RUSSIAN CHEMICAL BULLETIN
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2025
·Vol. 74
·期 3
·807-817
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IF 0
Balakina A. A.,Amozova V. I.,Stupina T. S.,Mumyatova V. A.,Podgurskaya A. D.,Gadomsky S. Ya.
A new method for the synthesis of pyridoxine salts with dicarboxylic acids was proposed. The specific features of the synthesis include the preliminary generation of free pyridoxine from the hydrochloride form by treatment with a solution of triethylamine in chloroform and conduction of the reaction of pyridoxine with dicarboxylic acid in a specially selected solvent mixture. The combination of pyridoxine as a known antioxidant and fumarate as an activator of the transcription factor Nrf2 in one molecule gave rise to a unique structure, bis[3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridinium] fumarate (DPNF). In vitro experiments showed the ability of this compound to bind superoxide, suppress lipid peroxidation processes, and behave as a mitochondrial cytoprotective agent and Nrf2 activator. The results of the study can be used to develop a new type of drugs based on activators of the transcription factor Nrf2 to protect cells and tissues from oxidative damage.
研究领域:
药物化学
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生物化学
·
分子生物学
✓ 已验证
DOI
BIOORGANIC CHEMISTRY
·
2020
·
IF 4.831
Zi-Long Song,Yanan Hou,Feifei Bai,Jianguo Fang
Oxidative stress is constantly involved in the etiopathogenesis of an ever-widening range of neurodegenerative diseases. As a consequence, effective repression of cellular oxidative stress to a redox homeostatic condition is a promising and feasible strategy to treat, or at least retard the progression of, such disorders. Nrf2, a primary orchestrator of cellular antioxidant response machine, is responsible for detoxifying and compensating for deleterious oxidative stress via transcriptional activation of a diverse array of antioxidant biomolecules. In the framework of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we report herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, most of which exhibit robust neuroprotective effect against H 2 O 2 -mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds 9b and 9c with marginal cytotoxicity were selected for the follow-up studies. Our results demonstrate that their neuroprotective effects are attributed to the up-regulation of a panel of antioxidant genes and corresponding gene products. Further mechanistic studies indicate that Nrf2 is indispensable for the cellular performances of 9b and 9c , arising from the fact that silence of Nrf2 gene drastically nullifies their protective action. Taken together, 9b and 9c discovered in this work merit further development as neuroprotective candidates for the treatment of oxidative stress-mediated pathological conditions.
研究领域:
神经科学
·
药物化学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2024
·
IF 3.9
Hong Huang,Ziyan Li,Zhanghua Qi,Linxi Ma,Gang Hu,Changwei Zou,Tingtao Chen
The highly toxic aflatoxin B1 (AFB1) is considered one of the primary risk factors for hepatocellular carcinoma, while effective measures after AFB1 exposure remain to be optimized. This study utilized cell-surface-display technique to construct an engineered S. cerevisiae -pYD1-ScFv-AFB1 (S.C-AF) that specifically binds AFB1, and verified the potential mechanism of S.C-AF in vivo through AFB1-induced (gastric perfused with 0.3 mg/kg/d AFB1 per day) liver injury mouse model. In this experiment, the C57BL/6 mouse model of AFB1-induced liver injury was treated with S.C (gastric perfused with 1 × 10 9 CFU/mL S.C per day) and S.C-AF (gastric perfused with 1 × 10 9 CFU/mL S.C-AF per day) for 4 weeks, respectively. With probiotic properties optimized, S.C.-AF achieved an in vitro AFB1 binding capacity 1.7 times higher than S. cerevisiae. Furthermore, S.C-AF could alleviate AFB1-induced liver injury by reducing proinflammatory cytokine secretion and apoptotic protein expression, enhancing antioxidative capacity via Nrf2 activation, and simultaneously reversing intestinal tight junction protein deficiency, increasing intestinal barrier permeability, and improving intestinal dysbiosis caused by AFB1 exposure. S.C-AF alleviates AFB1-induced liver lesions, which might be a novel intervention to mitigate aflatoxin toxicity.
研究领域:
微生物学
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毒理学
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分子生物学
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胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 7.088
Yuanyuan Wang,Baichen Xiong,Hongzhi Lin,Qi Li,Hongyu Yang,Yuting Qiao,Qihang Li,Ziwei Xu,Weiping Lyu,Wei Qu,Wenyuan Liu,Yao Chen,Feng Feng,Haopeng Sun
Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory ( ee AChE IC 50 = 0.07 ± 0.01 μM; h AChE IC 50 = 0.38 ± 0.04 μM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H 2 O 2 and A β 1-42 aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and A β 1-42 . At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.
研究领域:
神经科学
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药理学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2021
·
IF 4.451
Xiang-Rong Cheng,Piao-Han Tu,Wen-Le Dong,Bu-Tao Yu,Shu-Fang Xia,Mitchell N. Muskat,Bin Guan
Xiaoheiyao , the rhizomes of Inula nervosa Wall., is a culinary spice known to contain some electrophilic Nrf2 activators that could potentially intervene in nonalcoholic fatty liver disease (NAFLD). In this study, the electrophilic components from Xiaoheiyao were annotated by comprehensive cheminformatics analyses on UHPLC-MS/MS data after being knocked out with glutathione (GSH)-immobilized magnetic microspheres. Their intervention effects against hepatic steatosis were investigated in free fatty acid (FFA)-treated HepG2 cells. The electrophilic components in Xiaoheiyao were found to be the major bioactive components preventing hepatic steatosis in FFA-treated HepG2 cells. In particular, 10-isobutyryloxy-8,9-epoxythymol isobutyrate (XHY-1) improved hepatic lipid metabolism disorder, Krebs cycle activity, oxidative phosphorylation, and the cellular and mitochondrial redox status. Moreover, XHY-1 activates the Nrf2-ARE signaling pathway through the up-regulation of Nrf2 expression and promotion of Nrf2 nuclear translocation. Molecular docking further showed that XHY-1 could conjugate with Cys151 in the BTB domain of Keap1 through the epoxy group. In conclusion, the electrophilic components of Xiaoheiyao , especially XHY-1, attenuated hepatic steatosis in FFA-treated HepG2 cells through activation of the Nrf2-ARE signaling pathway.
研究领域:
药理学
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细胞生物学
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分子生物学
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药物化学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2015
·
IF 2.912
Chuanyang Su,Xiaomin Xia,Qiong Shi,Xiufang Song,Juanli Fu,Congxue Xiao,Hongjun Chen,Bin Lu,Zhiyin Sun,Shanmei Wu,Siyu Yang,Xuegang Li,Xiaoli Ye,Erqun Song,Yang Song
Neohesperidin dihydrochalcone (NHDC), a sweetener derived from citrus, belongs to the family of bycyclic flavonoids dihydrochalcones. NHDC has been reported to act against CCl4-induced hepatic injury, but its mechanism is still unclear. We first discovered that NHDC showed a strong ability to scavenge free radicals. In addition, NHDC induces the phase II antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1) through the activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) signaling. Further assays demonstrated that NHDC induces accumulation of Nrf2 in the nucleus and augmented Nrf2-ARE binding activity. Moreover, NHDC inhibits the ubiquitination of Nrf2 and suggests the modification of Kelch-like ECH-associated protein 1 (Keap1) and the disruption of the Keap1/Nrf2 complex. c-Jun N-terminal kinase (JNK) and p38 but not extracellular signal-regulated protein kinase (ERK) phosphorylations were up-regulated by NHDC treatment. Taken together, NHDC showed its protective antioxidant effect against CCl4-induced oxidative damage via the direct free radical scavenging and indirect Nrf2/ARE signaling pathway.
研究领域:
药理学
·
毒理学
·
分子生物学
✓ 已验证
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）