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Mastitis can seriously damage the physical and mental health of lactating women. The use of antibiotics and anti-inflammatory drugs may damage the flora balance in lactating women. To alleviate mastitis in lactating women and reduce drug-induced damage to the flora, we found that dehydroandrographolide (Deh) has good anti-inflammatory and bacterial balance functions. In vivo , we found that Deh significantly inhibited the expression of MPO, IL6, IL-1β, TNF-α, COX2 and iNOS and reduced pathological damage to the mammary gland. The feces in the control and Deh groups were collected and sequenced for 16S flora. The results showed that Deh did not change the primary intestinal microflora composition of the two groups. In vitro , our study showed that Deh significantly inhibited the expression of IL6, IL-1β and TNF-α in the EpH4-Ev cell line. When an AMPK inhibitor was added, the anti-inflammatory effect of Deh was blocked. To further study the anti-inflammatory mechanism of Deh, we found that Deh significantly promoted autophagy through the phosphorylation of AMPK, Beclin and ULK1. In conclusion, our study found that Deh promoted autophagy and played an anti-inflammatory role by activating the AMPK/Beclin/ULK1 signaling pathway and did not affect intestinal flora.

Mastitis is one of three bovine diseases recognized as a cause of substantial economic losses every year throughout the world. Niacin is an important feed additive that is used extensively for dairy cow nutrition. However, the mechanism by which niacin acts on mastitis is not clear. The aim of this study is to investigate the mechanism of niacin in alleviating the inflammatory response of mammary epithelial cells and in anti-mastitis. Mammary glands, milk, and blood samples were collected from mastitis cows not treated with niacin ( n = 3) and treated with niacin (30 g/d, n = 3) and healthy cows ( n = 3). The expression of GPR109A, IL-6, IL-1β, and TNF-α in the mammary glands of the dairy cows with mastitis was significantly higher than it was in the glands of the healthy dairy cows. We also conducted animal experiments in vivo by feeding rumen-bypassed niacin. Compared with those in the untreated mastitis group, the somatic cell counts (SCCs) and the expression of IL-6, IL-1β, and TNF-α in the blood and milk were lower. In vitro, we isolated the primary bovine mammary epithelial cells (BMECs) from the mammary glands of the healthy cows. The mRNA levels of IL-6, IL-1β, TNF-α , and autophagy-related genes were detected after adding niacin, shRNA, compound C, trans retinoic acid, 3-methyladenine to BMECs. Then GPR109A, AMPK, NRF-2, and autophagy-related proteins were detected by Western blot. We found that niacin can activate GPR109A and phosphorylate AMPK, and promote NRF-2 nuclear import and autophagy to alleviate LPS-induced inflammatory response in BMECs. In summary, we found that niacin can reduce the inflammatory response of BMECs through GPR109A/AMPK/NRF-2/autophagy. We also preliminarily explored the alleviative effect of niacin on mastitis in dairy cows.

Schisandrin A (Sch A), a dibenzocyclooctadiene lignan extracted from Schisandra chinensis (Turcz.) Baill., has anti-oxidant and anti-inflammatory effects, but the effect on masitits has not been studied. Therefore, we investigated the effect of Sch A in cell and mouse models of lipopolysaccharide (LPS)-induced mastitis. Studies in vivo showed that Sch A reduced LPS-induced mammary injury and the production of pro-inflammatory mediators. Sch A also decreased the levels of pro-inflammatory mediators and activated nuclear factor-E2 associated factor 2 (Nrf2) signaling pathway in mouse mammary epithelial cells (mMECs). The Nrf2 inhibitor partially abrogated the downregulation of Sch A on LPS-induced inflammatory response. In addition, LPS stimulation suppressed autophagy, while both Sch A and the autophagy inducer rapamycin activated autophagy in mMECs, which down-regulated inflammatory response. Sch A also restrained LPS-induced phosphorylation of mammalian target of rapamycin (mTOR) and activated AMP-activated protein kinase (AMPK) and unc-51 like kinase 1 (ULK1). In summary, these results suggest that Sch A exerts protective effects in LPS-induced mastitis models by activating Nrf2 signaling pathway and inducing autophagy and the autophagy is initiated by suppressing mTOR signaling pathway and activating AMPK-ULK1 signaling pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background/Aims: Mastitis is an acute clinical inflammatory response. The occurrence and development of mastitis seriously disturb women's physical and mental health. Licochalcone A, a phenolic compound in Glycyrrhiza uralensis , has anti-inflammatory properties. Here, we examined the effect of licochalcone A on blood-milk barrier and inflammatory response in LPS-induced mice mastitis. Methods: , we firstly established mice models of mastitis by canal injection of LPS to mammary gland, and then detected the effect of licochalcone A on pathological indexes, inflammatory responses and blood-milk barrier in this model. In vivo , we firstly established mice models of mastitis by canal injection of LPS to mammary gland, and then detected the effect of licochalcone A on pathological indexes, inflammatory responses and blood-milk barrier in this model. In vivo , Mouse mammary epithelial cells (mMECs) were treated with licochalcone A prior to the incubation of LPS, and then the inflammatory responses, tight junction which is the basic structure of blood-milk barrier were analyzed. Last, we elucidated the anti-inflammatory mechanism by examining the activation of mitogen-activated protein kinase ( MAPK) and AKT/NF-κB signaling pathways in vivo and in vitro . Result: The in vivo results showed that licochalcone A significantly decreased the histopathological impairment and the inflammatory responses, and improved integrity of blood-milk barrier. The in vitro results demonstrated that licochalcone A inhibited LPS-induced inflammatory responses and increase the protein levels of ZO-1, occludin, and claudin3 in mMECs. The in vivo mechanistic study found that the anti-inflammatory effect of licochalcone A in LPS-induced mice mastitis was mediated by MAPK and AKT/NF-κB signaling pathways. in vitro Our experiments collectively indicate that licochalcone A protected against LPS-induced mice mastitis via improving the blood-milk barrier integrity and inhibits the inflammatory response by MAPK and AKT/NF-κB signaling pathways.Conclusions and Implications: Our experiments collectively indicate that licochalcone A protected against LPS-induced mice mastitis via improving the blood-milk barrier integrity and inhibits the inflammatory response by MAPK and AKT/NF-κB signaling pathways.

Vanillin is used in a variety of food, chemical, and pharmaceutical applications, and exhibits anti-inflammatory properties. However, there are no reports about the effects of vanillin on lipopolysaccharide (LPS)-induced mastitis. In this study, we explored the effects of vanillin on the subsequent inflammatory response and blood-milk barrier in LPS-induced mastitis. Results showed that vanillin suppressed the inflammatory response by a) inhibiting myeloperoxidase activity; b) decreasing the production of pro-inflammatory mediators which include tumor necrosis factor alpha (Tnf-α; from 128.5 ± 14.59 to 67.51 ± 10.88,pg/mL, P < 0.01), interleukin-6 (Il-6; from 531.5 ± 196.4 to 109.3 ± 24.14, pg/mL, P < 0.05), interleukin-1β (Il-1β; from 2569 ± 1648 to 731.8 ± 171.7, pg/mL, P < 0.05), inducible nitric oxide synthase (Inos), and cyclooxygenase-2 (Cox-2); and c) repairing the blood-milk barrier by increasing the protein levels of the tight junction proteins, including zona occludens 1 (Zo-1), claudin-3, and occludin. In vitro experiment, Vanillin can inhibit LPS-induced inflammation and enhance the protein levels of tight junction proteins. Further studies have shown that vanillin inhibits inflammation by inhibiting mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Our findings showed that vanillin protects mammary gland from LPS-induced mastitis by enhancing the blood-milk barrier and inhibiting the inflammatory response., (Copyright © 2018. Published by Elsevier Inc.)

Peiminine, an alkaloid extracted from Fritillaria plants, has been reported to have potent anti-inflammatory properties. However, the anti-inflammatory effect of peiminine on a mouse lipopolysaccharide (LPS)-induced mastitis model remains to be elucidated. The purpose of this experiment was to investigate the effect of peiminine on LPS-induced mastitis in mice. LPS was injected through the canals of the mammary gland to generate the mouse LPS-induced mastitis model. Peiminine was administered intraperitoneally 1 h before and 12 h after the LPS injection. In vitro, mouse mammary epithelial cells (mMECs) were pretreated with different concentrations of peiminine for 1 h and were then stimulated with LPS. The mechanism of peiminine on mastitis was studied by hematoxylin-eosin staining (H&E) staining, western blotting, and enzyme-linked immunosorbent assay (ELISA). The results showed that peiminine significantly decreased the histopathological impairment of the mammary gland in vivo and reduced the production of pro-inflammatory mediators in vivo and in vitro. Furthermore, peiminine inhibited the phosphorylation of the protein kinase B (AKT)/ nuclear factor-κB (NF-κB), extracellular regulated protein kinase (ERK1/2), and p38 signaling pathways both in vivo and in vitro. All the results suggested that peiminine exerted potent anti-inflammatory effects on LPS-induced mastitis in mice. Therefore, peiminine might be a potential therapeutic agent for mastitis.

Farrerol has been proved to have an anti-inflammatory effect. However, the effects of farrerol on mastitis have not been investigated. This study was aimed to investigate the effect and mechanism of farrerol in lipopolysaccharide (LPS)-induced mouse mastitis and LPS-induced inflammatory response of mouse mammary epithelial cells (mMECs). In vivo, LPS were injected to the tetrad pair of nipples for establishing mouse mastitis, and then tested the effect of farrerol on histopathological changes, inflammatory response and activation degree of protein kinase B (AKT), nuclear factor-kappa B p65 (NF-κB p65), p38, extracellular regulated protein kinase (ERK1/2). In vitro, the mMECs were incubated by farrerol for 1 h following by stimulating with LPS, and then the inflammatory response and the related signaling pathways were detected. The in vivo results found that farrerol could improve pathological injury of mammary gland, attenuate the activity of myeloperoxidase (MPO), inhibit the production of pro-inflammatory mediators and the phosphorylation of AKT, NF-κB p65, p38 and ERK1/2. The in vitro results also found farrerol inhibited inflammatory response and the related signaling pathways. Collectively, this study revealed that farrerol inhibits the further development of LPS-induced mastitis by inhibiting inflammatory response via down regulating phosphorylation of AKT, NF-κB p65, p38, and ERK1/2. These findings suggest that farrerol may be used as an anti-inflammatory drug for mastitis.

Mastitis, an inflammation of mammary gland, is a serious disease that affects the health of dairy cows around the world. Myricetin, a flavonoid from Bayberry, has been reported to suppress various inflammatory response. The aim of this study was to evaluate the effect of myricetin on lipopolysaccharide (LPS)‐induced in vivo and in vitro mastitis model and clarify the underlying mechanism. In vivo experiments, myricetin attenuated the severity of inflammatory lesion and neutrophil infiltration. Moreover, myricetin pretreatment induced a significant decrease in the activity of myeloperoxidase (MPO) and the production of TNF‐α, IL‐6, and IL‐1β triggered by LPS. Myricetin pretreatment could also increase the integrity of the blood–milk barrier and upregulate the tight junction proteins in LPS‐induced mice mastitis. In vitro, myricetin inhibited LPS‐induced inflammatory response in mice mammary epithelial cells (mMECs). In the further mechanism studies, we found that the anti‐inflammatory effect of myricetin was mediated by inhibiting LPS‐induced phosphorylation of AKT, IKK‐α, IκB‐α, and P65 in vivo and in vitro. Collectively, these data suggested that myricetin effectively ameliorated the inflammatory response by inhibiting the AKT/IKK/NF‐κB signaling pathway and repairing the integrity of blood–milk barrier in LPS‐induced mice mastitis. [ABSTRACT FROM AUTHOR]