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1.
Proc Natl Acad Sci U S A ; 117(38): 23952-23959, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32900950

RESUMO

Glands of the uterus are essential for pregnancy establishment. Forkhead box A2 (FOXA2) is expressed specifically in the glands of the uterus and a critical regulator of glandular epithelium (GE) differentiation, development, and function. Mice with a conditional deletion of FOXA2 in the adult uterus, created using the lactotransferrin iCre (Ltf-iCre) model, have a morphologically normal uterus with glands, but lack FOXA2-dependent GE-expressed genes, such as leukemia inhibitory factor (LIF). Adult FOXA2 conditional knockout (cKO; Ltf iCre/+ Foxa2 f/f ) mice are infertile due to defective embryo implantation arising from a lack of LIF, a critical implantation factor of uterine gland origin. However, intraperitoneal injections of LIF can initiate embryo implantation in the uterus of adult FOXA2 cKO mice with pregnancies maintained to term. Here, we tested the hypothesis that FOXA2-regulated genes in the uterine glands impact development of the decidua, placenta, and fetus. On gestational day 8.5, the antimesometrial and mesometrial decidua transcriptome was noticeably altered in LIF-replaced FOXA2 cKO mice. Viable fetuses were reduced in FOXA2 cKO mice on gestational days 12.5 and 17.5. Sex-dependent differences in fetal weight, placenta histoarchitecture, and the placenta and metrial gland transcriptome were observed between control and FOXA2 cKO mice. The transcriptome of the placenta with a female fetus was considerably more altered than the placenta with a male fetus in FOXA2 cKO dams. These studies reveal previously unrecognized sexually dimorphic effects of FOXA2 and uterine glands on fetoplacental development with potential impacts on offspring health into adulthood.


Assuntos
Feto/metabolismo , Fator 3-beta Nuclear de Hepatócito , Placenta/metabolismo , Caracteres Sexuais , Útero/metabolismo , Animais , Decídua/metabolismo , Feminino , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Masculino , Camundongos , Camundongos Knockout , Gravidez , Transcriptoma/genética
2.
Anim Sci J ; 91(1): e13456, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32926548

RESUMO

In this study, we investigated whether bovine oviducts and endometria produce anti-Müllerian hormone (AMH) (for paracrine and autocrine signaling). Reverse transcription-polymerase chain reaction and western blotting detected AMH expression in oviductal and endometrial specimens. Immunohistochemistry revealed robust AMH expression in the ampulla and isthmus epithelia, and the glandular and luminal endometrial epithelia (caruncular endometria). AMH mRNA (measured by real-time PCR) and protein expression in these layers did not significantly differ among estrous phases in adult Japanese Black (JB) heifers (p > .1). Furthermore, the expression in these layers also did not differ among Holstein cows (93.8 ± 5.8 months old), JB heifers (25.5 ± 0.4 months old), and JB cows (97.9 ± 7.9 months old). We also compared AMH concentrations in the oviduct and uterine horn fluids among the three groups (measured by immunoassays). Interestingly, the AMH concentration in the oviduct fluid, but not in the uterine horn fluid, of Holstein cows was lower than those in JB heifers and cows (p < .05). Therefore, bovine oviducts and endometria express AMH and likely secrete it into the oviduct and uterine fluids.


Assuntos
Hormônio Antimülleriano/genética , Hormônio Antimülleriano/metabolismo , Endométrio/metabolismo , Células Epiteliais/metabolismo , Expressão Gênica , Oviductos/metabolismo , Animais , Bovinos , Endométrio/citologia , Ciclo Estral/metabolismo , Feminino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Útero/metabolismo
3.
Adv Exp Med Biol ; 1265: 111-131, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761573

RESUMO

Amino acids are not only the building blocks of proteins, an indispensable component of cells, but also play versatile roles in regulating cell metabolism, proliferation, differentiation and growth by themselves or through their derivatives. At the whole body level, the bioavailability and metabolism of amino acids, interacting with other macronutrients, is critical for the physiological processes of reproduction including gametogenesis, fertilization, implantation, placentation, fetal growth and development. In fertilization and early pregnancy, histotroph in oviductal and uterine secretions provides nutrients and microenvironment for conceptus (embryo and extraembryonic membranes) development. These nutrients include select amino acids in histotroph (arginine, leucine and glutamine of particular interest) that stimulate conceptus growth and development, as well as interactions between maternal uterus and the conceptus, thus impacting maintenance of pregnancy, placental growth, development and functions, fetal growth and development, and consequential pregnancy outcomes. Gestational protein undernutrition causes fetal growth restriction and predisposes cardiovascular, metabolic diseases and others in offspring via multiple mechanisms, whereas the supplementation of glycine, leucine and taurine during pregnancy partially rescues growth restriction and beneficially modulates fetal programming. Thus, amino acids are essential for the fertility of humans and all animals.


Assuntos
Aminoácidos/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Reprodução/fisiologia , Animais , Implantação do Embrião , Feminino , Desenvolvimento Fetal , Humanos , Gravidez , Útero/metabolismo
4.
PLoS One ; 15(7): e0235619, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634174

RESUMO

This study aimed to estimate energy requirements of pregnant Holstein × Gyr cows. Different planes of nutrition were established by two feeding regimens: ad libitum or maintenance. Sixty-two nonlactating cows with average body weight of 480 ± 10.1 kg and an age of 5 ± 0.5 years were used. Cows were divided into three groups: pregnant (n = 44), non-pregnant (n = 12), and baseline reference (n = 6). The 56 pregnant and non-pregnant cows were randomly allocated into a feeding regimen: ad libitum or maintenance. To evaluate the effects of days of pregnancy, pregnant and non-pregnant animals were slaughtered at 140, 200, 240, and 270 days of pregnancy. Energy requirements for maintenance differed between pregnant and non-pregnant cows, thus two equations were developed. Net energy and metabolizable energy requirements for maintenance of non-pregnant cows were 82 kcal/kg empty body weight0.75/day and 132 kcal/kg empty body weight0.75/day, respectively. The efficiency of use of metabolizable energy for maintenance of non-pregnant cows was 62.4%. Net energy and metabolizable energy for maintenance of pregnant cows were 86 kcal/kg empty body weight0.75/day and 137 kcal/kg empty body weight0.75/day, respectively. Efficiency of use of metabolizable energy for maintenance of pregnant cows was 62.5%. The efficiency of use of metabolizable energy for gain was 41.9%. The efficiency of use of metabolizable energy for pregnancy was 14.1%. Furthermore, net energy requirement for pregnancy was different from zero from day 70 of pregnancy onwards. In conclusion, net energy and metabolizable energy requirements for maintenance of non-pregnant cows are different from pregnant cows. Furthermore, we believe that the proposed non-linear equations to estimate net energy requirements for pregnancy are more adequate than current NRC equation, and should be recommended for Holstein × Gyr cows.


Assuntos
Ingestão de Energia , Necessidades Nutricionais , Animais , Peso Corporal , Bovinos , Metabolismo Energético , Feminino , Glândulas Mamárias Animais/metabolismo , Gravidez , Útero/metabolismo
5.
Proc Natl Acad Sci U S A ; 117(32): 19425-19434, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719113

RESUMO

Spiral artery remodeling is an important physiological process in the pregnant uterus which increases blood flow to the fetus. Impaired spiral artery remodeling contributes to preeclampsia, a major disease in pregnancy. Corin, a transmembrane serine protease, is up-regulated in the pregnant uterus to promote spiral artery remodeling. To date, the mechanism underlying uterine corin up-regulation remains unknown. Here we show that Krüppel-like factor (KLF) 17 is a key transcription factor for uterine corin expression in pregnancy. In cultured human uterine endometrial cells, KLF17 binds to the CORIN promoter and enhances the promoter activity. Disruption of the KLF17 gene in the endometrial cells abolishes CORIN expression. In mice, Klf17 is up-regulated in the pregnant uterus. Klf17 deficiency prevents uterine Corin expression in pregnancy. Moreover, Klf17-deficient mice have poorly remodeled uterine spiral arteries and develop gestational hypertension and proteinuria. Together, our results reveal an important function of KLF17 in regulating Corin expression and uterine physiology in pregnancy.


Assuntos
Artérias/fisiologia , Serina Endopeptidases/genética , Fatores de Transcrição/metabolismo , Útero/fisiologia , Animais , Células Cultivadas , Feminino , Fertilidade/genética , Regulação da Expressão Gênica , Humanos , Hipertensão Induzida pela Gravidez/genética , Masculino , Camundongos , Camundongos Knockout , Gravidez , Regiões Promotoras Genéticas , Proteinúria/genética , Serina Endopeptidases/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Útero/irrigação sanguínea , Útero/metabolismo , Remodelação Vascular
6.
Arterioscler Thromb Vasc Biol ; 40(9): 2143-2158, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640903

RESUMO

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17ß-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. CONCLUSIONS: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Fertilidade/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Mutação Puntual , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Ativação Enzimática , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Reepitelização/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/metabolismo , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
7.
Ecotoxicol Environ Saf ; 199: 110675, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32402895

RESUMO

An oral painless dietary therapy is also indispensable in the management of arsenic toxicity despite of its conventional painful therapeutic management. The present study focused on the management of arsenic mediated female reproductive dysfunctions by dietary therapy of N-acetyl cysteine (NAC). Here, sodium arsenite was given at the dose of 10 mg/kg body weight orally for the first 8 day. Day 9 onwards up to day 16 these arsenicated rats were provided with NAC (250 mg/kg body weight) enriched basal diet once daily. Arsenic intoxicated group exhibited a comparable inactivation of antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) due to oxidative stress in reproductive organs along with a simultaneous elevation of lipid peroxidation state and decline in non-protein soluble thiols (NPSH) level in female reproductive organs. Arsenic intoxication also accomplished with the up-regulation of inflammatory markers tumour necrosis factor (TNF α) and nuclear factor κB (NF κB). Pro-apoptotic Bax gene and p53 gene expressions were also raised due to arsenic intoxication while anti-apoptotic Bcl-2 gene expression was suppressed. In fact, arsenication decreased the circulating level of vitamin B12 and folic acid. Dietary NAC supplementation significantly reversed back the activity of antioxidant enzymes in arsenite fed rats towards normalcy and also sustained the normal reproductive cyclicity, utero-ovarian histo-morphology and estradiol receptor α (ER-α) expression in these reproductive organs. Dietary NAC exerted its positive action against arsenic intoxication by up-regulation of Bcl-2 gene expression along with the suppression of pro-apoptotic Bax gene and p53 gene. Thus, dietary NAC also plays anti-apoptotic, anti-inflammatory, and anti-oxidative role against arsenic toxicity. NAC also regulates the components (vitamin B12 and folic acid) of S-adenosylmethionine pool in the way of probable removal of arsenic from the system.


Assuntos
Acetilcisteína/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Arsenitos/toxicidade , Expressão Gênica/efeitos dos fármacos , Ovário/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Apoptose/genética , Suplementos Nutricionais , Feminino , Masculino , Ovário/metabolismo , Ovário/patologia , Ovário/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Útero/metabolismo , Útero/patologia , Útero/fisiopatologia
8.
Adv Exp Med Biol ; 1242: 37-58, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32406027

RESUMO

Leiomyoma, adenomyosis, and endometrial polyps are benign uterine disorders which seem to develop in the context of hormonal imbalances, due to steroid hormones, estrogen and progesterone, in association with various factors ranging from genetic factors to modifiable lifestyle factors. A growing body of evidence suggests that those hormones and their receptors are key modulators in the genesis and the growth of those pathologic entities. Further studies are required to understand their involvement in the pathogenesis of those lesions and their link to other factors such as extracellular matrix components, growth factors, chemokines, cytokines, and tissue repair mechanisms.


Assuntos
Adenomiose/metabolismo , Hormônios/metabolismo , Leiomioma/metabolismo , Pólipos/metabolismo , Útero/metabolismo , Útero/patologia , Feminino , Humanos
9.
Anim Sci J ; 91(1): e13396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468659

RESUMO

The objective of this study was to examine the expression profiles of follistatin (FST) and its associated molecules (MSTN, INHA, INHBB, INHBA, ACVR2A, and ACVR2B) in the oviduct of laying hens at 3 hr and 20 hr post-ovulation (p.o., n = 5; 35 weeks old), molting (n = 5; 60 weeks old), and non-laying (n = 4; 35-60 weeks old) hens and also to localize the FST by using immunohistochemistry assay. Expression of FST was significantly higher (p < .05), and MSTN was lower in the uterus of laying hens around 15-20 hr p.o. (during eggshell formation), however, their expressions in the magnum remain unchanged across different physiological stages of hens. FST was mainly expressed in the luminal and glandular epithelium of the uterine tissues, and their expression intensity was highest in laying hens during the eggshell mineralization. There was a relatively increased expression of INHA in the magnum of laying hens around 3 hr p.o. as compared to non-laying and molting hens. At the same time (3 hr p.o.), there was a significant (p < .05) decrease in the expression of the INHBB, ACVR2A, and ACV2B. These results indicate that follistatin may regulate the differentiation of uterine luminal and glandular epithelium during eggshell biomineralization.


Assuntos
Biomineralização/genética , Galinhas/genética , Galinhas/fisiologia , Casca de Ovo/embriologia , Folistatina/genética , Folistatina/metabolismo , Expressão Gênica/genética , Oviductos/metabolismo , Oviposição/genética , Oviposição/fisiologia , Ovulação/genética , Ovulação/fisiologia , Transcriptoma , Animais , Biomineralização/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Casca de Ovo/fisiologia , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Feminino , Oviductos/fisiologia , Útero/citologia , Útero/metabolismo
10.
Am J Physiol Endocrinol Metab ; 318(6): E981-E994, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315215

RESUMO

Chlamydia trachomatis infection is a primary cause of reproductive tract diseases including infertility. Previous studies showed that this infection alters physiological activities in mouse oviducts. Whether this occurs in the uterus and cervix has never been investigated. This study characterized the physiological activities of the uterine horn and the cervix in a Chlamydia muridarum (Cmu)-infected mouse model at three infection time points of 7, 14, and 21 days postinfection (dpi). Cmu infection significantly decreased contractile force of spontaneous contraction in the cervix (7 and 14 dpi; P < 0.001 and P < 0.05, respectively), but this effect was not observed in the uterine horn. The responses of the uterine horn and cervix to oxytocin were significantly altered by Cmu infection at 7 dpi (P < 0.0001), but such responses were attenuated at 14 and 21 dpi. Cmu infection increased contractile force to prostaglandin (PGF2α) by 53-83% in the uterine horn. This corresponded with the increased messenger ribonucleic acid (mRNA) expression of Ptgfr that encodes for its receptor. However, Cmu infection did not affect contractions of the uterine horn and cervix to PGE2 and histamine. The mRNA expression of Otr and Ptger4 was inversely correlated with the mRNA expression of Il1b, Il6 in the uterine horn of Cmu-inoculated mice (P < 0.01 to P < 0.001), suggesting that the changes in the Otr and Ptger4 mRNA expression might be linked to the changes in inflammatory cytokines. Lastly, this study also showed a novel physiological finding of the differential response to PGE2 in mouse uterine horn and cervix.


Assuntos
Infecções por Chlamydia/fisiopatologia , Chlamydia muridarum , Miométrio/fisiopatologia , Infecções do Sistema Genital/fisiopatologia , Contração Uterina/fisiologia , Útero/fisiopatologia , Animais , Colo do Útero/metabolismo , Colo do Útero/fisiopatologia , Infecções por Chlamydia/genética , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/metabolismo , Citocinas/genética , Dinoprosta/farmacologia , Dinoprostona/farmacologia , Feminino , Regulação da Expressão Gênica , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Interleucina-1beta/genética , Interleucina-6/genética , Camundongos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Oviductos/patologia , Ocitócicos/farmacologia , RNA Mensageiro/metabolismo , Receptores de Ocitocina/genética , Receptores de Prostaglandina/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Infecções do Sistema Genital/genética , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/metabolismo , Contração Uterina/efeitos dos fármacos , Útero/metabolismo
11.
Am J Physiol Endocrinol Metab ; 318(5): E646-E654, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32125882

RESUMO

Mouse models with lifelong inactivation of estrogen receptor-α (ERα) show that ERα is the main mediator of estrogenic effects in bone, thymus, uterus, and fat. However, ERα inactivation early in life may cause developmental effects that confound the adult phenotypes. To address the specific role of adult ERα expression for estrogenic effects in bone and other nonskeletal tissues, we established a tamoxifen-inducible ERα-inactivated model by crossing CAGG-Cre-ER and ERαflox/flox mice. Tamoxifen-induced ERα inactivation after sexual maturation substantially reduced ERα mRNA levels in cortical bone, trabecular bone, thymus, uterus, gonadal fat, and hypothalamus, in CAGG-Cre-ERαflox/flox (inducible ERαKO) compared with ERαflox/flox (control) mice. 17ß-estradiol (E2) treatment increased trabecular bone volume fraction (BV/TV), cortical bone area, and uterine weight, while it reduced thymus weight and fat mass in ovariectomized control mice. The estrogenic responses were substantially reduced in inducible ERαKO mice compared with control mice on BV/TV (-67%), uterine weight (-94%), thymus weight (-70%), and gonadal fat mass (-94%). In contrast, the estrogenic response on cortical bone area was unaffected in inducible ERαKO compared with control mice. In conclusion, using an inducible ERαKO model, not confounded by lack of ERα during development, we demonstrate that ERα expression in sexually mature female mice is required for normal E2 responses in most, but not all, tissues. The finding that cortical, but not trabecular bone, responds normally to E2 treatment in inducible ERαKO mice strengthens the idea of cortical and trabecular bone being regulated by estrogen via different mechanisms.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Útero/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Camundongos , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Timo/efeitos dos fármacos , Timo/metabolismo , Útero/metabolismo
12.
J Pharmacol Exp Ther ; 373(3): 381-390, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32205366

RESUMO

Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE2 analogs were used to investigate the functional E-type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus (n = 12), term gestation (n = 14), and labor (n = 12) and from the lower uterus of women undergoing hysterectomy (n = 12) or Caesarean section (n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both nonpregnant species, while the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP3 receptors have clear translational value.


Assuntos
Receptores de Prostaglandina E Subtipo EP2/metabolismo , Reprodução/fisiologia , Útero/metabolismo , Adulto , Animais , Cesárea/métodos , Dinoprostona/análogos & derivados , Dinoprostona/farmacologia , Feminino , Humanos , Camundongos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Gravidez , Reprodução/efeitos dos fármacos , Contração Uterina/efeitos dos fármacos , Contração Uterina/metabolismo , Útero/efeitos dos fármacos , Adulto Jovem
13.
Anim Sci J ; 91(1): e13348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219957

RESUMO

The underlying mechanism of taste receptor type 1 subunit 2 (T1R2) and taste receptor type 1 subunit 3 (T1R3) in the hormonal and reproductive system is still elusive. A low or a high dose of sweetness equivalent to that sodium saccharin (SS, 1.5 or 7.5 mM) and rebaudioside A (RA, 0.5 or 2.5 mM) was administered to young female guinea pigs for 28 consecutive days from the age of 28 days. Our results indicated that the sweet taste receptor subunit T1R2 was markedly expressed in the ovary and uterus of guinea pigs, whereas the T1R3 protein was expressed at a lower level. We elucidated that low-dose (1.5 mM) SS increased body and ovary weight associated with elevated ovarian expression of T1R2 in guinea pigs, unlike the high-dose (7.5 mM) SS, which suppressed the ovarian expression of T1R2 and resulted in certain adverse effects on ovarian and uterine morphology. Furthermore, high-dose (2.5 mM) RA increased the number of corpus luteum and elevated uterine expression of T1R2, whereas low-dose (0.5 mM) RA induced increased secretion of serum progesterone. Therefore, our findings suggest that we should pay more attention to the potential adverse effects, including increases in ovary weight, morphology changes, and increased progesterone that result from the dose-dependent regulation of T1R2 by non-nutritive sweeteners (NNS) in the ovaries and uteri of peripubertal females.


Assuntos
Expressão Gênica/efeitos dos fármacos , Cobaias/genética , Cobaias/metabolismo , Ovário/metabolismo , Puberdade/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Edulcorantes/efeitos adversos , Útero/metabolismo , Fenômenos Fisiológicos da Nutrição Animal , Animais , Relação Dose-Resposta a Droga , Feminino , Progesterona/metabolismo , Edulcorantes/administração & dosagem
14.
Mol Med Rep ; 21(3): 1461-1470, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016479

RESUMO

The present study was designed to elucidate the underlying mechanisms of Bao Gui capsule (BGC) against hyperandrogenism, insulin resistance and leptin resistance of PCOS. Letrozole was used to induce a PCOS model in rats, which were then randomly divided into four groups (n=9): Control, Model, high­dose BGC (BGC­H) and low­dose BGC (BGC­L) group. Serum levels of follicle­stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), insulin, leptin, and interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α (TNF­α) in the hypothalamus were determined by ELISA. Protein levels of cytochrome P450c17α and cytochrome P450 aromatase (P450arom) in ovaries were determined by immunohistochemistry and western blot analysis. Additionally, the expression of GLUT4 in uterus and muscle tissue, and NF­κB, IKKß and SOCS3 mRNA levels in the hypothalamus were evaluated. BGC significantly reduced body weight gain and decreased serum levels of LH/FSH, T, log T/E2, insulin and leptin compared with the PCOS model rats. Furthermore, BGC markedly reduced the expression of P450c17α and significantly increased the expression of P450arom in ovaries, and increased the expression of GLUT4 in uterus and muscle tissues. BGC also effectively reduced the level of IL­6 and TNF­α, and the expression of IKKß, NF­κB and SOCS3 in the hypothalamus of PCOS model rats. These results suggest that BGC may effectively improve hyperandrogenism, insulin resistance, endometrial receptivity and the low­grade chronic inflammation in the hypothalamus.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hiperandrogenismo/tratamento farmacológico , Resistência à Insulina , Fitoterapia , Preparações de Plantas/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Citocinas/sangue , Endométrio/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Transportador de Glucose Tipo 4/metabolismo , Hiperandrogenismo/metabolismo , Hipotálamo/metabolismo , Insulina/sangue , Leptina/sangue , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/metabolismo , Ratos , Testosterona/sangue , Útero/metabolismo
15.
Phytomedicine ; 68: 153151, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32058234

RESUMO

BACKGROUND AND PURPOSE: Primary dysmenorrhea is the most common gynaecologic problem in menstruating women and is characterized by spasmodic uterine contraction and pain symptoms associated with inflammatory disturbances. Paeonol is an active phytochemical component that has shown anti-inflammatory and analgesic effects in several animal models. The aim of this study was to explore whether paeonol is effective against dysmenorrhea and to investigate the potential mechanism of cannabinoid receptor signalling. EXPERIMENTAL APPROACH: Dysmenorrhea was established by injecting oestradiol benzoate into female mice. The effects of paeonol on writhing time and latency, uterine pathology and inflammatory mediators were explored. Isolated uterine smooth muscle was used to evaluate the direct effect of paeonol on uterine contraction. KEY RESULTS: The oral administration of paeonol reduced dysmenorrhea pain and PGE2 and TNF-α expression in the uterine tissues of mice, and paeonol was found to be distributed in lesions of the uterus. Paeonol almost completely inhibited oxytocin-, high potassium- and Ca2+-induced contractions in isolated uteri. Antagonists of CB2R (AM630) and the MAPK pathway (U0126), but not of CB1R (AM251), reversed the inhibitory effect of paeonol on uterine contraction. Paeonol significantly blocked L-type Ca2+ channels and calcium influx in uterine smooth muscle cells via CB2R. Molecular docking results showed that paeonol fits well with the binding site of CB2R. CONCLUSIONS AND IMPLICATIONS: Paeonol partially acts through CB2R to restrain calcium influx and uterine contraction to alleviate dysmenorrhea in mice. These results suggest that paeonol has therapeutic potential for the treatment of dysmenorrhea.


Assuntos
Acetofenonas/farmacologia , Dismenorreia/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , Útero/efeitos dos fármacos , Acetofenonas/química , Animais , Cálcio/metabolismo , Dinoprostona/metabolismo , Dismenorreia/induzido quimicamente , Dismenorreia/metabolismo , Estradiol/análogos & derivados , Estradiol/toxicidade , Feminino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Miócitos de Músculo Liso , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Ocitocina/farmacologia , Receptor CB2 de Canabinoide/química , Fator de Necrose Tumoral alfa/metabolismo , Contração Uterina/efeitos dos fármacos , Útero/metabolismo
16.
Nat Commun ; 11(1): 8, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911630

RESUMO

Biological tissues exhibit complex spatial heterogeneity that directs the functions of multicellular organisms. Quantifying protein expression is essential for elucidating processes within complex biological assemblies. Imaging mass spectrometry (IMS) is a powerful emerging tool for mapping the spatial distribution of metabolites and lipids across tissue surfaces, but technical challenges have limited the application of IMS to the analysis of proteomes. Methods for probing the spatial distribution of the proteome have generally relied on the use of labels and/or antibodies, which limits multiplexing and requires a priori knowledge of protein targets. Past efforts to make spatially resolved proteome measurements across tissues have had limited spatial resolution and proteome coverage and have relied on manual workflows. Here, we demonstrate an automated approach to imaging that utilizes label-free nanoproteomics to analyze tissue voxels, generating quantitative cell-type-specific images for >2000 proteins with 100-µm spatial resolution across mouse uterine tissue sections preparing for blastocyst implantation.


Assuntos
Automação/métodos , Espectrometria de Massas/métodos , Proteínas/química , Proteômica/métodos , Útero/química , Animais , Feminino , Microdissecção e Captura a Laser , Camundongos , Camundongos Endogâmicos C57BL , Microtomia , Proteínas/genética , Proteínas/metabolismo , Proteoma/química , Proteoma/genética , Proteoma/metabolismo , Útero/metabolismo
17.
Endocrinology ; 161(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748790

RESUMO

Decidualization, the process by which fibroblastic human endometrial stromal cells (HESC) differentiate into secretory decidual cells, is a critical event during the establishment of pregnancy. It is dependent on the steroid hormone progesterone acting through the nuclear progesterone receptor (PR). Previously, we identified insulin receptor substrate 2 (IRS2) as a factor that is directly regulated by PR during decidualization. IRS2 is an adaptor protein that functionally links receptor tyrosine kinases, such as insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R), and their downstream effectors. IRS2 expression was induced in HESC during in vitro decidualization and siRNA-mediated downregulation of IRS2 transcripts resulted in attenuation of this process. Further use of siRNAs targeted to IR or IGF1R transcripts showed that downregulation of IR, but not IGF1R, led to impaired decidualization. Loss of IRS2 transcripts in HESC suppressed phosphorylation of both ERK1/2 and AKT, downstream effectors of insulin signaling, which mediate gene expression associated with decidualization and regulate glucose uptake. Indeed, downregulation of IRS2 resulted in reduced expression and membrane localization of the glucose transporters GLUT1 and GLUT4, resulting in lowered glucose uptake during stromal decidualization. Collectively, these data suggest that the PR-regulated expression of IRS2 is necessary for proper insulin signaling for controlling gene expression and glucose utilization, which critically support the decidualization process to facilitate pregnancy. This study provides new insight into the mechanisms by which steroid hormone signaling intersects with insulin signaling in the uterus during decidualization, which has important implications for pregnancy complications associated with insulin resistance and infertility.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Decídua/efeitos dos fármacos , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Progesterona/farmacologia , Diferenciação Celular/genética , Células Cultivadas , Decídua/citologia , Decídua/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Fosforilação/efeitos dos fármacos , Gravidez , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Útero/citologia , Útero/metabolismo
18.
Environ Pollut ; 257: 113480, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31744678

RESUMO

Etoxazole is an organofluorine insecticide widely used in agriculture. Exposure to insecticides is a serious environmental problem owing to their cytotoxic effects in humans and animals. Reproductive toxicity of various organofluorine insecticides have been shown in previous studies. However, few studies have evaluated the toxicity of etoxazole in mammals. We aimed to examine the toxic effects of etoxazole in porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells. To estimate the effects of etoxazole, we conducted assays after treatment with multiple concentration of etoxazole (0, 2, 4, 6 and 9 µM) to pTr and pLE cells for 0-72 h. Etoxazole decreased the cell proliferation, viability, and migration of pTr and pLE cells. Further, etoxazole induced apoptosis via cell cycle arrest and disruption of mitochondrial membrane potential. We also found that pro-apoptotic proteins and endoplasmic reticulum (ER) stress-response proteins were activated in response to etoxazole. Finally, we observed that etoxazole altered the PI3K/AKT and MAPK signaling pathways and the mRNA expression of genes associated with implantation. Collectively, these results suggest that etoxazole disrupts normal cellular physiology and might cause early implantation failure.


Assuntos
Acaricidas/toxicidade , Oxazóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Morte Celular , Proliferação de Células/efeitos dos fármacos , Implantação do Embrião/efeitos dos fármacos , Estresse do Retículo Endoplasmático , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Suínos , Útero/metabolismo
19.
Theriogenology ; 142: 149-157, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31593882

RESUMO

Aquaporins play vital roles in reproductive physiology. This study evaluates the expression and localization dynamics of AQP1, AQP2, AQP3 and AQP8 in the endometrium and placental transference zone during pregnancy in queens by means of immunohistochemistry and Western blot. Animals were distributed into six groups: non-pregnant queens with low levels of serum progesterone (P4), non-pregnant animals with high P4 levels, and queens at 30, 40, 50 and 60 days of pregnancy. All AQPs were present in glandular and luminal epithelia and myometrium. AQP1 was also present in the endometrial endothelia. AQP2, AQP3 and AQP8 were found in trophoblast. In endometrial samples with P4 above 2 ng/mL, AQP2 and AQP8 were distributed across plasma membrane and cytoplasm, whereas progesterone levels under 1 ng/mL kept both AQPs confined to the plasma membrane. Western blot showed no significant changes in AQPs expression among the stages. In conclusion, our results indicate that the distribution of AQP2 and AQP8 in the queen reproductive tract is related to P4 levels.


Assuntos
Aquaporina 2/metabolismo , Aquaporinas/metabolismo , Placenta/metabolismo , Progesterona/sangue , Útero/metabolismo , Animais , Anticorpos , Aquaporina 2/genética , Aquaporinas/genética , Gatos , Feminino , Regulação da Expressão Gênica , Imuno-Histoquímica , Gravidez , Distribuição Tecidual
20.
Mol Cell Endocrinol ; 499: 110610, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31589912

RESUMO

Prenatal hyperandrogenization (PH) is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). In this study, we aimed to investigate the impact of prenatal exposure to androgen excess on the uterus when animals reach their adulthood. We found that PH altered the morphology of the uteri that show a hyperplastic morphology with increased total uterine thickness as well as luminal epithelium thickness, with both enhanced and altered distribution of glands as compared with controls. Morphological alterations were associated with an unbalanced homeostasis as assessed by the expression of regulators of cell cycle progression and cell death dynamics. PH also causes disturbances in the cell cycle of the uterine tissue and dysregulates cell death and survival pathways leading to the development of uterine hyperplasia. These findings suggest that PH may have a deleterious effect on the uterus.


Assuntos
Androgênios/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Útero/patologia , Animais , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Homeostase/efeitos dos fármacos , Hiperplasia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Útero/efeitos dos fármacos , Útero/metabolismo
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