TOXICOLOGICAL SCIENCES
·
2017
·Vol. 161
·期 2
·431-442
·
IF 4.081
Wang Jia,He Huan,Xiang Chen,Fan Xiao-Yang,Yang Li-Yun,Yuan Lian,Jiang Feng-Lei,Liu Yi
As a novel delocalized lipophilic cation, F16 selectively accumulates in mitochondria of carcinoma cells and shows a broad spectrum of antiproliferative action towards cancer cell lines. In order to reveal the mode of action and molecular mechanism of F16 inducing cytotoxicity, we investigated the effects of F16 on cancer cells and isolated mitochondria relative to its precursor compound (E)-3-(2-(pyridine-4yl)vinyl)-1 H-indole (PVI), which has a similar structure without positive charge. It was found that PVI did not accumulate in mitochondria, and exhibited lower cytotoxicity compared to F16. However, when they were directly incubated with mitochondria, both F16 and PVI were observed to induce damage to mitochondrial structure and function. Moreover, it was found that F16 as well as PVI acted as uncouplers on mitochondria, and further rescue experiments revealed that the addition of adenosine 5′-triphosphate was the most effective way to recover the cell viability decreased by F16. Thus it was concluded that the decreased intracellular adenosine 5′-triphosphate availability induced by the uncoupling effect of F16 was a major factor in F16-mediated cytotoxicity. Futhermore, the results indicated that the uncoupling effect of F16 is attributed to its chemical stucture in common with PVI but independent of its positive charge. The study may shed light on understanding the underlying mechanism of action for F16, and providing suggestions for the design of new mitochondria-targeted antitumor molecules.
研究领域:
肿瘤学
·
分子生物学
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药理学
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DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-13
·
IF 7
Jiang Xiaoxiao,Fan Zhijin,Zhang Zhenzhen,Zeng Fanchu,Sun Tong,Li Yuchen,Huang Guojia,Nie Liming
Tumor cells balance ATP production and carbon skeleton synthesis by flexibly altering catabolic pathways to sustain their significant growth advantage. Uncouplers have shown potential for tumor suppression by converting chemical energy from catabolism into heat. However, their use may be limited due to indiscriminate metabolic interference in both tumor and normal cells, as well as the uncertainty surrounding their effects on the immune microenvironment. Herein, we found that low-dose uncoupler BAM15 promoted AMPK, AKT signaling, and the TCA cycle without increasing cell proliferation or inducing cell death in vitro, suggesting an increase in futile cycling. Intratumoral injection of 50 ng/mL BAM15 accelerated catabolic processes while inhibiting anabolic pathways, resulting in a metabolomic reshaping with increased levels of linoleic acid, C5DC, and others. These changes were shown to enhance tumor-killing effects by T cells. To reduce side effects on normal tissues and improve tumor retention, BAM15 was targeted for delivery by loading it into TCVs. This TCV-BAM15 treatment significantly increased CD8+ T cell counts and granzyme B levels. Our findings highlight a previously unrecognized therapeutic effect and signaling mechanism of low-dose BAM15 treatment in tumors. We propose that this novel strategy holds promise as a tumor immunity therapy with fewer adverse effects compared to free uncoupling drugs at high concentrations.
研究领域:
肿瘤学
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免疫学
·
生物化学
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药理学
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DOI
PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2024
·
IF 5.9
Yecheng Wang,Caiyun Huang,Xiaoying Wang,Rong Cheng,Xue Li,Jiahao Wang,Lu Zhang,Fuhao Li,Hao Wang,Xinyu Li,Yi Li,Yiqing Xia,Jian Cheng,Xiaofan Pan,Jia Jia,Guo-dong Xiao
Aims: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. Results: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophage, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream AMP-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I or AMPK abolished the therapeutic effects of succinate following ICH. Innovation and Conclusion: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate. Key words: succinate; uncoupling protein 2; microglia; neuroinflammation; intracerebral hemorrhage
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Lu-Yao Zheng,Yan-Xin Da,Xiu Luo,Xiao Zhang,Zhi-Jie Sun,De-Li Dong
Sorafenib is a targeted anticancer drug in clinic. Low-dose sorafenib has been reported to activate AMPK through inducing mitochondrial uncoupling without detectable toxicities. AMPK activation has been the approach for extending lifespan, therefore, we investigated the effect of sorafenib on lifespan and physical activity of C. elegans and the underlying mechanisms. In the present study, we found that the effect of sorafenib on C. elegans lifespan was typically hermetic. Sorafenib treatment at higher concentrations (100 μM) was toxic but at lower concentrations (1, 2.5, 5 μM) was beneficial to C. elegans . Sorafenib (1 μM) treatment for whole-life period extended C. elegans lifespan and improved C. elegans physical activity as manifested by increasing pharyngeal pumping and body movement, preserving intestinal barrier integrity, muscle fibers organization and mitochondrial morphology. In addition, sorafenib (1 μM) treatment enhanced C. elegans stress resistance. Sorafenib activated AMPK through inducing mitochondrial uncoupling in C. elegans . Sorafenib treatment activated DAF-16, SKN-1, and increased SOD-3, HSP-16.2, GST-4 expression in C. elegans . Sorafenib treatment induced AMPK-dependent autophagy in C. elegans . We conclude that low-dose sorafenib protects C. elegans against aging through activating AMPK/DAF-16 dependent anti-oxidant pathways and stimulating autophagy responses. Low-dose sorafenib could be a strategy for treating aging and aging-related diseases.
研究领域:
药理学
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老年学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2018
·Vol. 6
·期 10
·1531-1542
·
IF 4.776
Jiaojiao Huang,Chenghong Sun,Dandan Yao,Chong-Zhi Wang,Lei Zhang,Yu Zhang,Lina Chen,Chun-Su Yuan
In the search for novel efficient nNOS–PSD-95 (nitric oxide synthase–postsynaptic density protein-95) uncouplers from natural products for stroke treatment, highly selective surface molecular imprinted polymers based on sandwich structured magnetic mesoporous silica (Fe3O4@nSiO2@mSiO2@MIPs, MMS@MIPs) were designed and optimized as artificial antibodies. The resultant polymers exhibited satisfactory adsorption performance and excellent recyclability, and were successfully utilized as sorbents to capture candidate uncouplers from natural products. Furthermore, the biological activity and the functional mechanism of the obtained candidates were investigated in vivo and in vitro. Consequently, coptisine, chelerythrine and nitidine chloride presented both potent neuroprotective effects on glutamate-injured PC12 cells and uncoupling activity targeting nNOS–PSD-95 in vitro. Simultaneously, they effectively ameliorated neurological deficit and reduced infarct volume of MCAO/R (middle cerebral artery occlusion and reperfusion) rats. Therefore, coptisine, chelerythrine and nitidine chloride were considered the most promising nNOS–PSD-95 uncouplers for further preclinical studies of ischemic stroke treatment.
研究领域:
药理学
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材料科学
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神经科学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Tao Peng,Xu Lu,Yang Jin,Xicheng Yang,Qian Liu,Chen Chen,Wanting Zhou,Yuting Guo,Yu Zhang,Yankun Gao,Hongjuan Zhang,Hongliang He,Lina Chen
It is effective through uncoupling postsynaptic density protein-95 (PSD95) and neuronal nitric oxide synthase (nNOS) for treating ischemic stroke with high disability, mortality and recurrence rate. However, there are no reliable uncouplers for PSD95-nNOS in clinical practice, and the established screening models for discovering PSD95-nNOS uncouplers have high costs and interference. In this study, epoxy functional fluorescent magnetic mesoporous silica (EFMMS) was synthesized by combining carbon dots (CDs), magnetic mesoporous silica and epoxy functionalization. Ni-EFMMS was further constructed by loading nickel ions to simultaneously purify and covalently immobilize His-tagged neuronal nitric oxide synthase (His-nNOS) and then couple with green fluorescent proteins (GFP) labeled PSD95, finally fabricating nano-biosensor (PSD95-nNOS/Ni-EFMMS). The nanomaterial was well constructed and characterized, and it distinctly constituted stable ratio fluorescence between CDs and GFP-PSD95. The ratio fluorescence intensity of PSD95-nNOS/Ni-EFMMS remained stable even after separately mixing with metal ions, amino acids and natural impurities, and the loss of ratio fluorescence intensity was less than 20% even at pH 4 or 10. PSD95-nNOS/Ni-EFMMS still kept the ratio fluorescence intensity above 90% after being recycled for seven times. Three compounds (gnetol, baicalein and emodin-8- O -β- D -glucoside) with strong uncoupling efficiency were screened from fourteen natural active ingredients. Furthermore, the theoretical feasibility of uncoupling was verified by molecular docking. In general, this study provides a novel “one-stone-four-birds strategy” to fabricate magnetic mesoporous nano-ratio fluorescence sensor for efficiently and accurately discovering PSD95-nNOS uncoupling active substances.
研究领域:
神经生物学
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药物化学
·
生物传感技术
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DOI
高影响因子
JOURNAL OF SEPARATION SCIENCE
·
2017
·Vol. 40
·期 17
·3522-3534
·
IF 2.557
Xiaoli Gu,Jiaojiao Huang,Lei Zhang,Yu Zhang,Chong-Zhi Wang,Chenghong Sun,Dandan Yao,Fei Li,Lina Chen,Chun-Su Yuan
In the scope of stroke treatment, new neuronal nitric oxide synthase–postsynaptic density protein-95 uncouplers from herbal medicines were discovered and captured. To do so, highly selective magnetic molecularly imprinted polymers with a core–shell structure were prepared as artificial antibodies. According to the results of computational simulations, we designed and synthesized various polymers with varying amounts and types of template, functional monomer, cross-linker, and solvent. Characterization and performance tests revealed that the most appropriate artificial antibodies showed uniform spherical morphologies, large adsorption capacities, fast-binding kinetics, high selectivity, and quick separation. These artificial antibodies were then used as sorbents for dispersive magnetic solid-phase extraction coupled with high-performance liquid chromatography and mass spectrometry to capture and identify structural analogs to ZL006 from extracts of Scutellariae radix, Psoraleae fructus, and Trifolium pratense. Furthermore, according to the neuroprotective effect and coimmunoprecipitation test, Baicalein, Neobavaisoflavone, Corylifol A, and Biochanin A can be the potential uncouplers of neuronal nitric oxide synthase–postsynaptic density protein-95. Therefore, this present study contributes valuable information for the discovery of neuronal nitric oxide synthase–postsynaptic density protein-95 uncouplers from herbal medicines.
研究领域:
药理学
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神经科学
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分析化学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2018
·
IF 2.831
Dandan Yao,Lei Zhang,Jiaojiao Huang,Chenghong Sun,Yu Zhang,Xiaoli Gu,Chong-Zhi Wang,Fei Li,Lina Chen,Chun-Su Yuan
In this work, surface magnetic molecularly imprinted polymers (SMMIPs) were synthesized and used as artificial receptors in the dispersive magnetic solid phase extraction (DMSPE) for capturing potential neuronal nitric oxide synthase–post synaptic density protein-95 (nNOS–PSD-95) uncouplers, which is known as neuroprotection against stroke. Factors that affected selective separation and adsorption of the artificial receptors, such as the amount of template, the types of functional monomer and porogen solvents, and the molar ratio of template/functional monomer/cross-linker were optimized. The artificial receptors were also characterized using fourier transformed infrared, scanning electron microscope, thermal gravimetric analysis and physical property measurement systems. Multiple interactions between template and SMMIPs led to larger binding capacities, faster binding kinetics, quicker separation abilities and more efficient selectivity than the surface magnetic nonimprinted polymers (SMNIPs). The SMMIPs were successfully applied to capture potential nNOS–PSD-95 uncouplers from complex samples, and eight compounds were seized and confirmed rapidly when combined with HPLC and MS. The detection of the new nNOS–PSD-95 uncouplers ranged from 0.001 to 1.500 mg/mL with correlation coefficients of 0.9990–0.9995. The LOD and LOQ were 0.10–0.68 μg/mL and 0.47–2.11 μg/mL, respectively. The neuroprotective effect and co-immunoprecipitation test in vitro revealed that Emodin-1- O -β- d -glucoside, Rhaponticin, Gnetol and 2,3,5,4′-Tetrahydroxystilbene-2- O -β- d -glucoside have neuroprotective and uncoupling activities, and that they may be the new uncouplers of nNOS–PSD-95
研究领域:
药理学
·
分析化学
·
神经科学
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DOI
PubMed
高影响因子
PEST MANAGEMENT SCIENCE
·
2022
·Vol. 78
·期 6
·2240-2249
·
IF 4.462
Tan Dai,Zhiwen Wang,Xingkai Cheng,Huige Gao,Li Liang,Pengfei Liu,Xili Liu
BACKGROUND Fungicide resistance has become a serious problem for different mode of action groups except for uncouplers, which makes their resistance mechanism a hot topic, which until now, has not been well clarified. SYP-14288, a newly developed diarylamine fungicide modeled on fluazinam, has shown good toxicity to both oomycete and fungus by the action of uncoupling. In this research, the resistance of Phytophthora capsici to SYP-14288 was studied to clarify the resistance mechanism of uncouplers. RESULTS The toxicity tests of resistant strains against SYP-14288 showed multidrug resistance. The high-performance liquid chromatography (HPLC) results showed that resistant strains could efflux the fungicide, and this ability could be inhibited by the efflux pump inhibitor amitriptyline. The target protein of amitriptyline is P-glycoprotein (P-gp), which was overexpressed in resistant strains. Three products of nitrate reduction of SYP-14288 were detected and determined by HPLC-Q-TOF. Eight cytochrome P450 monooxygenase (P450) proteins were differentially involved in the reduction reaction. CONCLUSION Both fungicide efflux and detoxification metabolism were involved in the resistance mechanisms of P. capsici to SYP-14288. © 2022 Society of Chemical Industry.
研究领域:
植物病理学
·
分子生物学
·
杀菌剂科学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2019
·Vol. 23
·期 3
·2174-2183
·
IF 4.658
Haiman Mu,Haiwen Liu,Jiayi Zhang,Jianhua Huang,Chen Zhu,Yue Lu,Yueping Shi,Yi Wang
In addition to the known antitumour effects of ursolic acid (UA), increasing evidence indicates that this molecule plays a role in cardiac protection. In this study, the effects of ursolic acid on the heart in mice treated with doxorubicin (DOX) were assessed. The results showed that ursolic acid improved left ventrical fractional shortening (LVFS) and left ventrical ejection fraction (LVEF) of the heart, increased nitrogen oxide (NO) levels, inhibited reactive oxygen species (ROS) production and decreased cardiac apoptosis in mice treated with doxorubicin. Mechanistically, ursolic acid increased AKT and endothelial nitric-oxide synthase (eNOS) phosphorylation levels, and enhanced eNOS expression, while inhibiting doxorubicin induced eNOS uncoupling through NADPH oxidase 4 (NOX4) down-regulation. These effects of ursolic acid resulted in heart protection from doxorubicin-induced injury. Therefore, ursolic acid may be considered a potential therapeutic agent for doxorubicin-associated cardiac toxicity in clinical practice.
研究领域:
药理学
·
心脏病学
·
分子生物学
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DOI
PubMed
高影响因子
ACS Sustainable Chemistry & Engineering
·
2020
·
IF 7.632
Xia Hua,GenLai Du,Jian Han,Yong Xu
A basic scheme of using 2,4-dinitrophenol (2,4-DNP) as an uncoupler between electron transport chain and oxidative phosphorylation for the biochemical regulation of Gluconobacter oxydans (G. oxydans) is raised. Under the weakly acidic environment, the lipophilic 2,4-DNP as an uncoupling agent destroys the electrochemical proton (H+) gradient in mitochondria, which leads to a loss of the driving force for adenosine triphosphate (ATP) synthesis. Based on the main enzyme system of G. oxydans, four typical substrates were studied for exploring the biochemical effects of uncoupling on the cells. As a result, it was found that under uncoupling conditions, cells receive a feedback signal of ATP deficiency, which promotes the utilization of catabolized substrates such as sorbitol and glucose through the substrate level phosphorylation pathway in order to make up for the deficiency of ATP. The proposal of strategy has a further understanding of the basic biochemical knowledge of G. oxydans and lays a theoretical foundation for the directional regulation of G. oxydans.
研究领域:
生化工程
·
微生物生物技术
·
代谢工程
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产品关联
DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Le Wang,Zhaobin Lei,Guanjie Zhang,Yang Cheng,Mingwei Zhong,Guangyong Zhang,Sanyuan Hu
The escalating incidence of metabolic pathologies such as obesity and diabetes mellitus underscores the imperative for innovative therapeutics targeting lipid metabolism modulation. Within this context, augmenting thermogenic processes in adipose cells emerges as a viable therapeutic approach. Given the limitations of previous β3-adrenergic receptor (β3-AR) agonist treatments in human diseases, there is an increasing focus on therapies targeting the β2-adrenergic receptor (β2-AR). Olodaterol (OLO) is a potent β2-AR agonist that is a potential novel pharmacological candidate in this area. Our study explores the role and underlying mechanisms of OLO in enhancing brown adipose thermogenesis, providing robust evidence from in vitro and in vivo studies. OLO demonstrated a dose-dependent enhancement of lipolysis, notably increasing the expression of Uncoupling Protein 1 (UCP1) and raising the rate of oxygen consumption in primary brown adipocytes. This suggests a significant increase in thermogenic potential and energy expenditure. The administration of OLO to murine models noticeably enhanced cold-induced nonshivering thermogenesis. OLO elevated UCP1 expression in the brown adipose tissue of mice. Furthermore, it promoted brown adipocyte thermogenesis by activating the β2-AR/cAMP/PKA signaling cascades according to RNA sequencing, western blotting, and molecular docking analysis. This investigation underscores the therapeutic potential of OLO for metabolic ailments and sheds light on the intricate molecular dynamics of adipocyte thermogenesis, laying the groundwork for future targeted therapeutic interventions in human metabolic disorders.
研究领域:
药理学
·
代谢学
·
内分泌学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）