TOXICOLOGY
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2017
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IF 3.582
Chuanyang Su,Zixuan Liu,Yawen Wang,Yuxin Wang,Erqun Song,Yang Song
The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is the most important cellular defense mechanisms against oxidative attack. BTB and CNC homology-1 (Bach1), like Kelch-like ECH-associated protein 1 (Keap1), is one of a negative regulator of Nrf2 that control antioxidant response elements (ARE)-dependent gene expressions. In the current study, we found that quinones show greater capacity than hydroquinones in nuclear Bach1 export, as well as ubiquitin-dependent Bach1 degradation in our experimental time frame. Consistently, quinones are easier than hydroquinones in Nrf2 activation and ARE-driven antioxidant protein expressions. Considering the redox cycling potential of quinone-hydroquinone couple, we investigated the effect of transit metal oxidation on the regulation of Nrf2 activity. As shown, Fe 3+ enhanced hydroquinone-induced Nrf2 activation and ARE-driven gene expressions, suggesting quinones rather than hydroquinone activate Nrf2 through Bach1 arylation. Taking together, our investigation illustrated that the electrophilic character of quinones ensure their conjugation with Bach1, which is important for the downregulation of Bach1 and the upregulation of Nrf2 signaling.
研究领域:
生物化学
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分子生物学
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细胞信号传导
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氧化应激
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2021
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IF 8.128
Yaxin Zhou,Qian Du,Qingyun Zhao,Mengzhu Zhang,Xiaohan Qin,Yue Jiang,Yuxia Luan
Non-small cell lung cancer (NSCLC) is a type of cancer dominated by metastasis-induced death. The transcription factor BTB and CNC homology 1 (Bach1) regulates almost all metastasis steps by activating the transcription of critical metastatic genes. It is urgent to engineer a nanodrug enabling regulation of Bach1 against tumor metastasis. Herein, a minimalist nanodrug integrating chemodynamic therapy (CDT) and Bach1 degradation was reported to prevent metastasis of NSCLC. The nanodrug was achieved by self-assembly of ferrocene (Fc) and Tin protoporphyrin IX (TinPPIX). In our nanodrug, Fc not only triggers the production of highly cytotoxic ∙OH for tumor ablation via Fenton reaction, but also induces heme release from heme-containing proteins to stimulate Bach 1 degradation. Moreover, TinPPIX further augments the free heme level along with amplifies the CDT efficacy by disabling heme oxygenase-1 (HO-1)-mediated heme conversion into antioxidative bilirubin . The results showed that, compared with control group, TinPPIX/Fc nanodrug caused a four-fold increase in heme level, which triggered remarkable Bach1 degradation in Fbxo22-mediated manner and successfully inhibited Bach1-dominated metastasis. Therefore, this nanodrug could powerfully impeded NSCLC progression and metastasis, offering an innovative heme-regulatable chemodynamic therapeutic approach for lung cancer with strong metastasis capability.
研究领域:
肿瘤学
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分子生物学
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纳米医学
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TOXICOLOGY
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2016
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IF 3.817
Chuanyang Su,Qiong Shi,Xiufang Song,Juanli Fu,Zixuan Liu,Yawen Wang,Yuxin Wang,Xiaomin Xia,Erqun Song,Yang Song
Our previous studies demonstrated that tetrachlorobenzoquinone (TCBQ), an active metabolite of pentachlorophenol, has effects on the generation of reactive oxygen species (ROS) and oxidative stress in vitro and in vivo . Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a cellular sensor of electrophilic or oxidative stress that regulates the expression of antioxidant enzymes and defensive proteins. We have illustrated that TCBQ activates Nrf2 signaling by promoting the formation of the Kelch-like ECH-associated protein 1 (Keap1) cross-linking dimer and the formation of an ubiquitination switch from Nrf2 to Keap1. The activation of Nrf2 by TCBQ may serve as an adaptive response to a TCBQ-induced oxidative insult. BTB and CNC homolog 1 (Bach1) compete with Nrf2, leading to the negative regulation of the antioxidant response element (ARE). In this report, we propose that TCBQ induces the dynamic inactivation of Bach1. We observed a rapid nuclear efflux of Bach1 and an accumulation of Nrf2 in nuclei upon TCBQ treatment that precedes the binding of Nrf2 with ARE. We found that the nuclear export of Bach1 is dependent on its chromosomal region maintenance 1 (Crm1) interaction and tyrosine phosphorylation. Although TCBQ induces the ubiquitination of Bach1, TCBQ also increases the mRNA and protein levels of Bach1, returning Bach1 to normal levels. Moreover, we found that TCBQ-induced activation of Nrf2 involves c-Jun N-terminal kinase (JNK)-P62 signaling.
研究领域:
分子生物学
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细胞信号传导
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毒理学
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氧化应激
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高影响因子
ARCHIVES OF TOXICOLOGY
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2024
·
IF 4.8
Wang Yanwei,Qiu Jingru,Yan Hua,Zhang Nan,Gao Shixuan,Xu Ning,Wang Cuiyan,Lou Haiyan
Doxorubicin (DOX) is one of the most frequently used chemotherapeutic drugs belonging to the class of anthracyclines. However, the cardiotoxic effects of anthracyclines limit their clinical use. Recent studies have suggested that ferroptosis is the main underlying pathogenetic mechanism of DOX-induced cardiomyopathy (DIC). BTB-and-CNC homology 1 (Bach1) acts as a key role in the regulation of ferroptosis. However, the mechanistic role of Bach1 in DIC remains unclear. Therefore, this study aimed to investigate the underlying mechanistic role of Bach1 in DOX-induced cardiotoxicity using the DIC mice in vivo (DOX at cumulative dose of 20 mg/kg) and the DOX-treated H9c2 cardiomyocytes in vitro (1 μM). Our results show a marked upregulation in the expression of Bach1 in the cardiac tissues of the DOX-treated mice and the DOX-treated cardiomyocytes. However, Bach1 −/− mice exhibited reduced lipid peroxidation and less severe cardiomyopathy after DOX treatment. Bach1 knockdown protected against DOX-induced ferroptosis in both in vivo and in vitro models. Ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, significantly alleviated DOX-induced cardiac damage. However, the cardioprotective effects of Bach1 knockdown were reversed by pre-treatment with Zinc Protoporphyrin (ZnPP), a selective inhibitor of heme oxygenase-1(HO-1). Taken together, these findings demonstrated that Bach1 promoted oxidative stress and ferroptosis through suppressing the expression of HO-1. Therefore, Bach1 may present as a promising new therapeutic target for the prevention and early intervention of DOX-induced cardiotoxicity.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
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Journal of Inflammation Research
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2021
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IF 6.922
Yongqing Cai,Bin Li,Dan Peng,Xianfeng Wang,Pan Li,Mingchun Huang,Haiyan Xing,Jianhong Chen
Background Nrf2-Bach1 antioxidant signaling pathway is considered as one of the most important mechanisms of cellular resistance to oxidative injury. The effect of hyperoside (Hyp) on the expression and distribution of Bach1, the relationship of Hyp’s antioxidative effect and the influence of Bach1 remains unclear. Purpose The aim of this study was to investigate the role and mechanisms of Bach1 in the protective effect of Hyp on oxidative liver injury. Methods The protective effect of Hyp on oxidative stress injury was observed in vivo and in vitro. Next, the influence of Hyp on Bach1 expression and distribution, and competitive combination of Nrf2-Bach1 with ARE in H 2 O 2 -induced L02 cell was studied by Western blot, RT-PCR, immunofluorescence and CHIP assay. Finally, the expressions of Crm1, ERK and p38 and their roles on Hyp mediated nuclear export of Bach1 were investigated by Western blot. Results Hyp ameliorated the pathological damage, reduced the liver index, AST, ALT and MDA activities, and increased SOD and GSH levels in the CCl 4 -induced acute liver injury mouse model. Hyp attenuated H 2 O 2 -induced oxidative stress injury in L02 cells. Hyp promoted the early rapid redistribution of Bach1 from nucleus to cytoplasm. CHIP analyses demonstrated that Hyp enhanced the levels of Nrf2-ARE complex, and weakened the levels of Bach1-ARE complex within three hours. In addition, Hyp enhanced transport protein Crm1 expression and ERK1/2 activity. And LMB, a Crm1 inhibitor, attenuated the effect of Hyp on Bach1 nuclear export and anti-oxidation. U0126, an ERK1/2 inhibitor, reduced the effect of Hyp on Crm1 expression and the Bach1 redistribution. Conclusion The hepatoprotective mechanism of Hyp was related to improve Bach1 nuclear export depending on ERK1/2-Crm1 to upregulate the level of Nrf2 binding to ARE.
研究领域:
药理学
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肝病学
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分子生物学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2026
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IF 7.5
Wen-yuan Zhang,Qian-qian Wei,Tao Zhang,Chunmei Geng,Hai-yan Wu,Chang-shui Wang,Jing Chen,Lei Feng,Pei Jiang
Background and Purpose Despite breakthroughs in immunotherapy and targeted therapies, chemotherapy remains indispensable in oncology. Experimental Approach This study seeks to pinpoint key pathways in doxorubicin (DOX)-treated mouse hippocampus, utilising comprehensive transcriptomic and metabolomic analyses, and validating the mechanisms in vitro and in vivo. Key Results Our multi-omics investigation revealed that sustained DOX exposure induced significant down-regulation of 5-aminolevulinate synthase 2 (ALAS2) and its catalytic product 5-aminolevulinic acid (5-ALA) in the hippocampal region. ALAS2 deficiency was specific to hippocampal neurons, which were more sensitive to oxidative damage than astrocytes or microglia. In vivo and in vitro studies demonstrated that 5-ALA administration or ALAS2 overexpression protected the brain from DOX-induced neurotoxicity. ALAS2 catalyses the condensation of glycine and succinyl-CoA to form 5-ALA, the key precursor of haem. Beyond its role in erythropoiesis, haem is a metabolite that modulates cellular redox homeostasis through interactions with the BACH1 (BTB and CNC homology 1)/NRF2 (nuclear factor erythroid 2 like 2) pathway. We found that DOX suppressed the ALAS2/5-ALA axis, thereby enhancing BACH1 stability. This stabilised BACH1 competes with NRF2 for binding to antioxidant response elements (AREs) in target gene promoters. Conversely, reinforcing the ALAS2/5-ALA axis elevated intracellular haem levels, promoting BACH1 degradation and enhancing NRF2 activity. Using a zebrafish model, we further highlighted the antioxidant and neuroprotective role of 5-ALA against DOX-induced neurotoxicity. Conclusions and Implications In conclusion, this study elucidates a novel endogenous neuroprotective mechanism wherein the ALAS2/5-ALA axis modulates the BACH1/NRF2 pathway. 5-ALA shows promise for repurposing to mitigate chemotherapy-associated neurotoxicity. Graphical
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高影响因子
GENOME BIOLOGY
·
2022
·Vol. 23
·期 1
·1-29
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IF 17.906
Li Conghui,Yin Zhinang,Xiao Ruijing,Huang Beili,Cui Yali,Wang Honghong,Xiang Ying,Wang Lingrui,Lei Lingyu,Ye Jiaqin,Li Tianyu,Zhong Youquan,Guo Fangteng,Xia Yuchen,Fang Pingping,Liang Kaiwei
Background G-quadruplexes (G4s) are unique noncanonical nucleic acid secondary structures, which have been proposed to physically interact with transcription factors and chromatin remodelers to regulate cell type-specific transcriptome and shape chromatin landscapes.Results Based on the direct interaction between G4 and natural porphyrins, we establish genome-wide approaches to profile where the iron-liganded porphyrin hemin can bind in the chromatin. Hemin promotes genome-wide G4 formation, impairs transcription initiation, and alters chromatin landscapes, including decreased H3K27ac and H3K4me3 modifications at promoters. Interestingly, G4 status is not involved in the canonical hemin-BACH1-NRF2-mediated enhancer activation process, highlighting an unprecedented G4-dependent mechanism for metabolic regulation of transcription. Furthermore, hemin treatment induces specific gene expression profiles in hepatocytes, underscoring the in vivo potential for metabolic control of gene transcription by porphyrins.Conclusion sThese studies demonstrate that G4 functions as a sensor for natural porphyrin metabolites in cells, revealing a G4-dependent mechanism for metabolic regulation of gene transcription and chromatin landscapes, which will deepen our knowledge of G4 biology and the contribution of cellular metabolites to gene regulation.
研究领域:
分子生物学
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表观遗传学
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转录调控
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代谢
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Ke Gong,Jiangtao Lin,Xiaoyan Chen,Yi Duan,Jiali Zhang,Jian Yu,Jing Wang,Ruifang Sun,Jie Li,Yourong Duan
In esophageal cancer (EC), clinical specimen testing has uncovered a significant increase in BTB and CNC homolog 1 (BACH1) expression and a shift towards an immunosuppressive environment, alongside a notable decrease in p53 protein expression. Therefore, therapeutic strategies focusing on BACH1 inhibition and p53 upregulation appear promising. Traditional oral treatments for EC lack precision and efficacy. Here, we propose a novel approach employing tumor-targeted nanoparticles (NPs) for drug delivery. However, the formation of a drug reservoir at the esophageal site, crucial for the sustained release of therapeutics, presents significant challenges in nano-delivery systems for EC treatment. To address this, we developed a thermosensitive hydrogel composed of F127 and tannic acid, serving as a vehicle for NP loading. These NPs, synthesized through the emulsion/volatization methods of mPEG-PLGA-PLL-cRGD, facilitate in situ drug delivery. Upon contacting esophageal tissue, the hydrogel transitions to a gel, adhering to the lining and enabling sustained release of encapsulated therapeutics. The formulation encompasses NPs laden with small interfering RNA targeting BACH1 (siBACH1) and the p53 activator PRIMA-1, creating a cohesive gel-nano system. Preliminary biological assessments demonstrate that this injectable, thermosensitive gel-nano system adheres effectively to esophageal tissue and targets EC cells. For better modeling clinical outcomes, a patient-derived organoid xenograft (PDOX) model was innovated, involving transplantation of EC-derived organoids into humanized mice, reconstructed with peripheral blood mononuclear cells (PBMCs). Post-treatment analysis showed substantial EC growth inhibition (89.51% tumor inhibition rate), significant BACH1 level reduction, restored anti-tumor immune responses, and pronounced tumor apoptosis. In summary, our study introduces a thermosensitive gel-nano system for EC treatment via restoring p53 activity and boosting T-cell immunity, with potential for clinical application.
研究领域:
肿瘤学
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药学
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生物技术
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免疫学
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Scientific Reports
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2026
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IF 4.9
Zhang Panpan,Zhang Xun,Ma Siyu,Jiang Mengqiang,Zhao Wenhong
Astaxanthin (ATX), a natural antioxidant whose benefits in age-related liver and kidney damage remain unclear. We established a D-galactose-induced ageing model in rats and observed the daily behaviour of the rats. Using staining methods to detect ROS, apoptosis and histopathological changes in liver and brain tissue. Determination of antioxidant levels of IL-2, IL-6 and AGES in rats. Assessment of cognitive function using the Morris water maze and ChAT. The mRNA and protein expression levels of Nrf2, Bach1, SOD1, SOD2, HO-1 were determined by real-time PCR and Western blotting. To investigate the role of the Nrf2/Bach1-ARE pathway, we used ML385, a specific inhibitor of the Nrf2 pathway, to treat rats in the inhibitor group. Aging rats showed impaired learning and memory, along with decreased levels of neurotransmitters and antioxidant enzymes. ATX and vitamin E (VE) interventions significantly alleviated these symptoms and activated the Nrf2/Bach1-ARE pathway in liver and brain tissues of aged SD rats. Furthermore, the protective effects of ATX were attenuated by the addition of the Nrf2 inhibitor ML385. ATX reduces oxidative stress and ameliorates liver and brain damage in aged rats via activation of the Nrf2/Bach1-ARE pathway.
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