes/fisiologia , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Perfilação da Expressão Gênica , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Passeriformes/genética , Área Pré-Óptica/metabolismo , Receptores da Bombesina/genética , Receptores da Bombesina/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Receptores da Prolactina/metabolismo , Somatostatina/genética , Somatostatina/metabolismo
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