Nesfatin-1 and Nesfatin-1-like peptide suppress basal and TRH-Induced expression of prolactin and prolactin regulatory element-binding protein mRNAs in rat GH3 somatolactotrophs.

Prolactin (PRL), mainly synthesized and secreted by the lactotrophs and somatolactotrophs of the anterior pituitary, is a pleiotropic hormone that regulates lactation. In the last decade, nesfatin-1 (NESF) and NESF-like peptide (NLP), encoded in nucleobindin 1 and 2 (NUCB1 and NUCB2), respectively, were characterized as metabolic factors with a potential role in the control of pituitary hormones. We hypothesized that NUCBs and their encoded peptides (NESF and NLP) suppress PRL transcription in the pituitary. The main objective of this research was to determine whether exogenous NESF and NLP, and/or endogenous NUCB1 and NUCB2 regulate the expression of prl and preb mRNAs. Using immortalized rat somatolactotrophs (GH3 cells), dose-response studies were performed to test whether NESF and NLP affect prl and preb. Moreover, the ability of these peptides to modulate the effects of the PRL stimulator thyrotropin releasing hormone (TRH) was studied. Besides, the effects of siRNA-mediated knockdown of endogenous NUCBs on prl and preb mRNAs were determined. NESF and NLP reduced the transcription of prl and preb in GH3 cells. Both NESF and NLP also prevented the stimulatory effects of TRH prl and preb expression. The knockdown of endogenous NUCB1 attenuates both basal prl and TRH-induced expression of prl and preb, while the silencing of NUCBs did not affect the actions of exogenous NESF or NLP. Overall, this work reveals that NUCBs and encoded-peptides are novel regulators of PRL. Future research should test whether the effects observed here in GH3 cells are preserved both in vivo and at the post-transcriptional level.

Total barley maiya alkaloids inhibit prolactin secretion by acting on dopamine D2 receptor and protein kinase A targets.

ETHNOPHARMACOLOGICAL RELEVANCE: Barley maiya from gramineous plants (Hordeum vulgare L.) is obtained from ripe fruits through germination and drying. It is often used to treat diseases associated with high prolactin levels. OBJECTIVE: To investigate the anti-hyperprolactinemia (anti-HPRL) mechanisms of total barley maiya alkaloids (TBMA) and hordenine. METHODS: This experiment included 9 groups: Normal group, TBMA group, hordenine group, TBMA + haloperidol group, TBMA + forskolin group, TBMA + 8-bromo-cAMP group, hordenine + haloperidol group, hordenine + forskolin group, and hordenine + 8-bromo-cAMP group. The prolactin (PRL) concentration in the supernatant and the total cAMP concentration in the cells were detected by ELISA. The expression levels of PRL, dopamine D2 receptor (DRD2) and cAMP/PKA/CREB protein were measured by Western Blot. RESULTS: In the TBMA group and the hordenine group, the PRL level in MMQ cells was significantly decreased, but in GH3 cells there was no change. DRD2 expression level was markedly increased, cAMP concentration was decreased, and the activity of PKA and CREB declined in MMQ cells. Compared with the TBMA group, there was a significant decrease of DRD2 expression level, a remarkable increase of PRL secretion and an increase of cAMP/PKA/CREB expression in MMQ cells within the TBMA + haloperidol group. Compared with the forskolin group, there was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + forskolin group. There was a decrease in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. Compared with the hordenine group, DRD2 expression level was significantly decreased, PRL secretion was markedly increased, and cAMP/PKA/CREB expression level was increased in MMQ cells within the hordenine + haloperidol group. There was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the hordenine + forskolin group compared with the forskolin group and within the hordenine + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. CONCLUSION: TBMA and hordenine can both play an anti-HPRL role via DRD2, and TBMA can also act on PKA targets to exert its anti-HPRL effect. TBMA and hordenine may be potential treatment strategies for HPRL.

Gestational dioxin exposure suppresses prolactin-stimulated nursing in lactating dam rats to impair development of postnatal offspring.

A number of epidemiological studies have implicated environmental chemicals including dioxins in the induction of negative effects on child development. To clarify the underlying mechanisms, almost all toxicologists have concentrated on effects on the offspring themselves. We examined an alternative hypothesis that gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, targets factors related to maternal childcare to disturb offspring development. Oral administration of TCDD (1 µg/kg) to pregnant rats on gestational day 15 suppressed maternal licking behavior, a nursing behavior, and mammary gland maturation during the lactational stage, as well as the body weight and short-term memory of postnatal offspring. In support of these findings, maternal production of prolactin, a pituitary hormone essential for nursing including milk production, was decreased during the same period. Intracerebroventricular infusion of prolactin to dioxin-exposed dams restored or tended to restore many of the above defects observed both in mothers and offspring. The TCDD-dependent defects in maternal nursing behaviors can be due to a direct action on aryl hydrocarbon receptor (AHR) of lactating dams, because they did not emerge in AHR-knockout dams or control dams with TCDD-exposed offspring. Further examinations revealed that TCDD induces transforming growth factor ß1 expression, which suppresses prolactin-producing cell proliferation, in a nursing period-specific manner. In agreement with this, the number of prolactin-positive cells in nursing dams was decreased by TCDD. These results provide novel evidence that gestational dioxin exposure attenuates prolactin-stimulated nursing in lactating dams to impair offspring development, and that immaturity of prolactin-producing cells can contribute to them.

MiR-130a-3p Inhibits PRL Expression and Is Associated With Heat Stress-Induced PRL Reduction.

MicroRNAs (MiRNAs) play critical roles in the regulation of pituitary function. MiR-130a-3p has previously been found to be down-regulated in prolactinoma, but its roles in prolactin (PRL) regulation and the underlying mechanisms are still unclear. Heat stress has been shown to induce alteration of endocrine hormones and miRNAs expressions. However, there is limited information regarding the emerging roles of miRNAs in heat stress response. In this study, we transfected miR-130a-3p mimic into the pituitary adenoma cells (GH3 cells) to investigate the function of miR-130a-3p in regulating PRL. Our results showed that miR-130a-3p overexpression significantly decreased the PRL expression at both mRNA and protein levels. Subsequently, estrogen receptor α (ERα) was identified as a direct target of miR-130a-3p by bioinformatics prediction, luciferase reporter assay and western blotting assay. Furthermore, the inhibition of ERα caused by estrogen receptor antagonist significantly reduced the PRL expression. Overexpression of ERα rescued the suppressed expression of PRL caused by miR-130a-3p mimic. Besides, we also studied the effect of heat stress on PRL and miRNAs expressions. Interestingly, we found that heat stress reduced PRL and ERα expressions while it increased miR-130a-3p expression both in vitro and in vivo. Taken together, our results indicate that miR-130a-3p represses ERα by targeting its 3'UTR leading to a decrease in PRL expression, and miR-130a-3p is correlative with heat stress-induced PRL reduction, which provides a novel mechanism that miRNAs are involved in PRL regulation.

Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer. AIM OF THE STUDY: We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance. MATERIALS AND METHODS: Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells. RESULTS: Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer-related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells. CONCLUSIONS: Collectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer.

The prolactin-release inhibitor paeoniflorin suppresses proliferation and induces apoptosis in prolactinoma cells via the mitochondria-dependent pathway.

Prolactinomas are the most prevalent functional pituitary adenomas that cause chronic pathological hyperprolactinemia. Prolactin is known to promote cell growth and inhibit apoptosis in cells. Paeoniflorin is the principal component of radix Paeoniae alba (the main ingredient in some traditional herbal formulas clinically used for hyperprolactinemia-associated disorders). Recent findings from intensive studies have suggested that paeoniflorin regulates cell proliferation and apoptosis in many cell lines. However, the effects of paeoniflorin in pituitary tumor cells remain unknown. Here the results by the Cell Counting Kit-8 and colony formation assays showed that paeoniflorin concentration-dependently decreased cell viability in both MMQ and GH3 cells and colony formation in GH3 cells, suggesting inhibition of cell proliferation by paeoniflorin. By flow cytometry, paeoniflorin was found to increase apoptotic rate in MMQ cells. Mechanistically, Western blot results revealed that paeoniflorin enhanced protein expression of cleave caspase-9 and -3, and Bax, whereas it suppressed Bcl-2 protein expression in MMQ cells. Furthermore, paeoniflorin upregulated phosphorylated p53 protein expression, but it decreased prolactin concentration and prolactin protein expression in both MMQ and GH3 cells. Thus, the present results demonstrate that paeoniflorin inhibits cell proliferation and induces the mitochondrial pathway-mediated apoptosis in prolactinoma cells. These antitumor property is associated with inhibition of prolactin secretion. Our findings may provide new insight into the mechanisms underlying improving prolactinoma-associated disorders of paeoniflorin-enriched herbs and formulas.

Inhibiting prolactin by cabergoline accelerates mammary gland remodeling during the early dry period in dairy cows.

The inhibition of prolactin release using cabergoline, a dopamine agonist, is an effective strategy to accelerate the changes in mammary secretion composition after drying-off. The objective of this study was to determine how cabergoline may affect mammary tissue remodeling during early involution. Holstein dairy cows were treated with either a single i.m. administration of 5.6 mg of cabergoline (Velactis, Ceva Santé Animale, Libourne, France, n = 7) or placebo (n = 7) at the time of drying-off. Mammary biopsy samples were collected 1 wk before drying-off (d -6), after 30 h of milk accumulation (d 1), and again 8 d following drying-off (d 8) to determine changes in gene expression, lactoferrin content, and cell turnover. Blood and mammary secretion samples were collected at d -6 and again at d 1, 2, 3, 4, 8, and 14 following the abrupt cessation of lactation to evaluate indicators of blood-milk barrier integrity and other markers of mammary tissue remodeling. Cabergoline induced less SLC2A1, BAX, CAPN2, and IGFBP5 mRNA expression. In contrast, cabergoline did not modify changes in cell proliferation and apoptosis. Following the cessation of lactation, changes in mammary secretion composition (Na+ and K+) and blood lactose concentrations were indicative of a loss in the blood-milk barrier function in both treatment groups. Cabergoline treatment affected only Na+ and K+ concentrations at d 1, suggesting a moderate increase in tight junction permeability. The increase in the activity of MMP9 and in mammary epithelial cell concentration in mammary secretions was greater in cabergoline-treated cows than in control cows, suggesting more mammary tissue remodeling. The increase in lactoferrin immunostaining in the mammary tissue occurred earlier for cabergoline-treated cows than for control cows, and was essentially localized in the stroma. Changes in some key markers of mammary involution suggest that cabergoline accelerates mammary gland remodeling. Thus, a single injection of cabergoline after the last milking would facilitate drying-off by enhancing mammary gland involution.

Effect of inhibiting the lactogenic signal at calving on milk production and metabolic and immune perturbations in dairy cows.

During the periparturient period, the abrupt increase in energy demand for milk production often induces metabolic and immunological disturbances in dairy cows. Our previous work has shown that reducing milk output by milking once a day or incompletely in the first few days of lactation reduces these disturbances. The aim of this study was to reduce metabolic and immunological disturbances by limiting milk production during the first week of lactation by inhibiting the lactogenic signal driven by prolactin. Twenty-two fresh cows received 8 i.m. injections of the prolactin-release inhibitor quinagolide (QUIN; 2 mg) or water as a control (CTL). The first injection was given just after calving, and the subsequent 7 injections were given every 12 h. Milk production was measured until d 28 after calving. Blood samples were taken from d 1 (calving) to d 5 and then on d 7, 10, 14, 21, and 28 to measure concentrations of urea, phosphorus, calcium, glucose, nonesterified fatty acids (NEFA), ß-hydroxybutyrate, and prolactin. Other blood samples were taken on d 2, 5, 10, and 28 to analyze oxidative burst, phagocytosis, and the effect of the serum on the lymphoproliferation of peripheral blood mononuclear cells from donor cows. Blood prolactin concentration was lower from d 2 to 5 but higher from d 10 to 28 in the QUIN cows than in the CTL cows. Milk production was lower from d 2 to 6 in the QUIN cows than in the CTL cows (24.3 ± 6.4 and 34.8 ± 4.1 kg/d on average, respectively). We observed no residual effect of quinagolide on milk production after d 6. During the first week of lactation, blood glucose and calcium concentrations were higher and ß-hydroxybutyrate concentration was lower in the QUIN cows than in the CTL cows. Blood NEFA, urea, and phosphorus concentrations were not affected by the treatment. At d 2 and 5, the phagocytosis ability of polymorphonuclear leukocytes was not affected by treatment; however, quinagolide injection enhanced the proportion of cells that entered oxidative burst, The mitogen-induced proliferation of peripheral blood mononuclear cells was greater when they were incubated with serum harvested from the CTL cows and was negatively correlated with the NEFA concentration in the serum. Reducing the prolactin peak at calving was effective in reducing milk production during the first week of lactation without compromising the dairy cow's overall productivity. Slowing the increase in milk production allowed a more gradual transition from pregnancy to lactation and led to a reduction in metabolic stress and an improvement in some immune system aspects during this period.

Prolactin inhibits a major tumor-suppressive function of wild type BRCA1.

Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21.

The pituitary TGFß1 system as a novel target for the treatment of resistant prolactinomas.

Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists (DAs). However, a subset of prolactinomas fails to respond to such therapies and is considered as DA-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. Transforming growth factor ß1 (TGFß1) is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFß1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGFß1 system including latent binding proteins, local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFß receptors. Pituitary TGFß1 activity and the expression of different components of the TGFß1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFß1 activity as well as reduced expression of several components of the TGFß1 system. Therefore, restoration of TGFß1 inhibitory activity represents a novel therapeutic approach to bypass dopamine action in DARPs. The aim of this review is to summarize the large literature supporting TGFß1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGFß1 activity as an effective treatment in experimental prolactinomas.

Regulation of cell number in the mammary gland by controlling the exfoliation process in milk in ruminants.

Milk yield is partly influenced by the number of mammary epithelial cells (MEC) in the mammary gland. It is well known that variations in MEC number are due to cell proliferation and apoptosis. The exfoliation of MEC from the mammary epithelium into milk is another process that might influence MEC number in the mammary tissue. The rate of MEC exfoliation can be assessed by measuring the milk MEC content through light microscopy, flow cytometry analysis, or an immuno-magnetic method for MEC purification. Various experimental models have been used to affect milk yield and study the rate of MEC exfoliation. Reducing milking frequency from twice to once daily did not seem to have any effect on MEC loss in goat and cow milk after 7 d, but increased MEC loss per day in goats when applied for a longer period. An increase in MEC exfoliation was also observed during short days as compared with long days, or in response to an endotoxin-induced mastitis in cows. Other animal models were designed to investigate the endocrine control of the exfoliation process and its link with milk production. Suppression of ovarian steroids by ovariectomy resulted in a greater persistency of lactation and a decrease in MEC exfoliation. Administering prolactin inhibitors during lactation or at dry-off enhanced MEC exfoliation, whereas exogenous prolactin during lactation tended to prevent the negative effect of prolactin inhibitors. These findings suggest that prolactin could regulate MEC exfoliation. In most of these studies, variations of MEC exfoliation were associated with variations in milk yield and changes in mammary epithelium integrity. Exfoliation of MEC could thus influence milk yield by regulating MEC number in mammary tissue.

In vivo inhibition followed by exogenous supplementation demonstrates galactopoietic effects of prolactin on mammary tissue and milk production in dairy cows.

It has been previously shown that the long-term inhibition of milking-induced prolactin (PRL) release by quinagolide (QN), a dopamine agonist, reduces milk yield in dairy cows. To further demonstrate that PRL is galactopoietic in cows, we performed a short-term experiment that used PRL injections to restore the release of PRL at milking in QN-treated cows. Nine Holstein cows were assigned to treatments during three 5-d periods in a 3×3 Latin square design: 1) QN: twice-daily i.m. injections of 1mg of QN; 2) QN-PRL: twice-daily i.m. injections of 1mg of QN and twice-daily (at milking time) i.v. injections of PRL (2µg/kg body weight); and 3) control: twice-daily injections of the vehicles. Mammary epithelial cells (MEC) were purified from milk so that their viability could be assessed, and mammary biopsies were harvested for immunohistological analyses of cell proliferation using PCNA and STAT5 staining. In both milk-purified MEC and mammary tissue, the mRNA levels of milk proteins and BAX were determined using real-time reverse-transcription PCR. Daily QN injections reduced milking-induced PRL release. The area under the PRL curve was similar in the control and PRL injection treatments, but the shape was different. The QN treatment decreased milk, lactose, protein, and casein production. Injections of PRL did not restore milk yield but tended to increase milk protein yield. In mammary tissue, the percentage of STAT5-positive cells was reduced during QN but not during QN-PRL in comparison with the control treatment. The percentage of PCNA-positive cells was greater during QN-PRL injections than during the control or QN treatment and tended to be lower during QN than during the control treatment. In milk-purified MEC, κ-casein and α-lactalbumin mRNA levels were lower during QN than during the control treatment, but during QN-PRL, they were not different from the control treatment. In mammary tissue, the BAX mRNA level was lower during QN-PRL than during QN. The number of MEC exfoliated into milk was increased by QN injections but tended to be decreased by PRL injections. Injections of PRL also increased the viability of MEC harvested from milk. Although PRL injections at milking could not reverse the effect of QN treatment on milk production, their effects on cell survival and exfoliation and on gene expression suggest that the effect of QN treatment on the mammary gland is due to QN's inhibition of PRL secretion.

Initial study on the possible mechanisms involved in the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion.

Perfluorooctane sulfonate (PFOS) is a fluorinated organic compound. This chemical is neurotoxic and can alter the pituitary secretion. This is an initial study aimed at knowing the toxic effects of high doses of PFOS on prolactin secretion and the possible mechanisms involved in these alterations. For that, adult male rats were orally treated with 3.0 and 6.0 mg of PFOS/kg body weight (b.w.)/day for 28 days. At the end of the treatment, the serum levels of prolactin and estradiol as well as the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and gamma-aminobutyric acid (GABA) were quantified in the anterior and in the mediobasal hypothalamus. PFOS, at the administered doses, reduced prolactin and estradiol secretion, increased the concentration of dopamine and GABA in the anterior hypothalamus, and decreased the ratios DOPAC/dopamine and HVA/dopamine in this same hypothalamic area. The outcomes reported in this study suggest that (1) high doses of PFOS inhibit prolactin secretion in adult male rats; (2) only the periventricular-hypophysial dopaminergic (PHDA) neurons seem to be involved in this inhibitory effect but not the tuberoinfundibular dopaminergic (TIDA) and the tuberohypophysial dopaminergic (THDA) systems; (3) GABAergic cells from the paraventricular and supraoptic nuclei could be partially responsible for the PFOS action on prolactin secretion; and finally (4) estradiol might take part in the inhibition exerted by elevated concentration of PFOS on prolactin release.

ß-Hydroxybutyric sodium salt inhibition of growth hormone and prolactin secretion via the cAMP/PKA/CREB and AMPK signaling pathways in dairy cow anterior pituitary cells.

ß-hydroxybutyric acid (BHBA) regulates the synthesis and secretion of growth hormone (GH) and prolactin (PRL), but its mechanism is unknown. In this study, we detected the effects of BHBA on the activities of G protein signaling pathways, AMPK-α activity, GH, and PRL gene transcription, and GH and PRL secretion in dairy cow anterior pituitary cells (DCAPCs). The results showed that BHBA decreased intracellular cAMP levels and a subsequent reduction in protein kinase A (PKA) activity. Inhibition of PKA activity reduced cAMP response element-binding protein (CREB) phosphorylation, thereby inhibiting GH and PRL transcription and secretion. The effects of BHBA were attenuated by a specific Gαi inhibitor, pertussis toxin (PTX). In addition, intracellular BHBA uptake mediated by monocarboxylate transporter 1 (MCT1) could trigger AMPK signaling and result in the decrease in GH and PRL mRNA translation in DCAPCs cultured under low-glucose and non-glucose condition when compared with the high-glucose group. This study identifies a biochemical mechanism for the regulatory action of BHBA on GH and PRL gene transcription, translation, and secretion in DCAPCs, which may be one of the factors that regulate pituitary function during the transition period in dairy cows.

Antagonism of tumoral prolactin receptor promotes autophagy-related cell death.

Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized G129R, an antagonist peptide of PRL, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced the accumulation of redundant autolysosomes in 3D cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a noncanonical beclin-1-independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide an understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications.

Prolactin mediates psychological stress-induced dysfunction of regulatory T cells to facilitate intestinal inflammation.

OBJECTIVE: The dysfunction of immune regulation plays a critical role in the pathogenesis of a number of chronic inflammatory disorders, such as IBD. A close relationship between psychological stress and intestinal inflammation has been noted; the underlying mechanism remains elusive. This study aims to elucidate a pathological pathway between psychological stress and the dysfunction of regulatory T cells (Treg), and its effect on facilitating intestinal inflammation. DESIGN: A restraint stress model was employed to induce psychological stress in mice. The functions of Tregs were determined by assessing the immune suppressor effects in the intestine. A mouse model of intestinal inflammation was established using a low dose of trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) together with the challenge of chronic stress. RESULTS: After treating mice with restraint stress, the suppressor function of intestinal Treg was compromised, although the frequency of Treg was not changed in the intestine. Further observation revealed that stress induced Tregs in the intestine to differentiate into foxhead box P3(+) interleukin (IL)-17(+) tumour necrosis factor (TNF)-α(+) T cells. We also observed that exposure to stress-derived prolactin induced dendritic cells (DC) to produce IL-6 and IL-23 in vitro and in vivo, which played a critical role in altering Treg's phenotypes. Treating mice with chronic stress facilitated the initiation of intestinal inflammation by a low dose of TNBS or DSS, which was abolished by pretreatment with an inhibitor of prolactin, the cabergoline. CONCLUSIONS: Psychological stress-derived prolactin alters DC and Treg's properties to contribute to intestinal inflammation.

Demographic characteristics, presentations and treatment outcome of patients with prolactinoma.

BACKGROUND: Prolactinomas are the most common type of functional pituitary tumours. The objective of this study was to determine demographic profile of patients with prolactinomas, and to compare the outcomes in patients treated with Cabergoline versus those receiving Bromocriptine treatment. METHODS: This descriptive study was conducted at Endocrinology Section, Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan. We reviewed the medical record of 68 patients with prolactinoma. Data about demographic characteristics, clinical presentation and treatment were entered on a pre-designed pro forma. RESULTS: Out of the total 68 patients, 36.8% were males and 63.2% were females, with a mean age of 34±10.7 years. The most frequent presenting complaint amongst the patients was of headache, present in 57.4% patients. Galactorrhea, amenorrhea and infertility were next highest reported symptoms. Results of the tumour size on initial MRI showed macroprolactinomas 52.9% (36), microprolactinomas in 33.8% (23), and giant prolactinomas in 13.3 % (9) patients. Decreasing trend of prolactin levels were also seen on follow up visits at 9 months and 12 months. Tumour size was decreased in 48.53% (33) patients and lesion completely disappeared in 16.18% (11) patients after 6 months of treatment and also almost similar trend in tumour size change was seen after one year. There was no significant difference between the two drugs in bringing prolactin to, normal range at each follow up duration. CONCLUSION: Most of the prolactinoma patients were females and the common the most frequent presenting complaint was headache. The decreasing trend of serum prolactin and tumour size reduction in patients was noted, suggesting the beneficial impact of medical therapy as it is the first line treatment modality in these patients.

Concomitant myasthenia gravis and macroprolactinoma: the immunomodulatory role of prolactin and its potential therapeutic use.

Considerable evidence attests to the role of the hypothalamic-pituitary endocrine axis (HPA) in the maintenance of normal immunocompetence. The immune and neuroendocrine systems are integrally linked and coordinated with bidirectional communication maintaining immune balance. Any disturbance of the normal function of the HPA may significantly alter native immunocompetence and therefore be associated with the development of disorders which have a clearly established autoimmune basis. Molecular and functional evidence shows prolactin, produced by the anterior pituitary, to be a cytokine, exerting its effect via both paracrine and endocrine mechanisms [1]. Its involvement in the activation of multiple immune responses may adversely upregulate certain autoimmune diseases. Myasthenia gravis (MG) has long been recognized as an autoimmune disorder. In this mini review, we present the coterminous presentation of MG and prolactin-secreting macroadenoma. We review published cases in the world literature, discuss pathological mechanism, and consider future targeted therapies.

Short-chain fatty acids inhibit growth hormone and prolactin gene transcription via cAMP/PKA/CREB signaling pathway in dairy cow anterior pituitary cells.

Short-chain fatty acids (SCFAs) play a key role in altering carbohydrate and lipid metabolism, influence endocrine pancreas activity, and as a precursor of ruminant milk fat. However, the effect and detailed mechanisms by which SCFAs mediate bovine growth hormone (GH) and prolactin (PRL) gene transcription remain unclear. In this study, we detected the effects of SCFAs (acetate, propionate, and butyrate) on the activity of the cAMP/PKA/CREB signaling pathway, GH, PRL, and Pit-1 gene transcription in dairy cow anterior pituitary cells (DCAPCs). The results showed that SCFAs decreased intracellular cAMP levels and a subsequent reduction in PKA activity. Inhibition of PKA activity decreased CREB phosphorylation, thereby inhibiting GH and PRL gene transcription. Furthermore, PTX blocked SCFAs- inhibited cAMP/PKA/CREB signaling pathway. These data showed that the inhibition of GH and PRL gene transcription induced by SCFAs is mediated by Gi activation and that propionate is more potent than acetate and butyrate in inhibiting GH and PRL gene transcription. In conclusion, this study identifies a biochemical mechanism for the regulation of SCFAs on bovine GH and PRL gene transcription in DCAPCs, which may serve as one of the factors that regulate pituitary function in accordance with dietary intake.

Effects of running wheel training on adult obese rats programmed by maternal prolactin inhibition.

The inhibition of maternal prolactin production in late lactation leads to metabolic syndrome and hypothyroidism in adult offspring. Physical training is a therapeutic strategy that could prevent or reverse this condition. We evaluated the effects of a short-duration low-intensity running wheel training program on the metabolic and hormonal alterations in rats. Lactating Wistar rats were treated with bromocriptine (Bro, 1 mg twice a day) or saline on days 19, 20, and 21 of lactation, and the training of offspring began at 35 days of age. Offspring were divided into sedentary and trained controls (C-Sed and C-Ex) and sedentary and trained Bro-treated rats (Bro-Sed and Bro-Ex). Chronic exercise delayed the onset of weight gain in Bro-Ex offspring, and the food intake did not change during the experimental period. At 180 days, visceral fat mass was higher (+46%) in the Bro-Sed offspring than in C-Sed and Bro-Ex rats. As expected, running capacity was higher in trained animals. Most parameters observed in the Bro-Sed offspring were consistent with hypothyroidism and metabolic syndrome and were reversed in the Bro-Ex group. Chronic exercise did not influence the muscle glycogen in the C-Ex group; however, liver glycogen was higher (+30%) in C-Ex group and was unchanged in both Bro offspring groups. Bro-Ex animals had higher plasma lactate dehydrogenase levels, indicating skeletal muscle damage and intolerance of the training program. Low-intensity chronic training is able to normalize many clinical aspects in Bro animals; however, these animals might have had a lower threshold for exercise adaptation than the control rats.