It is well established that cancer cells depend upon aerobic glycolysis to provide the energy they need to survive and proliferate. However, anti‐glycolytic agents have yielded few positive results in human patients, in part due to dose‐limiting side effects. Here, we discovered the unexpected anti‐cancer efficacy of Polydatin (PD) combined with 2‐deoxy‐D‐glucose (2‐DG), which is a compound that inhibits glycolysis. We demonstrated in two breast cell lines (MCF‐7 and 4T1) that combination treatment with PD and 2‐DG induced cell apoptosis and inhibited cell proliferation, migration and invasion. Furthermore, we determined the mechanism of PD in synergy with 2‐DG, which decreased the intracellular reactive oxygen (ROS) levels and suppressed the PI3K/AKT pathway. In addition, the combined treatment inhibited the glycolytic phenotype through reducing the expression of HK2. HK2 deletion in breast cancer cells thus improved the anti‐cancer activity of 2‐DG. The combination treatment also resulted in significant tumour regression in the absence of significant morphologic changes in the heart, liver or kidney in vivo. In summary, our study demonstrates that PD synergised with 2‐DG to enhance its anti‐cancer efficacy by inhibiting the ROS/PI3K/AKT/HIF‐1α/HK2 signalling axis, providing a potential anti‐cancer strategy.
Engeletin (dihydrokaempferol 3-rhamnoside) is a flavanonol glycoside. It can be found in the skin of white grapes and white wine and is widely distributed in southeast Asia, and the leaves are used in a tea. Here, we explored the impact of engeletin against the inflammatory reaction in a lipopolysaccharide (LPS)-induced endometritis mouse model. Engeletin treatment significantly attenuated uterus damage and decreased myeloperoxidase activity. ELISA and qPCR assays showed that engeletin dose-dependently suppressed the expression of TNF-α, IL-1β, and IL-6. Molecular studies also demonstrated that the levels of iNOS, COX-2, and TLR4, along with their downstream molecules MyD88, IRAK1, TRAF6, and TAK1, were also suppressed by engeletin. In addition, engeletin treatment inhibited NF-κB signaling-pathway activation. Moreover, immunofluorescence analysis demonstrated that engeletin suppressed NF-κB-p65 nuclear translocation. These data indicated the protective action of engeletin against LPS-stimulated endometritis in mice via negative regulation of pro-inflammatory mediators via the TLR4-regulated NF-κB pathway.
Hyperoside (quercetin 3-o-β-d-galactopyranoside) is one of the flavonoid glycosides with anti-inflammatory, antidepressant, and anti-cancer effects. But it remains unknown whether it had effects on breast cancer. Here, different concentrations of hyperoside were used to explore its therapeutic potential in both breast cancer cells and subcutaneous homotransplant mouse model. CCK-8 and wound healing assays showed that the viability and migration capability of Michigan Cancer Foundation-7 (MCF-7) and 4T1 cells were inhibited by hyperoside, while the apoptosis of cells were increased. Real-time quantitative PCR (qRT-PCR) and western blot analysis were used to detect mRNA and the protein level, respectively, which showed decreased levels of B cell lymphoma-2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and increased levels of Bax and cleaved caspase-3. After exploration of the potential mechanism, we found that reactive oxygen species (ROS) production was reduced by the administration of hyperoside, which subsequently inhibited the activation of NF-κB signaling pathway. Tumor volume was significantly decreased in subcutaneous homotransplant mouse model in hyperoside-treated group, which was consistent with our study in vitro. These results indicated that hyperoside acted as an anticancer drug through ROS-related apoptosis and its mechanism included activation of the Bax–caspase-3 axis and the inhibition of the NF-κB signaling pathway.
Acute lung injury (ALI) is a life-threatening inflammatory disease owing to the lack of specific and effective therapies. Oridonin (Ori) is an active diterpenoid isolated from Rabdosiarubescens (R.rubescens) that has been shown to possess a broadspectrum pharmacological properties including anti-inflammatory, antitumour, antioxidative and neuroregulatory effects. However, its potential protective mechanism in ALI is not well characterized. In this study, we demonstrated that Ori reduces the mortality of mice with ALI induced by a high dose of lipopolysaccharide (LPS), which suggests that Ori has a protective effect on LPS induced ALI. Next, our results confirmed that Ori improves LPS-induced localized pulmonary pathology and decreased the concentration of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum. Nuclear factor-kappa B (NF-κB) is capable of regulating the transcription of pro-inflammatory factors. Interestingly, our results showed that Ori inhibits the expression of TLR4/MyD88 and phosphorylation of NF-κB p65 in lung tissues. To confirm this, we further validated the possible regulatory anti-inflammatory mechanisms of Ori in vitro. LPS-induced RAW264.7 cells, which are widely used as an inflammation model to evaluate the potential protective effect of drugs in vitro, were chosen for this study. Similar results were observed, that is, pre-treatment with Ori, markedly inhibited the nuclear translocation and phosphorylation of NF-κB p65 induced by LPS and subsequently decreased the release of pro-inflammatory cytokines that were increased by LPS. Overall, these results demonstrated that Ori exerts a therapeutic effect on ALI by inhibiting the release of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, through the TLR4/MyD88/NF-κB axis.
Staphylococcus aureus (S. aureus) causes severe inflammation in various infectious diseases, leading to high mortality. The clinical application of antibiotics has gained a significant curative effect. However, it has led to the emergence of various resistant bacteria. Therefore, in this study, we investigated the protective effect of polydatin (PD), a traditional Chinese medicine extract, on S. aureus lipoteichoic acid (LTA)‐induced injury in vitro and in vivo. First, a significant improvement in the pathological conditions of PD in vivo was observed, suggesting that PD had a certain protective effect on LTA‐induced injury in a mouse model. To further explore the underlying mechanisms of this protective effect of PD, LTA‐induced murine macrophages were used in this study. The results have shown that PD could reduce the NF‐κB p65, and IκBα phosphorylation levels increased by LTA, resulting in a decrease in the transcription of pro‐inflammatory factors, such as TNF‐α, IL‐1β and IL‐6. However, LTA can not only activate NF‐κB through the recognition of TLR2 but also increase the level of intracellular reactive oxygen species (ROS), thereby activating NF‐κB signalling. We also detected high levels of ROS that activate caspases 9 and 3 to induce apoptosis. In addition, using a specific NF‐κB inhibitor that could attenuate apoptosis, namely NF‐κB p65, acted as a pro‐apoptotic transcription factor in LTA‐induced murine macrophages. However, PD could inhibit the generation of ROS and NF‐κB p65 activation, suggesting that PD suppressed LTA‐induced injury by attenuating ROS generation and TLR2‐NFκB signalling.
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.
The purpose of this study was to investigate the effects of thymol on lipopolysaccharide (LPS)-induced inflammatory responses and to clarify the potential mechanism of these effects. LPS-induced mouse endometritis was used to confirm the anti-inflammatory action of thymol in vivo. RAW264.7 cells were used to examine the molecular mechanism and targets of thymol in vitro. In vivo, thymol markedly alleviated LPS-induced pathological injury, myeloperoxidase (MPO) activity, and the production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in mice. Further studies were performed to examine the expression of the Toll-like receptor 4 (TLR4) -mediated nuclear factor-κB (NF-κB) pathway. These results showed that the expression of the TLR4-mediated NF-κB pathway was inhibited by thymol treatment. In vitro, we observed that thymol dose-dependently inhibited the expression of TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 cells. Moreover, the results obtained from immunofluorescence assays also indicated that thymol dose-dependently suppressed LPS-induced reactive oxygen species (ROS) production. Silencing of TLR4 inhibited NF-κB pathway activation. Furthermore, H2O2 treatment increased the phosphorylation of p65 and IκBα, which were decreased when treated with N-acetyl cysteine or thymol. In conclusion, the anti-inflammatory effects of thymol are associated with activation of the TLR4 or ROS signaling pathways, contributing to NF-κB activation, thereby alleviating LPS-induced oxidative and inflammatory responses.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.