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Empagliflozin reduces oxidative stress through inhibition of the novel inflammation/NHE/[Na+]c/ROS-pathway in human endothelial cells.
Uthman, L, Li, X, Baartscheer, A, Schumacher, CA, Baumgart, P, Hermanides, J, Preckel, B, Hollmann, MW, Coronel, R, Zuurbier, CJ, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112515
Abstract
Inflammation causing oxidative stress in endothelial cells contributes to heart failure development. Sodium/glucose cotransporter 2 inhibitors (SGLT2i's) were shown to reduce heart failure hospitalization and oxidative stress. However, how inflammation causes oxidative stress in endothelial cells, and how SGLT2i's can reduce this is unknown. Here we hypothesized that 1) TNF-α activates the Na+/H+ exchanger (NHE) and raises cytoplasmatic Na+ ([Na+]c), 2) increased [Na+]c causes reactive oxygen species (ROS) production, and 3) empagliflozin (EMPA) reduces inflammation-induced ROS through NHE inhibition and lowering of [Na+]c in human endothelial cells. Human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) were incubated with vehicle (V), 10 ng/ml TNF-α, 1 µM EMPA or the NHE inhibitor Cariporide (CARI, 10 µM) and NHE activity, intracellular [Na+]c and ROS were analyzed. TNF-α enhanced NHE activity in HCAECs and HUVECs by 92% (p < 0.01) and 51% (p < 0.05), respectively, and increased [Na+]c from 8.2 ± 1.6 to 11.2 ± 0.1 mM (p < 0.05) in HCAECs. Increasing [Na+]c by ouabain elevated ROS generation in both HCAECs and HUVECs. EMPA inhibited NHE activity in HCAECs and in HUVECs. EMPA concomitantly lowered [Na+]c in both cell types. In both cell types, TNF α-induced ROS was lowered by EMPA or CARI, with no further ROS lowering by EMPA in the presence of CARI, indicating EMPA attenuated ROS through NHE inhibition. In conclusion, inflammation induces oxidative stress in human endothelial cells through NHE activation causing elevations in [Na+]c, a process that is inhibited by EMPA through NHE inhibition.
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Roles of four feedback loops in mitochondrial permeability transition pore opening induced by Ca^{2+} and reactive oxygen species.
Qi, H, Xu, G, Peng, XL, Li, X, Shuai, J, Xu, R
Physical review. E. 2020;(6-1):062422
Abstract
Transient or sustained permeability transition pore (PTP) opening is important in normal physiology or cell death, respectively. These are closely linked to Ca^{2+} and reactive oxygen species (ROS). The entry of Ca^{2+} into mitochondria regulates ROS production, and both Ca^{2+} and ROS trigger PTP opening. In addition to this feedforward loop, there exist four feedback loops in the Ca^{2+}-ROS-PTP system. ROS promotes Ca^{2+} entering (F1) and induces further ROS generation (F2), forming two positive feedback loops. PTP opening results in the efflux of Ca^{2+} (F3) and ROS (F4) from the mitochondria, forming two negative feedback loops. Owing to these complexities, we construct a mathematical model to dissect the roles of these feedback loops in the dynamics of PTP opening. The qualitative agreement between simulation results and recent experimental observations supports our hypothesis that under physiological conditions the PTP opens in an oscillatory state, while under pathological conditions it opens in a high steady state. We clarify that the negative feedback loops are responsible for producing oscillations, wherein F3 plays a more prominent role than F4; whereas the positive feedback loops are beneficial for maintaining oscillation robustness, wherein F1 has a more dominant role than F2. Furthermore, we manifest that the proper increase in negative feedback strength or decrease in positive feedback strength not only facilitates the occurrence of oscillations and thus protects the system against a high steady state, but also assists in lowering the oscillation peak. This study may provide potential therapeutic strategies in treating neurodegenerative diseases due to PTP dysfunction.
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Mechanisms and Treatments of Oxidative Stress in Atrial Fibrillation.
Ren, X, Wang, X, Yuan, M, Tian, C, Li, H, Yang, X, Li, X, Li, Y, Yang, Y, Liu, N, et al
Current pharmaceutical design. 2018;(26):3062-3071
Abstract
Atrial fibrillation (AF) is a frequent cardiac arrhythmia. It is a common major cause of serious diseases and is an increasing health-care burden. AF is associated with an excess amount of reactive oxygen species. In this review, we summarize several possible reactive oxygen species pathways that induce AF based on atrial electrical and structural remodeling data. The sources and factors implicated in AF-related oxidative stress include NADPH oxidase activation, calcium overloading and mitochondrial damage, angiotensin system activation, nitric oxide synthase uncoupling, and xanthine oxidase activation-associated cardiovascular conditions. Scavenging oxidative stress markers and related substances are essential aspects of these molecular mechanisms, and may be a therapeutic target in AF.
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A novel fluorinated thiosemicarbazone derivative- 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide induces apoptosis in human A549 lung cancer cells via ROS-mediated mitochondria-dependent pathway.
Zhao, Y, Guo, C, Wang, L, Wang, S, Li, X, Jiang, B, Wu, N, Guo, S, Zhang, R, Liu, K, et al
Biochemical and biophysical research communications. 2017;(1):65-71
Abstract
Thiosemicarbazone, a class of compounds with excellent biological activity, especially antitumor activity, have attracted wide attention. In this study, a novel fluorinated thiosemicarbazone derivative, 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide (compound 1) was synthesized and its antitumor activities were further investigated on a non-small cell lung cancer cell line (A549) along with its underlying mechanisms. Compound 1 showed significant anti-proliferative activity on A549 cells, which was further proved by colony formation experiment. Compound 1 also inhibits the invasion of A549 cells in a trans-well culture system. Moreover, compound 1 markedly induced apoptosis on A549 cells, and the ratio of Bcl-2/Bax was decreased while the amount of p53, Cleaved-Caspase 3 and Cleaved-PARP expression were increased significantly. Compound 1 decreased the mitochondrial membrane potential, while the content of reactive oxygen was increased obviously. It is revealed that compound 1 mediated cell cycle arrest in G0/G1 phase by reducing G1 phase dependent proteins, CDK4 and Cyclin D1. As a result, it is indicated that compound 1 induced apoptosis on A549 cells was realized by regulating ROS-mediated mitochondria-dependent signaling pathway.
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ASCT2 (SLC1A5) is an EGFR-associated protein that can be co-targeted by cetuximab to sensitize cancer cells to ROS-induced apoptosis.
Lu, H, Li, X, Lu, Y, Qiu, S, Fan, Z
Cancer letters. 2016;(1):23-30
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Abstract
Therapeutic targeting of ASCT2, a glutamine transporter that plays a major role in glutamine uptake in cancer cells, is challenging because ASCT2 also has a biological role in normal tissues. In this study, we report our novel finding that ASCT2 is physically associated in a molecular complex with epidermal growth factor receptor (EGFR), which is often overexpressed in human head and neck squamous cell carcinoma (HNSCC). Furthermore, we found that ASCT2 can be co-targeted by cetuximab, an EGFR antibody approved for treating metastatic HNSCC. We demonstrated that cetuximab downregulated ASCT2 in an EGFR expression-dependent manner via cetuximab-mediated EGFR endocytosis. Downregulation of ASCT2 by cetuximab led to decreased intracellular uptake of glutamine and subsequently a decreased glutathione level. Cetuximab thereby sensitized HNSCC cells to reactive oxygen species (ROS)-induced apoptosis and, importantly, it is independent of effective inhibition of EGFR downstream signaling by cetuximab. In contrast, knockdown of EGFR by siRNA or inhibition of EGFR kinase with gefitinib, an EGFR kinase inhibitor, failed to sensitize HNSCC cells to ROS-induced apoptosis. Our findings support a novel therapeutic strategy for EGFR-overexpressing and cetuximab-resistant cancers by combining cetuximab with an oxidative therapy.
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Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy.
Zhao, Y, Qu, T, Wang, P, Li, X, Qiang, J, Xia, Z, Duan, H, Huang, J, Zhu, L
Apoptosis : an international journal on programmed cell death. 2016;(5):517-31
Abstract
Macroautophagy (Autophagy), an evolutionarily conserved cellular self-digesting process implicated in various physiological and pathological processes, is activated by different stimuli including oxidative stress. Reactive oxygen species (ROS) are involved in autophagy modulation through multiple signaling pathways and transcription regulators. Accumulating data support both a positive and negative role of ROS-modulated autophagy in cancer. As a tumor suppressive mechanism, autophagy induces autophagic cell death and maintains genome stability. Conversely, autophagy may promote cancer development by limiting metabolic stress and supplying high-energetic nutrients. Mitochondrial ROS (mitoROS), the main source of endogenous ROS, serve as essential signal transducers that mediate autophagy, while autophagy can also regulate mitochondrial ROS generation in turn. Here, we untangle the knot between mitochondrial ROS and autophagy, which may be of great significance to solve the conundrum of the inter-conversion between cytoprotective and cytotoxic roles of autophagy; thus providing new insights for current cancer therapies. Whilst, we focus on anti-tumor agents that target mitoROS-regulated autophagy, in the hope of fueling the exploration of more potential novel anti-cancer drugs in the future.
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Liver X receptor agonist alleviated high glucose-induced endothelial progenitor cell dysfunction via inhibition of reactive oxygen species and activation of AMP-activated protein kinase.
Li, X, Song, Y, Han, Y, Wang, D, Zhu, Y
Microcirculation (New York, N.Y. : 1994). 2012;(6):547-53
Abstract
OBJECTIVE Liver X receptors (LXRs) are key regulators of cholesterol homeostasis. Synthetic LXR agonists are anti-atherogenic and anti-inflammatory. However, the effect of LXR agonists on endothelial progenitor cell (EPC) function is largely unknown. Here, we explored the effect of the LXR agonist TO901317 (TO) on EPC biology and the underlying mechanisms. METHODS Endothelial progenitor cells were cultured in mannitol or 30 mm glucose (high glucose) for 24 hours. For TO treatments, cells were pretreated with TO (10 μm) for 12 hours, then mannitol or high glucose was added for an additional 24 hours. EPCs function, reactive oxygen species (ROS) release, and phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) were analyzed. RESULTS TO could restore the high glucose-impaired adhesion and migration capacity of EPCs. High glucose impaired EPC-mediated angiogenesis, and TO reversed the impairment. TO also alleviated ROS release induced by high glucose. Western blot analysis revealed that high glucose downregulated the phosphorylation of AMPK and endothelial nitric oxide synthase, which could be reversed with TO treatment. Furthermore, inhibiting AMPK activation by compound C could abolish the protective effects of TO on EPCs. CONCLUSIONS TO had a protective effect on EPCs under high glucose by inhibiting ROS release and activating AMPK.