Adriamycin (ADR) resistance poses a significant challenge for successfully treating breast cancer (BCa). The mechanism underlying intrinsically acquisition of the resistance remains to be fully elucidated. Here, we describe that small extracellular vesicles (sEVs) mediated Hsp70 transfer is implicated in ADR resistance. The resistant cells derived sEVs were incubated with sensitive cells, thereby transmitting the resistant phenotype to the recipient cells. The internalization of the sEVs in the recipient cells and sEV-mediated Hsp70 transfer into mitochondria were examined by confocal microscope and transmission electron microscopy (TEM). Oxygen consumption rate (OCR) incorporated with extracellular acidification rate (ECAR) was quantified by Seahorse XF Analyzer. Mechanistically, sEVs transported Hsp70, leading to increased reactive oxygen species (ROS) and impaired mitochondria in the recipient cells, thereby inhibiting respiration but promoting glycolysis. The sEVs effect on the metabolism of the recipient cells was alleviated by silencing Hsp70 in sEVs donor cells. The aspect of sEV-Hsp70 on drug-resistant transmission was further validated by tumor zebrafish xenografts. The finding from this work suggests that sEV-mediated Hsp70 intercellular delivery enhances ADR resistance mainly through reprogramming the recipient cell energy metabolism.Radiation-induced pulmonary fibrosis (RIPF) is a common complication during thoracic radiotherapy, but there are few effective treatments. Here, we identify IR-780, a mitochondria-targeted near-infrared (NIR) dye, can selectively accumulate in the irradiated lung tissues. Besides, IR-780 significantly alleviates radiation-induced acute lung injury and fibrosis. Furthermore, our results show that IR-780 prevents the differentiation of fibroblasts and the release of pro-fibrotic factors from alveolar macrophages induced by radiation. Besides, IR-780 downregulates the expression of glycolysis-associated genes, and 2-Deoxy-d-glucose (2-DG) also prevents the development of fibrosis in vitro, suggesting radioprotective effects of IR-780 on RIPF might be related to glycolysis regulation. Finally, IR-780 induces tumour cell apoptosis and enhances radiosensitivity in representative H460 and A549 cell lines. These findings indicate that IR-780 is a potential therapeutic small-molecule dye during thoracic radiotherapy.It has been established that 8-oxoguanine DNA glycosylase 1 (OGG1) is the main enzyme removing oxidized guanine under oxidative stress. However, increasing evidence has shown that OGG1 is not only a base excision repair protein but also a new transcriptional coactivator involved in oxidative stress-induced gene expression. Its downstream target genes and the underlying regulatory mechanisms still need to be discerned. Here, it was discovered that c-Myc is a downstream target of OGG1 under oxidative stress and that H4R3me2a is involved in this transcriptional regulation. The increased level of H4R3me2a induced by H2O2 is regulated by OGG1, which may directly interact with the specific arginine methyltransferase PRMT1 and promote the asymmetrical dimethylation of H4R3me1. H4R3me2a enrichment on the promoter of c-Myc can recruit YY1 and activate c-Myc transcription. Moreover, knocking down OGG1 or PRMT1 suppresses c-Myc transcription under oxidative stress by downregulating H4R3me2a formation. Furthermore, the overexpression of wild type (WT) H4R3 promotes c-Myc transcription, but the expression of mutant H4R3Q does not have this effect. Taken together, our data show that the 8-oxoG/OGG1/PRMT1/H4R3me2a/YY1 axis senses oxidative stress and promotes gene transcription.

Our previous findings have demonstrated the protective effect of endothelial Nox4-based NADPH oxidase on atherosclerosis. check details One of the possible mechanisms is the inhibition of soluble epoxide hydrolase (sEH), a proinflammatory and atherogenic factor. Our goal was to investigate whether in vivo inhibition of sEH by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) alleviates endothelial Nox4 dysfunction caused atherosclerosis and the regulatory mechanism of endothelial Nox4 on sEH.

& results We used endothelial human Nox4 dominant-negative (EDN) transgenic mice in ApoE deficient background to mimic the dysfunction of endothelial Nox4 in atherosclerosis-prone conditions. In EDN aortic endothelium, sEH and the inflammatory marker vascular cell adhesion molecule 1 (VCAM1) were upregulated. TPPU reduced atherosclerotic lesions in EDN mice. In EDN endothelial cells (ECs), the endoplasmic reticulum (ER) stress markers (BIP, IRE1α, phosphorylation of PERK, ATF6) were upregulated, and they can be suppressed by ER stress inhibitor 4-phenyl butyric acid (4-PBA). In EDN ECs, 4-PBA downregulated the expression of sEH and VCAM1, suppressed inflammation, and its application in vivo reduced atherosclerotic lesions of EDN mice.

Endothelial Nox4 dysfunction upregulated sEH to enhance inflammation, probably by its induction of ER stress. Inhibition of ER stress or sEH is beneficial to alleviate atherosclerosis caused by endothelial Nox4 dysfunction.

Endothelial Nox4 dysfunction upregulated sEH to enhance inflammation, probably by its induction of ER stress. Inhibition of ER stress or sEH is beneficial to alleviate atherosclerosis caused by endothelial Nox4 dysfunction.Fuchs endothelial corneal dystrophy (FECD) is an age-related disease whereby progressive loss of corneal endothelial cells (CEnCs) leads to loss of vision. There is currently a lack of therapeutic interventions as the etiology of the disease is complex, with both genetic and environmental factors. In this study, we have provided further insights into the pathogenesis of the disease, showing a causal relationship between senescence and endothelial-mesenchymal transition (EMT) using in vitro and in vivo models. Ultraviolet A (UVA) light induced EMT and senescence in CEnCs. Senescent cells were arrested in G2/M phase of the cell cycle and responsible for the resulting profibrotic phenotype. Inhibiting ATR signaling and subsequently preventing G2/M arrest attenuated EMT. In vivo, UVA irradiation induced cell cycle re-entry in post mitotic CEnCs, resulting in senescence and fibrosis at 1- and 2-weeks post-UVA. Selectively eliminating senescent cells using the senolytic cocktail of dasatinib and quercetin attenuated UVA-induced fibrosis, highlighting the potential for a new therapeutic intervention for FECD.