Inflammation Of Mammary Gland Research Articles

Expresión de las b-defensinas LAP (péptido antimicrobiano lingual) y TAP (péptido antimicrobiano traqueal), así como psoriasina (S100A7), en la glándula mamaria bovina con mastitis crónica por Staphylococcus aureus

Bovine mastitis is a worldwide disease that affects dairy cattle and is characterized by inflammation of mammary gland. Severity of inflammation depends of causative agent and host response to it. Antimicrobial peptides play an important role in innate immune defense mechanisms of mammary gland against mastitis causative microorganisms. By using qPCR on mammary gland tissues: cistern, parenchyma, Fuerstenberg’ rosette, streak canal, and inguinal lymph node, with mastitis by Sthapylococcus aureus , we found that β -defensins lingual antimicrobial peptide (LAP) and tracheal antimicrobial peptide (TAP) were mainly expressed in cisternal and parenchymal tissues. The S100A7 protein was highly expressed in streak canal, although some expression was detected in Fuerstenberg’s rosette, cistern, inguinal lymph node, but no in parenchymal tissue. Therefore, these peptides could play a key role in the mammary gland with mastitis by S. aureus .

Increased Epstein–Barr virus in breast milk occurs with subclinical mastitis and HIV shedding

Epstein-Barr virus (EBV) in breast milk and subclinical mastitis (SCM) are both associated with human immunodeficiency virus (HIV) shedding and possibly with postnatal HIV transmission. The objective of this nested case-control study was to investigate the interplay between SCM and EBV replication in breast milk of HIV-infected mothers.The relationships between EBV deoxyribonucleic acid (DNA) shedding, HIV-1 ribonucleic acid (RNA) level, and SCM were explored in breast milk samples of Zambian mothers participating in the ANRS 12174 trial. Mammary gland inflammation was defined as a breast milk sodium to potassium ratio (Na/K) greater than 0.6 and further subclassified as either "possible SCM" (Na/K ratio 0.6-1.0) or SCM (Na/K ratio ≥ 1.0). Breast milk interleukin 8 (IL-8) was measured as a surrogate marker of mammary gland inflammation.EBV DNA was detected in breast milk samples from 42 out of 83 (51%) participants and was associated with HIV-1 shedding in breast milk (P = 0.006). EBV DNA levels were higher in samples with SCM and "possible SCM" compared to non-SCM breast milk samples (P = 0.06; P = 0.007). An EBV DNA level of >200 copies/mL was independently associated with SCM and "possible SCM" (OR: 2.62; 95%: 1.13-6.10). In patients with SCM, higher EBV replication in the mammary gland was associated with a lower induction of IL-8 (P = 0.013). Resistance to DNase treatment suggests that EBV DNA in lactoserum is encapsidated.SCM and decreased IL-8 responses are associated with an increased EBV shedding in breast milk which may in turn facilitate HIV replication in the mammary gland.

Dietary Poly Unsaturated Fatty Acid (PUFA) regulation of Organ and Tissue Microenvironments in an Iso-Caloric Pair-Fed Mouse Model

Abstract The majority of omega-3 (ω3) and ω3 PUFA diet studies have not differentiated dietary PUFA content from obesity. Our studies used pair-fed iso-caloric diets containing 35.5% of calories from fat with an ω6:ω3 ratio in ω6 and ω3 diets of 42:1 and 1:1 respectively with DeCarli diets and fish oil substituting for 70% of olive oil. The ω3 diet contained eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid at a 3:1 ratio, while the ω6 diet contained linoleic acid and a low level of linolenic acid. Female BALB/c mice were monitored for weight gain, diet consumption and sacrificed (12 wks) to examine mammary gland, spleen, bone and hepatic histopathology, leukocyte phenotypes and organ and tissue lipidomics. In association with pair feeding there were no differences in diet consumed and weight gain. The ω6 cohort had decreased numbers of progenitor cells and an increase in splenic subcapsular extramedullary hematopoiesis and hepatocyte lipidosis, hypertrophy and multinucleation and increased hepatic vascularity with thicker intima. The ω-6 cohort also had mammary fat pads (MFPs) with increased adipocytes in the tubular epithelium, stromal cellularity and epithelial tissue density. These changes and subclinical inflammation were accompanied by organ specific lipodemic changes, including increases in arachidonic acid (AA) in the plasma, spleen and liver, but not MFPs, of the ω-6 mice, and an increase in EPA and DHA in the plasma, spleen, MFPs and liver of the ω-3 mice. Further, B and T cells and macrophages had an increase in the % of phospho NFκβ+ cells and the liver and MFPs had an increase in the ω3 PUFA, docosapentaenoic acid. In summary, the dietary ω6:ω3 ratio, independent of obesity, regulates mammary gland, spleen and hepatic inflammation.

Spontaneous Reproductive Tract Lesions in Aged Captive Chimpanzees.

Chimpanzees (Pan troglodytes) have served as an important model for studies of reproductive diseases and aging-related disorders in humans. However, limited information is available about spontaneously occurring reproductive tract lesions in aging chimpanzees. In this article, the authors present histopathologic descriptions of lesions identified in the reproductive tract, including the mammary gland, of 33 female and 34 male aged chimpanzees from 3 captive populations. The most common findings in female chimpanzees were ovarian atrophy, uterine leiomyoma, adenomyosis, and endometrial atrophy. The most common findings in male chimpanzees were seminiferous tubule degeneration and lymphocytic infiltrates in the prostate gland. Other less common lesions included an ovarian granulosa cell tumor, cystic endometrial hyperplasia, an endometrial polyp, uterine artery hypertrophy and mineralization, atrophic vaginitis, mammary gland inflammation, prostatic epithelial hyperplasia, dilated seminal vesicles, a sperm granuloma, and lymphocytic infiltrates in the epididymis. The findings in this study closely mimic changes described in the reproductive tract of aged humans, with the exception of a lack of malignant changes observed in the mammary gland and prostate gland.

Expression of the bovine neutrophil β-defensins4 (BNBD4) and 10 (BNBD10), and β-defensin 1(DEFB1) in the bovine mammary gland with chronic mastitis by Staphylococcus aureus

Bovine mastitis is the most costly infectious disease of dairy cattle worldwide and ischaracterized by inflammation of the mammary gland. The etiology of the pathogens influences the severity of the inflammation and the immune response, and specifically some elements of the innate immunity, like the antimicrobial peptides, are known to display some pathogen specificity. The antimicrobial peptides play an important role in the innate immune defense mechanisms of the mammary gland against mastitis causative microorganisms. In the present study the expression of three β -defensins was estimated across 5 localizations of the mammary gland infected with Sthapylococcus aureus , by quantitative real-time PCR. Copies of mRNA for BNBD10 and DEFB1 were detected in Lymph node, parenchyma, streak canal, cisterna, andRosette of Furstenberg, with the highest level observed in lymph node and the lowest in Rosette of Furstenberg, and the level of expression was higher for BNBD10 . The level of mRNA expression for BNBD4 was very low in all localizations, with respect to BNBD10 and DEFB1 . Therefore, BNBD10 and DEFB1 could play a key role in the mammary gland with mastitis by S. aureus .

Evaluation of immunotherapeutic potential of Ocimum sanctumin bovine subclinical mastitis

Mastitis, the inflammation of mammary glands, is caused by a wide range of contagious and environmental microbes, whose clearance from the udder is generally dependent on the use of antibiotics. However, antibiotic therapy may result in development of drug-resistant microbes and depress the activity of polymorphonuclear cells. The present study was therefore undertaken to explore the immunotherapeutic potential of an herb, Ocimum sanctum, in mastitis in dairy cows. The study involved twenty HF × Sahiwal lactating dairy cows, each identified with at least one specific subclinical mastitis quarter as per International Dairy Federation criteria. The cows were divided into two equal groups: a control group and a group administered O. sanctum leaf powder at 600 mg/kg body weight daily divided into two doses orally for 7 days. The treatment could eliminate 69.23% of intramammary infections (χ 2 = 5.07; P ≤ 0.5) and resulted in a significant reduction in somatic cell count and ceruloplasmin concentration, thus subsiding udder inflammation and improving milk quality. The herb was also found to possess immunomodulation potential, as evidenced by the significant increase in phagocytic activity of milk neutrophils and enhanced lactoperoxidase and myeloperoxidase activities. Thus, the results indicated the immunotherapeutic potential of O. sanctum in treating bovine-specific subclinical mastitis.

Culture-dependent assessment of bacterial diversity from human milk with lactational mastitis

Mastitis, an inflammation of mammary gland, is a deliberately painful condition experienced by lactating women. Etiology of mastitis is still underexplored due to the paucity of research conducted on it. The objective of this study was to explore culturable bacterial diversity present in the breast milk of mastitis-suffering women by 16S rDNA sequencing and evaluate its antibiotic susceptibility. The culturable bacteria present in the breast milk of 32 women with lactational mastitis were studied. Thirty-seven bacterial isolates comprised of distinct colony characteristics were checked for antibiotic susceptibility and identified by 16S rDNA sequencing. Sequencing of 16S rDNA and BLAST analysis revealed the presence of 17 genera and 30 different species indicating highly diverse community in mastitis milk. The Proteobacteria (51.35 % of total clones) and Firmicutes (37.83 %) were the most abundant phyla and included representatives from the class Gammaproteobacteria, Alphaproteobacteria, and Bacilli. Pseudomonas (6 species) and Staphylococcus (4 species) were the most prevalent genera while Brevundimonas, Bacillus, Enterococcus, Micrococcus, and Macrococcus were infrequently isolated. Staphylococcus sp. (87.5 % of mastitis samples), Staphylococcus aureus (75 %), Pseudomonas aeruginosa (53.12 %), Klebsiella pneumoniae (43.75 %), and Brevundimonas diminuta (37.5 %) were frequently isolated from mastitis milk. Antibiotics like chloramphenicol, gentamicin, ofloxacin, and ciprofloxacin proved to be most effective against mastitis pathogens. Overall analysis suggested that high bacterial diversity in diseased condition could be the result of colonization of mammary gland by opportunistic pathogens but the actual role of bacteria in mastitis is still a debatable question.

Estrogen Protects against Obesity-Induced Mammary Gland Inflammation in Mice.

Obesity is a risk factor for the development of hormone receptor (HR)-positive breast cancer in postmenopausal women. Obesity causes subclinical inflammation in white adipose tissue (WAT), characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase. Previously, we demonstrated CLS and elevated levels of proinflammatory mediators and aromatase in the mammary glands of obese mice and breast tissue of obese women. Here, we tested the hypothesis that supplemental estrogen could prevent or reverse WAT inflammation (WATi) and related molecular changes in the mammary gland. C57BL/6J mice were ovariectomized (OVX) to simulate the postmenopausal state. Supplementation with 17β-estradiol (E2) protected against high fat diet (HFD)-induced weight gain and mammary glands WATi. Expression of proinflammatory mediators (Cox-2, TNFα, IL1β) and aromatase were also reduced in the mammary glands of mice that received supplemental E2. Next, to determine whether E2 supplementation can reverse WATi, obese OVX mice were treated with E2 or placebo and then continued on HFD. E2 supplementation induced weight loss, reversed mammary gland inflammation, and downregulated expression of proinflammatory mediators and aromatase. Finally, we determined whether the protective effects of E2 were mediated by estrogen receptor-α (ERα). Knocking out ERα in ovary intact mice fed a HFD led to weight gain, WATi and elevated levels of proinflammatory mediators and aromatase mimicking the effects of OVX. Taken together, our findings indicate that estrogen via ERα protects against weight gain, WATi and associated increases in proinflammatory mediators and aromatase in the mammary gland.

Abstract 2876: Supplemental estrogen protects against obesity induced mammary gland inflammation in mice

Abstract Obesity is a risk factor for the development of several malignancies including hormone receptor-positive breast cancer in postmenopausal women and has been associated with an increased risk of recurrence and reduced survival. A link between obesity, breast inflammation and hormone receptor-positive breast cancer was unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue (WAT), characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase. Previously, we demonstrated CLS and elevated levels of pro-inflammatory mediators and aromatase in the mammary glands (MG) of obese mice and breast tissue of obese women. Recent clinical data suggests that supplemental estrogen given as monotherapy may reduce the risk of breast cancer. Here we tested the hypothesis that supplemental estrogen could prevent or reverse WAT inflammation (WATi) and related molecular changes in the MG of mice. In a prevention study, female C57BL/6J mice were ovariectomized (OVX) to simulate the postmenopausal state. The OVX mice received subcutaneous 17β estradiol (E2) or placebo prior to being initiated on a high fat diet (HFD). E2 supplementation protected mice against HFD-induced weight gain at least, in part, by suppressing caloric consumption. Suppression of weight gain was associated with a marked decrease in MG WATi (CLS/cm2) and a corresponding reduction in adipocyte diameter. Furthermore, expression of pro-inflammatory mediators (Cox-2, TNF-α, IL-1β) and aromatase were also reduced in the MG of mice that received supplemental E2. Next, to determine whether E2 supplementation can also reverse WATi, obese OVX mice were treated with either E2 or placebo and then continued on HFD. E2 supplementation led to physiologically relevant concentrations of 17β estradiol and caused weight loss along with a reversal in MG inflammation (CLS/cm2). Caloric consumption, adipocyte hypertrophy and MG expression of pro-inflammatory mediators and aromatase were also reduced with E2 treatment. Finally, we determined whether the protective effects of E2 were mediated by estrogen receptor-α (ERα), which has been suggested to play a key role in metabolic processes. Interestingly, ovary intact ERα knockout mice gained more weight and consumed more calories than HFD fed ovary intact wild-type mice. These changes were paralleled by adipocyte hypertrophy, WATi and elevated levels of pro-inflammatory mediators and aromatase in the MG. Collectively, our findings indicate that estrogen via ERα protects against weight gain, CLS formation and associated increases in pro-inflammatory mediators and aromatase in the MG. Whether similar effects occur in women warrants further investigation. Citation Format: Priya Bhardwaj, Baoheng Du, Xi Kathy Zhou, Erika Sue, Dilip Giri, Michael D. Harbus, Domenick J. Falcone, Clifford A. Hudis, Kotha Subbaramaiah, Andrew J. Dannenberg. Supplemental estrogen protects against obesity induced mammary gland inflammation in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2015-2876

Association of milk components with intra-mammary inflammation in Jaffrabadi buffaloes.

Aim:To study the alteration of major milk components such as milk fat, protein, lactose, solid not fat (SNF) and total solids (TS) and their association with different degree of intra-mammary inflammation (IMI) in Jaffrabadi buffaloes.Materials and Methods:Milk samples (n=1516) were collected from Jaffrabadi buffaloes separately from each quarter. Milk samples were analyzed for milk fat, protein, lactose, SNF and TS percent on the same day using milk analyzer “LACTOSCAN.” Milk samples were checked for IMI by California mastitis test (CMT), and the results were expressed as negative (0), +, ++, and +++ CMT score. The traits of milk components which showed significant difference (p<0.05) between samples from inflamed and non-inflamed quarters were analyzed by receiver operating characteristic (ROC) analysis to see the accuracy and degree of association with IMI.Results:Among several milk components, milk protein and lactose percent showed a significant difference (p<0.05) between milk samples from normal and inflamed quarters. Though, during the early stage of mammary gland inflammation milk protein percent remained significantly high (p<0.05), later with an increase in the degree of severity of inflammation it did not show any difference. Milk samples from normal udder quarters had significantly higher lactose percent than inflamed quarters (p<0.05). Milk lactose percent decreased gradually with an increase in the degree of severity of inflammation. ROC analysis revealed that milk samples having lactose content below the threshold values had significantly higher chances to come from inflamed udder quarters (p<0.05). Though, the value of the area under curve (AUC) indicated that milk lactose was significantly associated with IMI (p<0.05), the accuracy was moderate (AUC=0.71-0.75).Conclusions:The results of the present study indicated that milk lactose percent gradually and significantly reduced during IMI and can be used as a marker for identification of IMI in buffaloes. However, ROC analysis further confirmed that using milk lactose IMI can be identified with moderate accuracy.

Laboratory Methods Used for Early Diagnosis in Bitch Mastitis

The aim of this paper is to review the existing literature regarding the current methods used to diagnose bitch mastitis. Compared to the information available on ruminant mammary gland inflammation, the data regarding bitch mastitis is limited.So far microbiology assays are most widely used to identify, (based on antibiograms) and to treat mammary gland infections. Milk cytology has also been taken into consideration as a diagnostic tool. Clinicians have also started to use haematology, biochemistry and pH assays to confirm clinical signs of mastitis.It is well known that one of the causes of neonatal mortality is undiagnosed episodes of mastitis. Early diagnosing of subclinical cases of glandular tissue inflammation and avoiding chronic episodes of infection, can limit neonatal mortality.

Combining Genome Wide Association Studies and Differential Gene Expression Data Analyses Identifies Candidate Genes Affecting Mastitis Caused by Two Different Pathogens in the Dairy Cow

Mastitis is a costly disease which hampers the dairy industry. Inflammation of the mammary gland is commonly caused by bacterial infection, mainly Escherichia coli, Streptococcus uberis and Staphylococcus aureus. As more bacteria become multi-drug resistant, one potential approach to reduce the disease incidence rate is to breed selectively for the most appropriate and potentially protective innate immune response. The genetic contribution to effective disease resistance is, however, difficult to identify due to the complex interactions that occur. In the present study two published datasets were searched for common differentially expressed genes (DEGs) with similar changes in expression in mammary tissue following intra-mammary challenge with either E. coli or S. uberis. Additionally, the results of seven published genome-wide association studies (GWAS) on different dairy cow populations were used to compile a list of SNPs associated with somatic cell count. All genes located within 2 Mbp of significant SNPs were retrieved from the Ensembl database, based on the UMD3.1 assembly. A final list of 48 candidate genes with a role in the innate immune response identified from both the DEG and GWAS studies was further analyzed using Ingenuity Pathway Analysis. The main signalling pathways highlighted in the response of the bovine mammary gland to both bacterial infections were 1) granulocyte adhesion and diapedesis, 2) ephrin receptor signalling, 3) RhoA signalling and 4) LPS/IL1 mediated inhibition of RXR function. These pathways comprised a network regulating the activity of leukocytes, especially neutrophils, during mammary gland inflammation. The timely and properly controlled movement of leukocytes to infection loci seems particularly important in achieving a good balance between pathogen elimination and excessive tissue damage. These results suggest that polymorphisms in key genes in these pathways such as SELP, SELL, BCAR1, ACTR3, CXCL2, CXCL6, CXCL8 and FABP may influence the ability of dairy cows to resist mastitis.

Bergenin Plays an Anti-Inflammatory Role via the Modulation of MAPK and NF-κB Signaling Pathways in a Mouse Model of LPS-Induced Mastitis.

Mastitis is a major disease in humans and other animals and is characterized by mammary gland inflammation. It is a major disease of the dairy industry. Bergenin is an active constituent of the plants of genus Bergenia. Research indicates that bergenin has multiple biological activities, including anti-inflammatory and immunomodulatory properties. The objective of this study was to evaluate the protective effects and mechanism of bergenin on the mammary glands during lipopolysaccharide (LPS)-induced mastitis. In this study, mice were treated with LPS to induce mammary gland mastitis as a model for the disease. Bergenin treatment was initiated after LPS stimulation for 24h. The results indicated that bergenin attenuated inflammatory cell infiltration and decreased the concentration of NO, TNF-α, IL-1β, and IL-6, which were increased in LPS-induced mouse mastitis. Furthermore, bergenin downregulated the phosphorylation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathway proteins in mammary glands with mastitis. In conclusion, bergenin reduced the expression of NO, TNF-α, IL-1β, and IL-6 proinflammatory cytokines by inhibiting the activation of the NF-κB and MAPKs signaling pathways, and it may represent a novel treatment strategy for mastitis.

Physiological functions of MTA family of proteins.

Although the functional significance of the metastasic tumor antigen (MTA) family of chromatin remodeling proteins in the pathobiology of cancer is fairly well recognized, the physiological role of MTA proteins continues to be an understudied research area and is just beginning to be recognized. Similar to cancer cells, MTA1 also modulates the expression of target genes in normal cells either by acting as a corepressor or coactivator. In addition, physiological functions of MTA proteins are likely to be influenced by its differential expression, subcellular localization, and regulation by upstream modulators and extracellular signals. This review summarizes our current understanding of the physiological functions of the MTA proteins in model systems. In particular, we highlight recent advances of the role MTA proteins play in the brain, eye, circadian rhythm, mammary gland biology, spermatogenesis, liver, immunomodulation and inflammation, cellular radio-sensitivity, and hematopoiesis and differentiation. Based on the growth of knowledge regarding the exciting new facets of the MTA family of proteins in biology and medicine, we speculate that the next burst of findings in this field may reveal further molecular regulatory insights of non-redundant functions of MTA coregulators in the normal physiology as well as in pathological conditions outside cancer.

Expression patterns of β-defensin and cathelicidin genes in parenchyma of bovine mammary gland infected with coagulase-positive or coagulase-negative Staphylococci.

BackgroundMastitis is still considered to be the most economically important infectious disease in dairy cattle breeding. The immune response in mammary gland tissues could help in developing support strategies to combat this disease. The role of neutrophils and macrophages in the innate response of mammary gland is well known. However, the immune response in mammary gland tissues, including levels of antimicrobial peptide transcripts, has not been well recognized. Moreover, most studies are conducted in vitro, on cell cultures, or on artificially infected animals, with analysis being done within a several dozen hours after infection.The aim of the study was to examine the in vivo transcript levels of beta-defensin and cathelicidins genes in cow mammary gland secretory tissue (parenchyma) with the chronic, recurrent and incurable mammary gland inflammation induced by coagulase-positive or coagulase-negative Staphyloccoci vs. bacteria-free tissue.ResultsThe mRNA of DEFB1, BNBD4, BNBD5, BNBD10 and LAP genes, but not of TAP gene, were detected in all investigated samples regardless of the animals’ age and microbiological status of the mammary gland, but at different levels. The expression of most of the beta-defensin genes was shown to be much higher in tissues derived from udders infected with bacteria (CoPS or CoNS) than from bacteria-free udders, regardless of parity. Cathelicidins (CATH4, CATH5 and CATH6) showed expression patterns contrasting those of β-defensins, with the highest expression in tissues derived from bacteria-free udders.ConclusionIncreased expression of genes encoding β-defensins in the infected udder confirms their crucial role in the defense of the cow mammary gland against mastitis. On the other hand, the elevated cathelicidin transcripts in non-infected tissues indicate their role in the maintenance of healthy mammary tissues. The expression levels of investigated genes are likely to depend on the duration of the infection and type of bacteria.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-014-0246-z) contains supplementary material, which is available to authorized users.

Leonurine exerts anti-inflammatory effect by regulating inflammatory signaling pathways and cytokines in LPS-induced mouse mastitis.

Bovine mastitis is defined as the inflammation of mammary gland and is the most multiple diseases in dairy cattle. There is still no effective treatment now. Leonurine, extracted from Leonurus cardiaca, has been proved to have anti-inflammatory effect. In the present study, we utilized a mouse mastitis model to study the effect of leonurine on LPS-induced mastitis. Leonurine was administered three times during the 24 h after inducing infection in the mammary gland. The results showed that leonurine significantly alleviated LPS-induced histopathological changes, downregulated the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), upregulated the level of anti-inflammatory cytokine interleukin-10 (IL-10), and inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Further study revealed that leonurine inhibited the expression of Toll-like receptor 4 (TLR4) and the activation of nuclear factor-kappaB (NF-κB) and the phosphorylation of p38, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK). Therefore, the results demonstrated that leonurine could downregulate the expression of TNF-α, IL-6, iNOS, and COX-2 and upregulate the expression of IL-10 mainly by inhibiting the expression of TLR4 and the activation of NF-κB and the phosphorylation of p38, ERK, and JNK. Leonurine may be a potential agent for mastitis therapy.

Tongshu Capsule Down-Regulates the Expression of Estrogen Receptor α and Suppresses Human Breast Cancer Cell Proliferation

The Tongshu Capsule (TSC) is a prevalent form of traditional Chinese medicine widely used for its purported effects in treating mammary gland hyperplasia and inflammation. Though successful in several clinical studies, there is no clear evidence as to why TSC has a positive treatment effect, and little known about underlying mechanism that may account for it. In this study, we examined the effects of TSC and found that it has a comparatively strong growth inhibition on ERα positive breast cancer cells. TSC seems to cause G1 cell cycle arrest instead of apoptosis. Interestingly, TSC also down-regulated the expression of ERα and Cyclin D1. Consistently, TSC suppressed E2 mediated ERα downstream gene expression and cell proliferation in ERα positive breast cancer cell lines MCF7 and T47D. Depletion of ERα partially abolished the effects of TSC on the decrease of Cyclin D1 and cell viability. Our findings suggest that TSC may have therapeutic effects on ERα positive breast cancers and moreover that TSC may suppress breast epithelial cell proliferation by inhibiting the estrogen pathway.

Inflammatory Mediators in Mastitis and Lactation Insufficiency

Mastitis is a common inflammatory disease during lactation that causes reduced milk supply. A growing body of evidence challenges the central role of pathogenic bacteria in mastitis, with disease severity associated with markers of inflammation rather than infection. Inflammation in the mammary gland may be triggered by microbe-associated molecular patterns (MAMPs) as well as danger-associated molecular patterns (DAMPs) binding to pattern recognition receptors such as the toll-like receptors (TLRs) on the surface of mammary epithelial cells and local immune cell populations. Activation of the TLR4 signalling pathway and downstream nuclear factor kappa B (NFkB) is critical to mediating local mammary gland inflammation and systemic immune responses in mouse models of mastitis. However, activation of NFkB also induces epithelial cell apoptosis and reduced milk protein synthesis, suggesting that inflammatory mediators activated during mastitis promote partial involution. Perturbed milk flow, maternal stress and genetic predisposition are significant risk factors for mastitis, and could lead to a heightened TLR4-mediated inflammatory response, resulting in increased susceptibility and severity of mastitis disease in the context of low MAMP abundance. Therefore, heightened host inflammatory signalling may act in concert with pathogenic or commensal bacterial species to cause both the inflammation associated with mastitis and lactation insufficiency. Here, we present an alternate paradigm to the widely held notion that breast inflammation is driven principally by infectious bacterial pathogens, and suggest there may be other therapeutic strategies, apart from the currently utilised antimicrobial agents, that could be employed to prevent and treat mastitis in women.

Impact of obesity on mammary gland inflammation and local estrogen production.

Obesity rates have risen dramatically over the past century, having nearly doubled since 1980. Changes in diet and lifestyle have contributed to this occurrence in younger women, and changing hormone levels during the menopausal transition has no doubt exacerbated the issue in older women. The relationship between adiposity and breast cancer is clear in postmenopausal women, and is intimately linked to the increased expression of aromatase and the production of estrogens within the breast adipose. This, in turn, is highly dependent on the localized chronic inflammation observed in obese adipose. This review will therefore explore the relationship between obesity, inflammation and estrogens, with a particular focus on the molecular regulation of aromatase in the postmenopausal breast in the context of obesity and breast cancer.

The effects of diet induced obesity on breast cancer associated pathways in mice deficient in SFRP1.

BackgroundSecreted frizzled-related proteins (SFRPs) are a family of proteins that block the Wnt signaling pathway and loss of Sfrp1 expression is observed in breast cancer. The molecular mechanisms by which obesity contributes to breast tumorigenesis are not well defined, but involve increased inflammation. Mice deficient in Sfrp1 show enhanced mammary gland inflammation in response to diet induced obesity (DIO). Furthermore, mammary glands from Sfrp1 −/− mice exhibit increased Wnt signaling, decreased cell death responses, and excessive hyper branching. The work described here was initiated to investigate whether obesity exacerbates the aforementioned pathways, as they each play a key roles in the development of breast cancer.FindingsWnt signaling is significantly affected by DIO and Sfrp1 −/− loss as revealed by analysis of Myc mRNA expression and active β-catenin protein expression. Furthermore, Sfrp1 −/− mice fed a high fat diet (HFD) exhibit an increase in mammary cell proliferation. The death response is also impaired in the mammary gland of Sfrp1 −/− mice fed a normal diet (ND) as well as a HFD. In response to γ-irradiation, mammary glands from Sfrp1−/− mice express significantly less Bax and Bbc3 mRNA, caspase-3 positive cells, and p53 protein. The expression of Wnt4 and Tnfs11 are critical for normal progesterone mediated mammary gland development and in response to obesity, Sfrp1−/− mice express significantly more Wnt4 and Tnfs11 mRNA expression. Evaluation of progesterone receptor (PR) expression showed that DIO increases the number of PR positive cells.ConclusionsOur data indicate that the expression of Sfrp1 is a critical factor required for maintaining appropriate cellular homeostasis in response to the onset of obesity.