9 research outputs found
The Protective Effect of Magnesium Lithospermate B on Hepatic Ischemia/Reperfusion via Inhibiting the Jak2/Stat3 Signaling Pathway
Acute inflammation is an important component of the pathogenesis of hepatic ischemia/reperfusion injury (HIRI). Magnesium lithospermate B (MLB) has strong neuroprotective and cardioprotective effects. The purpose of this study was to determine whether MLB had underlying protective effects against hepatic I/R injury and to reveal the potential mechanisms related to the hepatoprotective effects. In this study, we first examined the protective effect of MLB on HIRI in mice that underwent 1 h ischemia followed by 6 h reperfusion. MLB pretreatment alleviated the abnormal liver function and hepatocyte damage induced by I/R injury. We found that serum inflammatory cytokines, including IL-6, IL-1β, and TNF-α, were significantly decreased by MLB during hepatic ischemia/reperfusion (I/R) injury, suggesting that MLB may alleviate hepatic I/R injury via inhibiting inflammatory signaling pathways. Second, we investigated the protein level of p-Jak2/Jak2 and p-Stat3/Stat3 using Western blotting and found that MLB could significantly inhibit the activation of the Jak2/Stat3 signaling pathway, which was further verified by AG490 in a mouse model. Finally, the effect of MLB on the Jak2/Stat3 pathway was further assessed in an in vitro model of RAW 264.7 cells; 1 µg/ml LPS induced the secretion of inflammatory mediators, including IL-6, TNF-α, and activation of the Jak2/Stat3 signaling pathway. MLB significantly inhibited the abnormal secretion of inflammatory factors and the activation of the Jak2/Stat3 signaling pathway in RAW264.7 cells. In conclusion, MLB was found for the first time to reduce inflammation induced by hepatic I/R via suppressing the Jak2/Stat3 pathway
Anti-Fibrosis Effects of Magnesium Lithospermate B in Experimental Pulmonary Fibrosis: By Inhibiting TGF-βRI/Smad Signaling
Pulmonary fibrosis is a severe and irreversible interstitial pulmonary disease with high mortality and few treatments. Magnesium lithospermate B (MLB) is a hydrosoluble component of Salvia miltiorrhiza and has been reported to have antifibrotic effects in other forms of tissue fibrosis. In this research, we studied the effects of MLB on pulmonary fibrosis and the underlying mechanisms. Our results indicated that MLB treatment (50 mg/kg) for seven days could attenuate bleomycin (BLM)-induced pulmonary fibrosis by reducing the alveolar structure disruption and collagen deposition in the C57 mouse model. MLB was also found to inhibit transforming growth factor-beta (TGF-β)-stimulated myofibroblastic transdifferentiation of human lung fibroblast cell line (MRC-5) cells and collagen production by human type II alveolar epithelial cell line (A549) cells, mainly by decreasing the expression of TGF-β receptor I (TGF-βRI) and regulating the TGF-β/Smad pathway. Further studies confirmed that the molecular mechanisms of MLB in BLM-induced pulmonary fibrosis mice were similar to those observed in vitro. In summary, our results demonstrated that MLB could alleviate experimental pulmonary fibrosis both in vivo and in vitro, suggesting that MLB has great potential for pulmonary fibrosis treatment
Reprogramming Tumor-Associated Macrophages To Reverse EGFR<sup>T790M</sup> Resistance by Dual-Targeting Codelivery of Gefitinib/Vorinostat
Gefitinib
is a first-line therapy in the EGFR-mutated nonsmall
cell lung cancer (NSCLC). However, the development of drug resistance
is almost unavoidable, thus leading to an unsustainable regimen. EGFR<sup>T790M</sup> mutation is the major cause responsible for the molecular-targeting
therapy failure in NSCLC. Although the recently approved osimertinib
is effective for the EGFR<sup>T790M</sup>-positive NSCLC, the osimertinib-resistant
EGFR mutation is rapidly developed, too. In this study, we proposed
a tumor-associated macrophage (TAM) reprogramming strategy for overcoming
the EGFR<sup>T790M</sup>-associated drug resistance via a dual-targeting
codelivery system of gefitinib/vorinostat that acted on both TAM with
overexpression of mannose receptors and the HER-2 positive NSCLC cells.
The trastuzumab-modified, mannosylated liposomal system was able to
repolarize the protumor M2 phenotype to the antitumor M1 and cause
the elevating ROS in the cancer cells, consequently modulating the
intracellular redox balance via ROS/NOX3/MsrA axis. The suppressed
MsrA facilitated the EGFR<sup>T790M</sup> degradation through 790M
oxidation by ROS, thus resensitizing the EGFR<sup>T790M</sup>-positive
cells to gefitinib. The dual-targeting codelivery and TAM-reprogramming
strategies provided a potential method for rescuing the EGFR<sup>T790M</sup>-caused resistance to tyrosine kinase inhibitor treatment