Betulin suppresses S. aureus -induced mammary gland inflammatory injury by regulating PPAR-γ in mice

Guo, Mengyao; Li, Wenyu; Zhang, Zhenbiao; Qiu, Changwei; Li, Chengye; Deng, Ganzhen

doi:10.1016/j.intimp.2015.08.035

Cited by 28 publications

(21 citation statements)

References 37 publications

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“…S aureus, a Gram-positive bacterium, is one of the major pathogens that causes mastitis [4] . The intramammary instillation of S aureus is a well-known model of mastitis in mice [19] . In our study, it was observed in the histopathological analysis that PD clearly suppressed the infiltration of inflammatory cells and reversed the mammary structural damage.…”

Section: Discussionmentioning

confidence: 99%

“…The method for establishing the S aureusinduced mastitis model was described previously [19] . Briefly, 100 μL of S aureus suspension (10 9 CFU) was injected into two abdominal mammary glands to induce mastitis.…”

Section: S Aureusmentioning

confidence: 99%

“…Cell integrity and cell viability assay Cytokeratin 18 is widely used to identify the integrity of mammary gland epithelial cells [19] . In our study, mMECs were pretreated with a blue fluorophore to observe the cell nucleus, and cytokeratin 18 was labeled with a green fluorophore to identify cell integrity ( Figure 4A).…”

Section: Effects Of Pd On Mpo Activitymentioning

confidence: 99%

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Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB pathway

et al. 2016

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Recent studies show that Polydatin (PD) extracted from the roots of Polygonum cuspidatum Sieb, a widely used traditional Chinese remedies, possesses anti-inflammatory activity in several experimental models. In this study, we investigated the anti-inflammatory effects of PD on Staphylococcus aureus-induced mastitis in mice and elucidated the potential mechanisms. In mice with S aureusinduced mastitis, administration of PD (15, 30, 45 mg/kg, ip) or dexamethasone (Dex, 5 mg/kg, ip) significantly suppressed the infiltration of inflammatory cells, ameliorated the mammary structural damage, and inhibited the activity of myeloperoxidase, a biomarker of neutrophils accumulation. Furthermore, PD treatment dose-dependently decreased the levels of TNF-α, IL-1β, IL-6 and IL-8 in the mammary gland tissues. PD treatment also dose-dependently decreased the expression of TLR2, MyD88, IRAK1, IRAK4 and TRAF6 as well as the phosphorylation of TAK1, MKK3/6, p38 MAPK, IκB-α and NF-κB in the mammary gland tissues. In mouse mammary epithelial cells (mMECs) infected by S aureus in vitro, pretreatment with PD dose-dependently suppressed the upregulated pro-inflammatory cytokines and signaling proteins, and the nuclear translocation of NF-κB p65 and AP-1. A TLR2-neutralizing antibody mimicked PD in its suppression on S aureus-induced upregulation of MyD88, p-p38 and p-p65 levels in mMECs. PD (50, 100 μg/mL) affected neither the growth of S aureus in vitro, nor the viability of mMECs. In conclusion, PD does not exhibit antibacterial activity against S aureus, its therapeutic effects in mouse S aureus-induced mastitis depend on its ability to down-regulate pro-inflammatory cytokine levels via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: S Aureusmentioning

confidence: 99%

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Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB pathway

et al. 2016

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“…According to a number of reports, betulin, a natural product derived from Betulae Cortex, a medicinal plant used for controlling various inflammatory diseases in folk medicine, showed the biological activities including anti-inflammatory effect [2223242526]. Betulin showed an alleviating effect on alcoholic liver injury and renal injury through SIRT1/AMPK and TLR4/NF-κB signaling pathways, respectively [2223].…”

Section: Introductionmentioning

confidence: 99%

“…Betulin showed an alleviating effect on alcoholic liver injury and renal injury through SIRT1/AMPK and TLR4/NF-κB signaling pathways, respectively [2223]. It also attenuates lung injury in sepsis and mammary gland inflammatory injury [2425]. Betulin suppresses the expression of pro-inflammatory cytokines in human cardiac cells [26].…”

Section: Introductionmentioning

confidence: 99%

Betulin suppressed interleukin-1β-induced gene expression, secretion and proteolytic activity of matrix metalloproteinase in cultured articular chondrocytes and production of matrix metalloproteinase in the knee joint of rat

Jong

HyunJaeLee

HoSeungJo

et al. 2017

Korean J Physiol Pharmacol

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We investigated whether betulin affects the gene expression, secretion and proteolytic activity of matrix metalloproteinase-3 (MMP-3) in primary cultured rabbit articular chondrocytes, as well as in vivo production of MMP-3 in the rat knee joint to evaluate the potential chondroprotective effect of betulin. Rabbit articular chondrocytes were cultured and reverse transcription-polymerase chain reaction (RT-PCR) was used to measure interleukin-1β (IL-1β)-induced gene expression of MMP-3, MMP-1, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), ADAMTS-5 and type II collagen. Effect of betulin on IL-1β-induced secretion and proteolytic activity of MMP-3 was investigated using western blot analysis and casein zymography, respectively. Effect of betulin on MMP-3 protein production was also examined in vivo. The results were as follows: (1) betulin inhibited the gene expression of MMP-3, MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5, but increased the gene expression of type II collagen; (2) betulin inhibited the secretion and proteolytic activity of MMP-3; (3) betulin suppressed the production of MMP-3 protein in vivo. These results suggest that betulin can regulate the gene expression, secretion, and proteolytic activity of MMP-3, by directly acting on articular chondrocytes.

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Gas6 negatively regulates the Staphylococcus aureus‐induced inflammatory response via TLR signaling in the mouse mammary gland

Zahoor

Yang

et al. 2020

Journal Cellular Physiology

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Staphylococcus aureus (S. aureus)-induced mastitis is the most frequent, pathogenic, and prevalent infection of the mammary gland. The ligand growth arrest-specific 6 (Gas6) is a secretory protein that binds to and activates Tyro3, Axl, and MerTK receptors. This study explored the role of Gas6 in S. aureus-induced mastitis. Our results revealed that TLR receptors initiate the innate immune response in mammary gland tissues and epithelial cells and that introducing S. aureus activates TLR2 and TLR6 to drive multiple intracellular mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) pathways. Moreover, S. aureus also induces Gas6, which then activates the TAM receptor kinase pathway, which is related to the inhibition of TLR2-and TLR6-mediated inflammatory pathways through SOCS1 and SOCS3 induction. Gas6 absence alone was found to be involved in the downregulation of TAM receptor-mediated anti-inflammatory effects by inducing significantly prominent expression of TRAF6 and low protein and messenger RNA expression of SOCS1 and SOCS3. S. aureus-induced MAPK and NF-ĸB p65 phosphorylation were also dependent on Gas6, which negatively regulated the production of Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in S. aureus-treated mammary tissues and mammary epithelial cells. Our in vivo and in vitro study uncovered the Gas6-mediated negative feedback mechanism, which inhibits TLR2-and TLR6-mediated MAPK and NF-ĸB signaling by activating TAM receptor kinase (MerTK, Axl, and Tyro3) through the induction of SOCS1/SOCS3 proteins.

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Betulin suppresses S. aureus -induced mammary gland inflammatory injury by regulating PPAR-γ in mice

Cited by 28 publications

References 37 publications

Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB pathway

Polydatin ameliorates Staphylococcus aureus-induced mastitis in mice via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB pathway

Betulin suppressed interleukin-1β-induced gene expression, secretion and proteolytic activity of matrix metalloproteinase in cultured articular chondrocytes and production of matrix metalloproteinase in the knee joint of rat

Gas6 negatively regulates the Staphylococcus aureus‐induced inflammatory response via TLR signaling in the mouse mammary gland

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