ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2021
·
IF 4.013
Lanqiu Zhang,Hejun Gao,Lei Yang,Tianyu Liu,Qi Zhang,Jing Xun,Caixia Li,Lihua Cui,Ximo Wang
FTY720 is an immunosuppressive agent which has been approved to treat multiple sclerosis (MS). The main object of the present study is to investigate whether FTY720 has the potential to induce the formation of neutrophil extracellular traps (NETs) in vitro. Using Sytox Green assay and fluorescence microscopy , our results showed that FTY720 trigged the NET formation. In contrast to classic NET formation induced by Phorbol 12-myristate 13-acetate (PMA), FTY720-induced NETs were detected earlier and independent of NADPH oxidase (NOX) activity. Pharmacological inhibitor experiments indicated that autophagy was also required for the NET formation induced by FTY720. Moreover, p38 and AKT inhibitor significantly suppressed the NET formation by FTY720, whereas ERK inhibitor had no effect, suggesting that FTY720-induced NETs depended on the activation of p38 and AKT. We further found that citrullination of histone H3 and peptidylarginine deiminase 4 (PAD4) did not mediated FTY720-induced NET formation. Interestingly, necroptosis signaling activation was involved in the vital NET formation by FTY720, however, plasma membrane rupture resulting from necroptosis was not a major component of NET formation described here. Collectively, these findings indicated that FTY720 could be a potential antibacterial drug to protect host against pathogen infection.
研究领域:
免疫学
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细胞生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Cells
·
2023
·Vol. 12
·期 19
·2351
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IF 6
Ziqi Zhou,Yan Zhang,Simin Xia,Xi Chen
Immunosuppressants are emerging as promising candidates for cancer therapy with lower cytotoxicity compared to traditional chemotherapy drugs; yet, the intrinsic side effects such as immunosuppression remain a critical concern. Herein, we introduce a photoactivatable antitumor immunosuppressant called dmBODIPY-FTY720 (BF) that shows no cytotoxicity but can be temporally and locally activated by deep-red light illumination to induce tumor cell apoptosis. To further reduce potential side effects, we integrate BF with another classic photosensitizer called methylene blue (MB) that is activated under the same wavelength of deep-red light (>650 nm) and successfully establish a red-light-activatable AND Boolean logic gate through a mechanism that we found to be synergetic apoptotic induction. At further decreased dosages, deep-red light illumination does not induce cell death in the presence of either BF or MB, but significant cancer cell death is triggered in the presence of both drugs. Therefore, the dosage of BF is further reduced, which will be highly beneficial to minimize any potential side effects of BF. This AND-gated strategy has been successfully applied in vivo for effective suppression of hepatocarcinoma tumors in living mice.Keywords:antitumor immunosuppressant;FTY720;logic gate;BODIPY photocage;red light;photodynamic therapy
研究领域:
癌症治疗
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药理学
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光化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
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2021
·
IF 5.75
Zhang Miao,Hu Yuan,Zhang Jiahui,Zhang Junjian
Vascular dementia (VD) and Alzheimer's disease (AD) are the most prevalent types of late-life dementia. Chronic cerebral hypoperfusion (CCH) contributes to both AD and VD. Recently, accumulating evidence has indicated that fingolimod (FTY720) is neuroprotective in acute cerebral ischemic stroke animal models, and the drug is now being used in clinical translation studies. However, fewer studies have addressed the role of FTY720 in chronic cerebral hypoperfusion (CCH)-related brain damage. In the present study, to investigate whether FTY720 can improve CCH-induced spatial memory loss and its underlying mechanism, two-vessel occlusion (2VO) rats were administered intraperitoneal FTY720 (1 mg/kg) for 7 consecutive weeks from post-operative day 8. Spatial memory was tested using the Morris Water Maze (MWM), and the rats' brains were harvested to allow molecular, biochemical, and pathological tests. We found that FTY720 treatment significantly reduced the escape latency and increased the target quadrant swimming time of the 2VO rats in the MWM task. The improvement in memory performance paralleled lower levels of pro-inflammatory cytokines and Iba-1 positive cells in the hippocampus of the 2VO rats, indicating that FTY720 had a beneficial effect in mitigating neuroinflammation. Furthermore, we found that FTY720 alleviated mitochondrial dysfunction in 2VO rats, as manifested by lower malondialdehyde levels, higher ATP content, and upregulation of ATP synthase activity in the hippocampus after treatment. FTY720 had no effect on the CCH-induced decrease in the activity of hippocampal Sirtuin-3, a master regulator of mitochondrial function and neuroinflammation. In summary, the results showed that FTY720 can improve CCH-induced spatial memory loss. The mechanism may involve Sirtuin-3-independent regulation of mitochondrial dysfunction and neuroinflammation in the hippocampus. The present study provides new clues to the pathological mechanism of CCH-induced cognitive impairment.
研究领域:
神经科学
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药理学
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痴呆症
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2022
·Vol. 35
·期 16
·2207227
·
IF 32.086
Yan-Jia Che,Xiao-He Ren,Zhi-Wei Wang,Qi Wu,Kai Xing,Min Zhang,Chang Xu,Di Han,Shun Yuan,Si-Hao Zheng,Yuan-Yang Chen,Xin-Ru Liao,Feng Shi,Xiao-Han Zhong,Xin Cai,Si-Xue Cheng
The chronic rejection responses and side effects of the systematic administration of immunosuppressants are the main obstacles to heart allograft and patient survival. The development of xenotransplantation also urgently requires more efficient immune regulation strategies. Herein, it is demonstrated that lymph-node (LN)-targeted drug delivery can realize LN-specific immunomodulation with attenuated immune suppression on distant peripheral immune organs to effectively prolong long-term survival after heart transplantation in a chronic murine heart transplantation model. A chemokine C-C motif ligand 21 (CCL21) specific aptamer for LN targeting is decorated onto the surface of the hybrid nanoparticular delivery vector mainly composed of CaCO 3 /CaP/heparin. The targeting delivery system can dramatically enhance accumulation of the loaded immunosuppressant, fingolimod hydrochloride (FTY720), in draining lymph nodes (dLNs) for inducing powerful immune suppression. By promoting the generation of endogenous regulatory T cells (T regs ) and decreasing the proportion of effector T cells (T effs ) in dLNs after heart transplantation, the LN-targeting strategy can effectively regulate local immune responses instead of systemic immunity, which reduces the incidence of long-term complications. This study provides an efficient strategy to improve the survival rate after organ transplantation by precise and localized immunoregulation with minimized side effects of immunosuppression.
研究领域:
药理学
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免疫学
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移植医学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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