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Menin, the protein encoded by the MEN1 gene, is abundantly expressed in the epithelial cells of mammary glands. Here, we found MEN1/menin expression slowly decreased with advancing lactation but increased by the end of lactation. It happened that the number of bovine mammary epithelial cells decreases since lactation, suggesting a role of menin in the control of mammary epithelial cell growth. Indeed, reduction of menin expression through MEN1-specific siRNA transfection in the bovine mammary epithelial cells caused cell growth arrest in G1/S phase. Decreased mRNA and protein expression of Cyclin D1 was observed upon MEN1 knockdown. Furthermore, menin was confirmed to physically bind to the promoter region of Cyclin D1 through a ChIP assay, indicating that menin plays a regulatory role in mammary epithelial cell cycle progression. Moreover, lower expression of MEN1/menin induced increased epithelial cell apoptosis and caused extracellular matrix remodeling by down-regulating its associated genes, such as DSG2 and KRT5, suggesting that menin's role may also be involved in the control of cell-cell adhesion in normal mammary glands. Taken together, our data revealed an unknown molecular function of menin in epithelial cell proliferation, which may be important in the regulation of lactation behavior of mammary glands.
Zika virus (ZIKV) belongs to the large category of arboviruses. Surprisingly, several human-to-human transmissions of ZIKV have been notified, either following sexual intercourse or from the mother to fetus during pregnancy. Importantly, high viral loads have been detected in the human breast milk of infected mothers, and the existence of breastfeeding as a new mode of mother-to-child transmission of ZIKV was recently hypothesized. However, the maternal origin of infectious particles in breast milk is currently unknown. Here, we show that ZIKV disseminates to the mammary glands of infected mice after both systemic and local exposure with differential kinetics. Ex vivo, we demonstrate that primary human mammary epithelial cells were sensitive and permissive to ZIKV infection in this study. Moreover, by using in vitro models, we prove that mammary luminal- and myoepithelial-phenotype cell lines are both able to produce important virus progeny after ZIKV exposure. Our data suggest that the dissemination of ZIKV to the mammary glands and subsequent infection of the mammary epithelium could be one mechanism of viral excretion in human breast milk.
MicroRNAs are small non-coding RNA molecules that are important regulators of gene expression at the post-transcriptional level. miRNAs impact the processes of cell proliferation, differentiation and apoptosis. Thus, the regulation of miRNA expression profiles associated with mastitis will be conducive for its control. In this study, Staphylococcus aureus (S. aureus) was administered to the mammary gland of Chinese Holstein cows to construct a bacteria-type mastitis model. Total RNA was isolated from bovine mammary gland tissue samples from the S. aureus-induced mastitis group and controls. miRNAs were analyzed using Solexa sequencing and bioinformatics processing for the experimental group and control group. Two miRNA libraries were constructed respectively. A total of 370 known bovine miRNAs and 341 novel mi RNAs were detected for the S. aureus and 358 known bovine miRNAs and 232 novel miRNAs for control groups. A total of 77 miRNAs in the S. aureus group showed significant differences compared to the control group. GO (Gene Ontology) analysis showed these target genes were involved in the regulation of cells, binding, etc., while KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that these genes were enriched in endocytosis, and olfactory transduction pathways involved in cancer. These results provide an experimental basis to reveal the cause and regulatory mechanism of mastitis and also suggest the potential of miRNAs to serve as biomarkers for the diagnosis of mastitis in dairy cows.
Epithelial barrier function in the mammary gland acts as a forefront of the defense mechanism against mastitis, which is widespread and a major disorder in dairy production. Chemerin is a chemoattractant protein with potent antimicrobial ability, but its role in the mammary gland remains unelucidated. The aim of this study was to determine the function of chemerin in mammary epithelial tissue of dairy cows in lactation or dry-off periods. Mammary epithelial cells produced chemerin protein, and secreted chemerin was detected in milk samples. Chemerin treatment promoted the proliferation of cultured bovine mammary epithelial cells and protected the integrity of the epithelial cell layer from hydrogen peroxide (H2O2)-induced damage. Meanwhile, chemerin levels were higher in mammary tissue with mastitis. Tumor necrosis factor alpha (TNF-α) strongly upregulated the expression of the chemerin-coding gene (RARRES2) in mammary epithelial cells. Therefore, chemerin was suggested to support mammary epithelial cell growth and epithelial barrier function and to be regulated by inflammatory stimuli. Our results may indicate chemerin as a novel therapeutic target for diseases in the bovine mammary gland.
The transient receptor potential melastatin-subfamily member 7 (TRPM7) cation channel is a bifunctional ion channel with intrinsic kinase activity and is ubiquitously expressed in the animal/human body. Accumulated knowledge of TRPM7 suggests that it plays an essential role in normal physiological processes, including the development, survival, proliferation, differentiation, and migration of cells. The aim of this study was to demonstrate the presence and expression patterns of TRPM7 in normal canine mammary glands using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry. Normal mammary gland tissue samples were obtained from five female beagle dogs. RT-PCR and sequencing of the amplified PCR products demonstrated the presence of TRPM7 mRNA in normal mammary glands, and the presence of TRPM7 protein was confirmed by Western blotting. Immunohistochemical investigations demonstrated the expression of TRPM7 in the apical membrane of acinar and ductal epithelial cells in the canine mammary glands. These results provide the first evidence of the presence and distribution of TRPM7 in the canine mammary gland and could help explain the physiological and pathological roles of TRPM7 in the canine mammary gland; however, additional studies are required to elucidate these roles.
Previously, we demonstrated the ability of the normal mammary microenvironment (niche) to direct non-mammary cells including testicular and embryonic stem cells (ESCs) to adopt a mammary epithelial cell (MEC) fate. These studies relied upon the interaction of transplanted normal MECs with non-mammary cells within the mammary fat-pads of recipient mice that had their endogenous epithelium removed. Here, we tested whether acellular mammary extracellular matrix (mECM) preparations are sufficient to direct differentiation of testicular-derived cells and ESCs to form functional mammary epithelial trees in vivo. We found that mECMs isolated from adult mice and rats were sufficient to redirect testicular derived cells to produce normal mammary epithelial trees within epithelial divested mouse mammary fat-pads. Conversely, ECMs isolated from omental fat and lung did not redirect testicular cells to a MEC fate, indicating the necessity of tissue specific components of the mECM. mECM preparations also completely inhibited teratoma formation from ESC inoculations. Further, a phenotypically normal ductal outgrowth resulted from a single inoculation of ESCs and mECM. To the best of our knowledge, this is the first demonstration of a tissue specific ECM driving differentiation of cells to form a functional tissue in vivo.
Allometric growth of ducts in the mammary glands (MGs) is widely held to be estrogen dependent. We previously discovered that the dietary fatty acid trans-10, cis-12 conjugated linoleic acid (CLA) stimulates estrogen-independent allometric growth and terminal end bud formation in ovariectomized mice. Given the similar phenotype induced by estrogen and CLA, we investigated the shared and/or divergent mechanisms underlying these changes. We confirmed MG growth induced by CLA is temporally distinct from that elicited by estrogen. We then used RNA sequencing to compare the transcriptome of the MG during similar proliferative and morphological states. Both estrogen and CLA affected the genes involved in proliferation. The transcriptome for estrogen-treated mice included canonical estrogen-induced genes, including Pgr, Areg, and Foxa1. In contrast, their expression was unchanged by CLA. However, CLA, but not estrogen, altered expression of a unique set of inflammation-associated genes, consistent with stromal changes. This CLA-altered signature included increased expression of epidermal growth factor receptor (EGFR) pathway components, consistent with the demonstration that CLA-induced MG growth is EGFR dependent. Our findings highlight a unique role for diet-induced inflammation that underlies estrogen-independent MG development.
Mammary gland development is controlled by several genes. Although miRNAs have been implicated in mammary gland function, the mechanism by which miR-486 regulates mammary gland development and lactation remains unclear. We investigated miR-486 expression in cow mammary gland using qRT-PCR and ISH and show that miR-486 expression was higher during the high-quality lactation period. We found that miR-486 targets phosphoinositide signaling in the cow mammary gland by directly downregulating PTEN gene expression and by altering the expression of downstream genes that are important for the function of the mammary gland, such as AKT, mTOR. We analyzed the effect of β-casein, lactose and triglyceride secretion in bovine mammary gland epithelial cells (BMECs) transfected by an inhibitor and by mimics of miR-486. Our results identify miR-486 as a downstream regulator of PTEN that is required for the development of the cow mammary gland.
The Caenorhabditis elegans n-3 fatty acid desaturase (Fat-1) acts on a range of 18- and 20-carbon n-6 fatty acid substrates. Transgenic female mice expressing the Fat-1 gene under transcriptional control of the goat β-casein promoter produce milk phospholipids having elevated levels of n-3 polyunsaturated fatty acids (PUFA). However, females from this line were also observed to have impaired reproductive performance characterized by a smaller litter size (2.7 ± 0.6 vs. 7.2 ± 0.7; P < 0.05) than wildtype controls. While there is a close association between PUFA metabolism, prostaglandin biosynthesis, and fertility; reproductive problems in these mice were unanticipated given that the Fat-1 transgene is primarily expressed in the lactating mammary gland. Using multiple approaches it was found that Fat-1 mice have normal ovulation and fertilization rates; however fewer embryos were present in the uterus prior to implantation. Small litter size was also found to be partly attributable to a high incidence of post-implantation fetal resorptions. Embryo transfer experiments revealed that embryos developing from oocytes derived from transgenic ovaries had an increased rate of post-implantation resorption, regardless of the uterine genotype. Ovary transplantation between Fat-1 and C57BL/6 wildtype females revealed that non-ovarian factors also contributed to the smaller litter size phenotype. Finally, surgical removal of the mammary glands from juvenile Fat-1 mice increased the subsequent number of implantation sites per female, but did not lessen the high rate of post-implantation resorptions. In conclusion, we herein report on a system where an exogenous transgene expressed predominately in the mammary gland detrimentally affects female reproduction, suggesting that in certain circumstances the mammary gland may function as an endocrine regulator of reproductive performance.
Clinical mastitis in sheep has gravely restrained production performance for a long time. Knowledge of mechanisms of its pathogenesis and resistance in meat sheep mammary gland with clinical mastitis are not yet understood, especially for clinical mastitis caused by natural infection. In this work, RNA-sequencing was firstly used to screen the differentially expressed genes (DEGs) in clinical mastitic mammary tissues (CMMTs) when compared with healthy mammary tissues (HMTs) from meat sheep flocks. We identified 420 DEGs including 316 upregulated and 104 downregulated genes in CMMTs. Gene ontology annotation revealed these DEGs were mainly engaged in immune response and inflammation response. Pathway enrichment showed they were primarily enriched in pathways relevant to inflammation, immune response and metabolism. Alternative splicing analysis showed most common differential splicing genes in CMMTs and HMTs were implicated in immune response. Immunostaining for three immune response-related proteins encoded by DEGs were mainly observed in mammary epithelium from both CMMTs and HMTs, and their positive signals were more intensive in CMMTs than those in HMTs. These findings provide experimental basis and reference for further researching the molecular genetic mechanisms, particularly immune defence mechanisms, of sheep mammary gland during clinical mastitis.
Staphylococcus aureus (S. aureus) is the causative agent for a wide variety of illnesses ranging from minor skin infections to life-threatening diseases. Development of antibiotic resistance by the bacteria has rendered many antibiotics ineffective. It has been known that plectasin-derived antimicrobial peptides (AMPs; NZ2114 and MP1102) are promising alternatives to antibiotics. However, their activities against S. aureus in mammary glands were unknown. Our objective was to assess the antimicrobial activities of NZ2114 and MP1102 against S. aureus in milk, in cultured mammary epithelial cells, and in a mouse model in order to evaluate their potentials as anti-mastitis agents. NZ2114 and MP1102 showed in vitro bactericidal effects against S. aureus in both the culture medium and the milk. NZ2114 and MP1102 at the concentration of 100 μg/mL reduced the number of S. aureus by almost 100% within 4 h in processed bovine milk. Similarly, both NZ2114 and MP1102 were efficient to reduce the number of internalized S. aureus in cultured mammary epithelial cells. Finally, both AMPs significantly reduced the S. aureus load and concentrations of TNF-α and IL-6 in mammary glands, compared to a buffer control in the mouse model. Our results suggest that NZ2114 and MP1102 may be used to treat S. aureus-induced mastitis.
MicroRNAs (miRNAs) play crucial roles in regulating innate and adaptive immunity in humans and animals. Infection with E. coli or S. aureus can cause inflammation of the mammary glands, which results in significant economic losses in dairy cattle. However, the regulatory mechanisms of miRNAs in response to E. coli or S. aureus infection in bovine mammary glands have not been thoroughly explored. To discover the differential expression of miRNA in bovine mammary gland challenged with E. coli or S. aureus, we performed miRNA sequencing on tissue samples. A total of 1838 miRNAs were identified, including 580 known-miRNAs (included in the miRbase database) and 1258 predicted novel miRNAs. The miRNA expression patterns indicated that, compared with control samples, 279 miRNAs and 305 miRNAs were differentially expressed miRNAs (DIE-miRNA) in S. aureus and E. coli infected tissues, respectively. Moreover, the results of comparison the DIE-miRNAs between the E. coli and S. aureus infected groups showed that 197 DIE-miRNAs are identical, 108 DIE-miRNAs are specific to the E. coli group, and 82 DIE-miRNAs are specific to the S. aureus group. Many DIE-miRNAs, such as bta-miR-144, bta-miR-451 and bta-miR-7863, might be the useful biomarkers of mastitis caused by E. coli and S. aureus. In addition, target genes of the DIE-miRNAs were predicted. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that these DIE-miRNAs are likely involved in many immune signaling pathways, including the Toll-like receptor signaling pathways, MAPK signaling pathway, cell adhesion molecules, TGF-β signaling pathway, leukocyte trans endothelial migration, cytokine-cytokine receptor interaction, and chemokine signaling pathways. This study has provided supportive evidence that miRNAs may serve as diagnostic biomarkers of mastitis in dairy cows, and suggests potentially of effective strategies to combat mastitis.
Breast cancer (BC) is one of the most commonly diagnosed cancers and the second leading cause of cancer mortality among women around the world. The purpose of this study is to present a non-labeled liquid crystal (LC) biosensor, based on the inherent feature of nematic LCs, for the evaluation of BC using the human epidermal growth factor receptor-2 (HER-2) biomarker. The mechanism of this sensing is supported by surface modification with dimethyloctadecyl [3-(trimethoxysilyl) propyl] ammonium chloride (DMOAP) encouraging the long alkyl chains that induce a homeotropic orientation of the LC molecules at the interface. To enhance the binding efficacy of more HER-2 antibody (Ab) on LC aligning agents, a simple ultraviolet radiation-assisted method was also used to increase functional groups on the DMOAP coated slides, thereby improving binding affinity and efficiency onto HER-2 Abs. The designed biosensor makes use of the specific binding of HER-2 protein to HER-2 Ab and disruption of the orientation of LCs. This orientation change leads to a transition of the optical appearance from dark to birefringent, enabling the detection of HER-2. This novel biosensor exhibits a linear optical response to HER-2 concentration in the wide dynamic range of 10-6-102 ng/mL, with an ultra-low detection limit of 1 fg/mL. As a proof of concept, the designed LC biosensor was successfully investigated for the quantification of HER-2 protein in patients suffering from BC. Owing to the sensitivity, selectivity, and label-free detection, this biosensor may amplify the application of LC-based biosensors for the detection of most types of cancers.
Rank signaling pathway regulates mammary gland homeostasis and epithelial cell differentiation. Although Rank receptor is expressed by basal cells and luminal progenitors, its role in each individual cell lineage remains unclear. By combining temporal/lineage specific Rank genetic deletion with lineage tracing techniques, we found that loss of luminal Rank reduces the luminal progenitor pool and leads to aberrant alveolar-like differentiation with high protein translation capacity in virgin mammary glands. These Rank-deleted luminal cells are unable to expand during the first pregnancy, leading to lactation failure and impairment of protein synthesis potential in the parous stage. The unfit parous Rank-deleted luminal cells in the alveoli are progressively replaced by Rank-proficient cells early during the second pregnancy, thereby restoring lactation. Transcriptomic analysis and functional assays point to the awakening of basal bipotency after pregnancy by the induction of Rank/NF-κB signaling in basal parous cell to restore lactation and tissue homeostasis.
The extracellular matrix (ECM) is abnormal in breast tumors and has been reported to contribute to breast tumor progression. One factor, which may drive ongoing matrix synthesis in breast tumors, is the loss of stromal caveolin-1 (cav-1), a scaffolding protein of caveolae, which has been linked to breast tumor aggressiveness. To determine whether loss of cav-1 results in the abnormal expression of matrix proteins, mammary glands from cav- 1-/- and cav- 1 +/+ mice were investigated for differences in expression of several ECM proteins. In addition, the presence of myofibroblasts, changes in the vessel density, and differences in duct number and size were assessed in the mammary glands of both animal models. Using immunohistochemistry, expression of fibronectin, tenascin-C, collagens and αSMA were significantly increased in the mammary glands of cav-1-/- mice. Second harmonic generation revealed more organized collagen fibers in cav-1 -/- glands and supported immunohistochemical analyses of increased collagen abundance in the glands of cav-1 -/- mice. Analysis of the ductal structure demonstrated a significant increase in the number of proliferating ducts in addition to significant increases in the duct circumference and area in cav-1 -/- glands compared to cav- 1 +/+ glands. Differences in microvessel density weren't apparent between the animal models. In summary, we found that the loss of cav-1 resulted in increased ECM and α-SMA protein expression in murine mammary glands. Furthermore, we found that an abnormal ductal architecture accompanied the loss of cav-1. These data support a role for cav-1 in maintaining mammary gland structure.
MicroRNAs are small noncoding RNAs that can regulate gene expression, and they can be involved in the regulation of mammary gland development. The differential expression of miRNAs during mammary gland development is expected to provide insight into their roles in regulating the homeostasis of mammary gland tissues. To screen out miRNAs that should have important regulatory function in the development of mammary gland from miRNA expression profiles and to predict their function, in this study, the target genes of differentially expressed miRNAs in the lactating mammary glands of Laoshan dairy goats are predicted, and then the functions of these miRNAs are analyzed via bioinformatics. First, we screen the expression patterns of 25 miRNAs that had shown significant differences during the different lactation stages in the mammary gland. Then, these miRNAs are clustered according to their expression patterns. Computational methods were used to obtain 215 target genes for 22 of these miRNAs. Combining gene ontology annotation, Fisher's exact test, and KEGG analysis with the target prediction for these miRNAs, the regulatory functions of miRNAs belonging to different clusters are predicted.
Mastitis is a common disease for mammals all around the world. Figuring out why mastitis mainly occurs around parturition may be helpful for dealing with the disease. Lipolytic activity and oxidative stress take place around parturition, which may leads to alteration in fatty acids profile and proinflammatory cytokine expression. Thus, the aim of the present study was to further our understanding about the high incidence of mastitis around parturition by comparison of plasma fatty acid profile and mammary inflammation indicators at different reproductive stages. A total of 47 female rats were included in the present study. After mating, all the pregnant and non-pregnant rats began to receive the same experimental diet. Blood samples were collected at day 1 and 14 of gestation as well as day 3 postpartum. Mammary samples were collected at day 14 of gestation and day 3 postpartum from pregnant and non-pregnant rats. The results showed that rats at d 3 postpartum had greater (P < 0.05) plasma concentrations of non-esterified fatty acids (NEFA), arachidonic acid (ARA) and docosahexaenoic acid (DHA) as well as ARA: eicosapentaenoic acid (EPA) ratio than those at d 14 of gestation. The mRNA abundances of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-8 and xanthine oxidoreductase (XOR) in mammary of the pregnant rats were greater (P < 0.05) than those in age-matched non-pregnant rats. Rats at d 3 postpartum had higher (P < 0.05) protein expression levels of IL-1β and TNF-α as well as meloperoxidase (MPO) activity and polymorphonuclear neutrophils (PMN) prevalence than those at d 1 of gestation. The rats at d 3 postpartum also had greater (P < 0.05) IL-1β and MPO activity than those at d 14 of gestation. The results indicated that elevated mammary expression of proinflammatory cytokines and XOR as well as altered fatty acid profile around parturition might facilitate the recruitment of neutrophils into mammary glands.
Background. Herbal galactagogues have been increasingly used to treat postpartum hypogalactia. The mechanism of action of herbal galactagogues remains unclear. The purpose of this study was to investigate the effect of an herbal galactagogue mixture on milk production and aquaporin (AQP) expression in lactating rats. Methods. Thirty female Sprague Dawley rats were randomized into virgin, lactating + H2O, and lactating + galactagogue groups (n = 10 per group). Lactating rats were administered the decoction of an herbal galactagogue mixture by oral gavage or the same amount of distilled water. Results. The herbal decoction significantly increased milk production in lactating rats (P < 0.05). Both immunohistochemical staining and western blot showed that protein levels of AQP-3 and AQP-5 were significantly increased during lactation compared with virgin stage and the herbal decoction further elevated their expression (P < 0.05). AQP-1 was predominantly expressed in the capillaries whereas AQP-3 and AQP-5 were mainly detected in the epithelial cells and ducts of the mammary glands. Conclusion. The expression of AQPs in the mammary glands of rats was developmentally regulated. Herbal galactagogues might have increased milk secretion by regulating the expression and function of AQPs in the mammary glands.
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