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Reproductive Sciences (Thousand Oaks,... Nov 2023Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA...
Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA cases are of unknown etiology. Our previous study found that the decidual tissue of patients with unexplained recurrent spontaneous abortion (URSA) had low expression levels of serum and glucocorticoid-induced protein kinase (SGK) 1. Endometrial decidualization is a key link in the early stage of pregnancy and is crucial to the development and maintenance of pregnancy. Decidualization is the proliferation and differentiation of endometrial stromal cells into deciduals, which involves a complex physiological process such as ovarian steroid hormones (estrogen, progesterone, prolactin, etc.), growth factors, and intercellular signaling. The binding of estrogen and its receptor stimulates the synthesis of endometrial deciduating markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP-1), which mediates the occurrence of decidualization. Among them, SGK1/ENaC is a signaling pathway closely related to decidualization. The purpose of this study was to further investigate the expression of SGK1 and decidualization-related molecules in the decidual tissue of URSA patients and to explore the potential mechanism of SGK1's protective effect in URSA patients and in mouse models. Decidual tissue samples from 30 URSA patients and 30 women who actively terminated pregnancy were collected, and a URSA mouse model was established and treated with dydrogesterone. Expression levels of SGK1 and its signaling pathway-related proteins (p-Nedd4-2, 14-3-3 protein and ENaC-a), estrogen and progesterone receptors (ERβ, PR), and decidualization markers (PRLR, IGFBP-1) were assessed. Our study found that SGK1, p-Nedd4-2, 14-3-3 proteins, and ENaC-a expression levels were reduced in the decidual tissue, the SGK1/ENaC signaling pathway was inhibited, and the expression levels of the decidualization markers PRLR and IGFBP-1 were downregulated in the URSA group compared with the controls. Additionally, the concentrations of E, P, and PRL in the serum of mice were decreased in the URSA group compared with the controls. However, SGK1/ENaC pathway-related proteins, estrogen and progesterone and their receptors, and decidualization-related molecules were upregulated by dydrogesterone. These data suggest that estrogen and progesterone can induce decidualization by activating the SGK1/ENaC signaling pathway; disruption of this pathway can lead to the development of URSA. Dydrogesterone can increase the expression level of SGK1 protein in decidual tissue.
Topics: Humans; Pregnancy; Female; Mice; Animals; Progesterone; Decidua; Insulin-Like Growth Factor Binding Protein 1; Abortion, Spontaneous; Prolactin; Dydrogesterone; Signal Transduction; Estrogens; Abortion, Habitual; Stromal Cells
PubMed: 37280474
DOI: 10.1007/s43032-023-01273-1 -
Neurochemical Research Jun 2024Despite the increase in the prevalence of postpartum depression among maternal disorder, its treatment outcomes remain suboptimal. Studies have shown that exercise can...
Wheel Running During Pregnancy Alleviates Anxiety-and Depression-Like Behaviors During the Postpartum Period in Mice: The Roles of NLRP3 Neuroinflammasome Activation, Prolactin, and the Prolactin Receptor in the Hippocampus.
Despite the increase in the prevalence of postpartum depression among maternal disorder, its treatment outcomes remain suboptimal. Studies have shown that exercise can reduce postpartum depressive episodes in the mother, but the effects of exercise during pregnancy on maternal behavior and the potential mechanisms involved remain poorly understood. From the second day of pregnancy to the day of birth, dams exercised for 1 h a day by running on a controlled wheel. The maternal behaviors of the dams were assessed on postpartum day 2 to postpartum day 8. Chronic restraint stress was applied from postpartum day 2 to day 12. Blood was collected on postpartum days 3 and 8, then subjected to ELISA to determine the serum concentration of prolactin. The weight of each dam and the food intake were recorded. Anxiety- and depression-like behavioral tests were conducted, and hippocampal neuroinflammation and prolactin receptor levels were measured. The dams exhibited elevated levels of anxiety and depression, decreased serum prolactin levels, decreased prolactin receptor expression, and activation of NLRP3-mediated neuroinflammation in the hippocampus following the induction of postpartum chronic restraint stress, which were reversed with controlled wheel running during pregnancy. Overall, the findings of this study revealed that the preventive effects of exercise during pregnancy on postpartum anxiety-and depression-like behaviors were accompanied by increased serum prolactin levels, hippocampal prolactin receptor expression and hippocampal NLRP3-mediated neuroinflammation.
PubMed: 38904910
DOI: 10.1007/s11064-024-04180-2 -
Journal of Neuroendocrinology Apr 2024The conserved and multifaceted functions of prolactin (PRL) are coordinated through varied distribution and expression of its cell-surface receptor (PRLR) across a range... (Review)
Review
The conserved and multifaceted functions of prolactin (PRL) are coordinated through varied distribution and expression of its cell-surface receptor (PRLR) across a range of tissues and physiological states. The resultant heterogeneous expression of PRLR mRNA and protein across different organs and cell types supports a wide range of PRL-regulated processes including reproduction, lactation, development, and homeostasis. Genetic variation within the PRLR gene also accounts for several phenotypes impacting agricultural production and human pathology. The goal of this review is to highlight the many elements that control differential expression of the PRLR across tissues, and the various phenotypes that exist across species due to variation in the PRLR gene.
PubMed: 38586906
DOI: 10.1111/jne.13385 -
Journal of Ethnopharmacology Jan 2024Jiawei Shoutai Pill (JWSTW) is a traditional herbal formula for recurrent spontaneous abortion (RSA). Although JWSTW significantly improves the clinical symptoms of RSA...
ETHNOPHARMACOLOGICAL RELEVANCE
Jiawei Shoutai Pill (JWSTW) is a traditional herbal formula for recurrent spontaneous abortion (RSA). Although JWSTW significantly improves the clinical symptoms of RSA patients, its molecular mechanism remains unclear.
AIM OF STUDY
This study evaluated the expression and function of the serum/glucocorticoid regulated kinase 1/epithelial sodium channel (SGK1/ENaC) pathway and decidualization level in RSA patients and mice. It also investigated the therapeutic effects and potential mechanisms of JWSTW.
MATERIALS AND METHODS
30 early RSA patients and 30 normal pregnant women undergoing induced abortion during the same period were included in the study. Decidual tissues were collected, and HE staining, immunohistochemistry, Western blot, and RT-PCR were used to detect protein and mRNA expression levels of SGK1, ENaC-a, estrogen Rreceptor β (ERβ), and progesterone receptor (PR) in patients' decidual tissues. Protein expression levels of prolactin receptor (PRLR) and insulin-like growth factor binding protein 1 (IGFBP-1) were also detected. A classical RSA mouse model was constructed, and the mice were randomly divided into four groups: normal, model, dydrogesterone (DQYT) (0.33 g/kg/d), and JWSTW (1.66 g/kg/d). The normal and model groups received the same volume of distilled water by gavage for 8 and 14 days after pregnancy. On the 14th day of pregnancy, the embryonic loss rate of each group, the number of offspring born to naturally delivered mice, and the protein or mRNA expression levels of key factors of the SGK1/ENaC pathway (SGK1, ENaC-a, ERβ, and PR), decidual proliferation marker (Ki67), mesenchymal-epithelial transition (E-cadherin and Vimentin), and decidualization markers (PRLR and IGFBP-1) in mouse decidual tissue on the eighth day of pregnancy were observed.
RESULTS
The decidual tissue structure of RSA patients was abnormal. Immunohistochemical analysis revealed significantly reduced positive expression of SGK1, ENaC-a, ERβ, and PR proteins in the decidual tissue of RSA patients (P < 0.001). Western blot and RT-PCR analyses demonstrated significantly decreased protein and mRNA expression of SGK1, ENaC-a, ERβ, and PR in the decidual tissue of RSA patients (all P < 0.05). Additionally, protein expression of PRLR and IGFBP-1 was significantly reduced (both P < 0.001). The RSA mouse model exhibited a significant increase in embryo loss rate and decreased litter size (both P < 0.001). Treatment with DQYT and JWSTW rescued the embryo loss rate and litter size to varying extents (all P < 0.05). The protein or mRNA expression levels of SGK1, ENaC-a, ERβ, PR, Ki67, E-cadherin, vimentin, PRLR, and IGFBP-1 in RSA mice were improved to different degrees after treatment with DQYT and JWSTW (all P < 0.05).
CONCLUSIONS
Abnormal SGK1/ENaC signaling pathway regulation is closely associated with early endometrial damage in RSA patients. JWSTW promotes endometrial proliferation and mesenchymal-epithelial transition through the SGK1/ENaC signaling pathway, improving endometrial shedding. Consequently, JWSTW is a potential treatment for RSA.
Topics: Pregnancy; Mice; Female; Humans; Animals; Insulin-Like Growth Factor Binding Protein 1; Vimentin; Embryo Loss; Estrogen Receptor beta; Ki-67 Antigen; Abortion, Habitual; Estrogens; Disease Models, Animal; RNA, Messenger
PubMed: 37479068
DOI: 10.1016/j.jep.2023.116939 -
Archives of Medical Research Dec 2023Prolactinomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Medical treatment with dopamine agonists (DA), mainly... (Review)
Review
Prolactinomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients. Prolactin normalization is achieved in 80-90% of prolactinomas treated with cabergoline. Patients resistant to the standard dose can escalate the dose of cabergoline up to the maximum tolerated dose. The expression of dopamine (D2) receptors and dopamine affinity is decreased in aggressive and resistant prolactinomas. Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent. TMZ is effective in 40-50% of treated lactotroph tumors showing at least a partial response. However, patients tend to escape from the effect of TMZ after a limited time of response. Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitor. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required.
Topics: Humans; Prolactinoma; Dopamine Agonists; Cabergoline; Dopamine; Pituitary Neoplasms; Temozolomide; Prolactin
PubMed: 37689507
DOI: 10.1016/j.arcmed.2023.102883 -
Journal of Medicine and Life Nov 2023Vitamin D receptor (VDR) expression in the female reproductive tract explains the regulatory role of vitamin D on inflammatory cytokine and prostaglandin (PGD)...
Vitamin D receptor (VDR) expression in the female reproductive tract explains the regulatory role of vitamin D on inflammatory cytokine and prostaglandin (PGD) synthesis. This study aimed to evaluate the effect of vitamin D on adolescents' primary dysmenorrhea and the relationship between Vit. D and adolescents' primary dysmenorrhea. Eighty-five adolescents were included in the current study. After a detailed evaluation, pelvic sonography was performed for all participants to rule out any pelvic pathology. Blood samples were collected to measure thyroid stimulating hormone (TSH), prolactin, glycosylated hemoglobin (HbA1C), and 25-hydroxyvitamin D (25[OH]D). Participants were administered vitamin D (50,000 IU weekly for five months), and their dysmenorrhea symptoms were evaluated before and after this period using the Visual Analog Scale (VAS) and the Verbal Multidimensional Scoring (VMS). The mean VAS and VMS scores of dysmenorrhea statistically decreased from 8.7±0.91 and 2.65±0.93 to 4.8±0.75 and 0.80±0.75, respectively, after vitamin D intake (p=0.03 and 0.025, respectively). Significant negative associations between 25(OH)D and VAS (R = -0.886; p<0.00001) and VMS of dysmenorrhea (R = -0.885; p<0.00001) were detected in this study. Vit. D could be a useful therapeutic option to reduce the severity of primary dysmenorrhea and could limit the use of non-steroidal anti-inflammatory drugs.
Topics: Female; Adolescent; Humans; Dysmenorrhea; Vitamin D; Vitamins; Vitamin D Deficiency; Calcifediol
PubMed: 38406787
DOI: 10.25122/jml-2023-0290 -
Neuroscience and Biobehavioral Reviews Jun 2024The introduction of sex-as-a-biological-variable policies at funding agencies around the world has led to an explosion of very recent observations of sex differences in... (Review)
Review
The introduction of sex-as-a-biological-variable policies at funding agencies around the world has led to an explosion of very recent observations of sex differences in the biology underlying pain. This review considers evidence of sexually dimorphic mechanisms mediating pain hypersensitivity, derived from modern assays of persistent pain in rodent animal models. Three well-studied findings are described in detail: the male-specific role of spinal cord microglia, the female-specific role of calcitonin gene-related peptide (CGRP), and the female-specific role of prolactin and its receptor. Other findings of sex-specific molecular involvement in pain are subjected to pathway analyses and reveal at least one novel hypothesis: that females may preferentially use Th1 and males Th2 T cell activity to mediate chronic pain.
PubMed: 38838876
DOI: 10.1016/j.neubiorev.2024.105749 -
Acta Medica Indonesiana Oct 2023Breast cancer is among the deadliest gynecology cancers in the world. However, the management of advanced-stage breast cancer is often harder as a result of... (Review)
Review
Breast cancer is among the deadliest gynecology cancers in the world. However, the management of advanced-stage breast cancer is often harder as a result of chemoresistance. This review aimed to discover the effect of bromocriptine on prolactin-positive breast cancer patients who received anthracycline-based chemotherapy. It is known that anthracycline works by inhibiting topoisomerase IIα (TOP2A), forming free radicals, binding DNA, and altering cell homeostasis, hence stopping the cell cycle and inducing cell death. However, reduction of TOP2A expression and increased glutathione s-transferase (GST) and ATP-binding cassette (ATP) membrane activity increase anthracycline efflux from the cell membrane, hence reducing its effectivity. Prolactin is one of the most common chemoresistance agents whose complex with its receptor will induce JAK/STAT pathway to increase GST. The regulation of Bcl-2 and ERK was also determined by prolactin. Bromocriptine is an agonist of the D2 dopamine receptor that inhibits adenyl cyclase and a D1 dopamine weak antagonist. Bromocriptine could reduce prolactin serum and receptors in various cases. Some studies have found that bromocriptine could improve the effectiveness of chemotherapy regimens, including cancer-related hyperprolactinemia, breast cancer that underwent cisplatin, and taxanes. Therefore, bromocriptine offers potential as it could improve outcomes and reduce resistance in prolactin-positive breast cancer patients who are administered anthracycline-based neoadjuvant chemotherapy.
Topics: Female; Humans; Adenosine Triphosphate; Anthracyclines; Breast Neoplasms; Bromocriptine; Janus Kinases; Prolactin; Signal Transduction; STAT Transcription Factors
PubMed: 38213041
DOI: No ID Found -
Breast Cancer Research : BCR Oct 2023About 20% of breast cancers in humans are basal-like, a subtype that is often triple-negative and difficult to treat. An effective translational model for basal-like...
BACKGROUND
About 20% of breast cancers in humans are basal-like, a subtype that is often triple-negative and difficult to treat. An effective translational model for basal-like breast cancer is currently lacking and urgently needed. To determine whether spontaneous mammary tumors in pet dogs could meet this need, we subtyped canine mammary tumors and evaluated the dog-human molecular homology at the subtype level.
METHODS
We subtyped 236 canine mammary tumors from 3 studies by applying various subtyping strategies on their RNA-seq data. We then performed PAM50 classification with canine tumors alone, as well as with canine tumors combined with human breast tumors. We identified feature genes for human BLBC and luminal A subtypes via machine learning and used these genes to repeat canine-alone and cross-species tumor classifications. We investigated differential gene expression, signature gene set enrichment, expression association, mutational landscape, and other features for dog-human subtype comparison.
RESULTS
Our independent genome-wide subtyping consistently identified two molecularly distinct subtypes among the canine tumors. One subtype is mostly basal-like and clusters with human BLBC in cross-species PAM50 and feature gene classifications, while the other subtype does not cluster with any human breast cancer subtype. Furthermore, the canine basal-like subtype recaptures key molecular features (e.g., cell cycle gene upregulation, TP53 mutation) and gene expression patterns that characterize human BLBC. It is enriched in histological subtypes that match human breast cancer, unlike the other canine subtype. However, about 33% of canine basal-like tumors are estrogen receptor negative (ER-) and progesterone receptor positive (PR+), which is rare in human breast cancer. Further analysis reveals that these ER-PR+ canine tumors harbor additional basal-like features, including upregulation of genes of interferon-γ response and of the Wnt-pluripotency pathway. Interestingly, we observed an association of PGR expression with gene silencing in all canine tumors and with the expression of T cell exhaustion markers (e.g., PDCD1) in ER-PR+ canine tumors.
CONCLUSIONS
We identify a canine mammary tumor subtype that molecularly resembles human BLBC overall and thus could serve as a vital translational model of this devastating breast cancer subtype. Our study also sheds light on the dog-human difference in the mammary tumor histology and the hormonal cycle.
Topics: Humans; Dogs; Animals; Female; Breast Neoplasms; Biomarkers, Tumor; Receptor, ErbB-2; Mammary Neoplasms, Animal; Receptors, Progesterone
PubMed: 37789381
DOI: 10.1186/s13058-023-01705-5 -
BMC Biology Oct 2023The maternal microbiota modulates fetal development, but the mechanisms of these earliest host-microbe interactions are unclear. To investigate the developmental impacts...
BACKGROUND
The maternal microbiota modulates fetal development, but the mechanisms of these earliest host-microbe interactions are unclear. To investigate the developmental impacts of maternal microbial metabolites, we compared full-term fetuses from germ-free and specific pathogen-free mouse dams by gene expression profiling and non-targeted metabolomics.
RESULTS
In the fetal intestine, critical genes mediating host-microbe interactions, innate immunity, and epithelial barrier were differentially expressed. Interferon and inflammatory signaling genes were downregulated in the intestines and brains of the fetuses from germ-free dams. The expression of genes related to neural system development and function, translation and RNA metabolism, and regulation of energy metabolism were significantly affected. The gene coding for the insulin-degrading enzyme (Ide) was most significantly downregulated in all tissues. In the placenta, genes coding for prolactin and other essential regulators of pregnancy were downregulated in germ-free dams. These impacts on gene expression were strongly associated with microbially modulated metabolite concentrations in the fetal tissues. Aryl sulfates and other aryl hydrocarbon receptor ligands, the trimethylated compounds TMAO and 5-AVAB, Glu-Trp and other dipeptides, fatty acid derivatives, and the tRNA nucleobase queuine were among the compounds strongly associated with gene expression differences. A sex difference was observed in the fetal responses to maternal microbial status: more genes were differentially regulated in male fetuses than in females.
CONCLUSIONS
The maternal microbiota has a major impact on the developing fetus, with male fetuses potentially more susceptible to microbial modulation. The expression of genes important for the immune system, neurophysiology, translation, and energy metabolism are strongly affected by the maternal microbial status already before birth. These impacts are associated with microbially modulated metabolites. We identified several microbial metabolites which have not been previously observed in this context. Many of the potentially important metabolites remain to be identified.
Topics: Pregnancy; Male; Female; Animals; Mice; Intestines; Placenta; Microbiota; Brain; Fetus
PubMed: 37794486
DOI: 10.1186/s12915-023-01709-9