MOLECULAR CELL
·
2025
·
IF 16.6
Jianfeng He,Yongyi Zhu,Zichao Tian,Mengqin Liu,Anmin Gao,Wangmi Fu,Fei Lu,Yutong Sun,Yajun Guo,Rongqing Pan,Yuchen Ji,Jianxiang Chen,Huasong Lu,Juan Lin,Xingguo Liang,Chun Kim,Chun Zhou,Huipeng Jiao
Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) regulates cell death and inflammation by sensing left-handed double-helical nucleic acids, including Z-RNA and Z-DNA. However, the physiological conditions that generate Z-form nucleic acids (Z-NAs) and activate ZBP1-dependent signaling pathways remain largely elusive. In this study, we developed a probe, Zα-mFc, that specifically detected both Z-DNA and Z-RNA. Utilizing this probe, we discovered that inhibiting spliceosome causes nuclear accumulation of Z-RNA:DNA hybrids, which are sensed by ZBP1 via its Zα domains, triggering apoptosis and necroptosis in mammalian cells. Furthermore, we solved crystal structures of the human or mouse Zα1 domain complexed with a 6-bp RNA:DNA hybrid, revealing that the RNA:DNA hybrid adopts a left-handed conformation. Our findings demonstrate that the spliceosome acts as a checkpoint preventing accumulation of Z-RNA:DNA hybrids, which potentially function as endogenous ligands activating ZBP1-dependent cell death pathways.
研究领域:
分子生物学
·
免疫学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2025
·
IF 30.9
Yu-Zhang Wang,Wei-Hai Chen,Zi-Yi Han,Shi-Man Zhang,Ping Ji,Cheng Zhang,Jun-Long Liang,Xian-Zheng Zhang
Bacteria-based metabolic therapy has been acknowledged as a promising strategy for tumor treatment. However, the insufficient efficiency of wild-type bacteria severely restricts their therapeutic efficacy. Here, we elaborately develop an ʟ-cyst(e)ine-addicted bacteria-nanodrug biohybrid for metabolic therapy through a dual-selection directed evolution strategy. Our evolved strain exhibits a 36-fold increase in ʟ-cystine uptake and a 23-fold improvement in total activity of cysteine desulfhydrases compared with the wild-type strain. By conjugating with DMXAA-loaded liposomes, the engineered bacteria-nanodrug biohybrid not only prevents the influx of nutrients into the tumor by blocking neovasculature but also achieves efficient and durable CySS catabolism locally. The unavailable of Cys species disrupts redox homeostasis and strikingly increases intracellular ROS level, achieving favorable therapeutic outcomes in multiple tumor models. Our study not only highlights the promise of directed evolution strategy in enhancing the stability and efficiency of bacteria-based living biocatalyst but also provides new opportunities for antitumor metabolic therapy.
研究领域:
生物医学工程
·
肿瘤学
·
合成生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Environmental Chemical Engineering
·
2024
·
IF 7.4
Qi Zhu,Fei Feng,Zhong-er Long,Yunhong Huang,Haiyan Ni,Xueqin Fu,Longhai Dai,Long Zou
Microbial reduction is an economical and environmentally benign route to deal with high-toxic Cr 6+ widely present in aquatic environments, but faces major challenges such as cytotoxicity and insufficient organic electron donors. Herein, we propose a route for the removal of Cr 6+ from water using a ternary FeS/reduced graphene oxide/ Shewanella oneidensis MR-1 (FeS/rGO/MR-1) hybrid with external electricity supply at an electrode potential of −0.36 V. The biohybrid with excellent redox activity is in-situ biosynthesized by virtue of the versatile metabolic pathway and powerful extracellular electron transfer ability of MR-1 cells without the need of organic carbon sources. The biohybrid is directly used to remove Cr 6+ under the condition of continuous electricity input, the removal rate is negatively correlated with the applied electrode potential. Compared with binary FeS/MR-1 and rGO/MR-1 counterpart, the FeS/rGO/MR-1 hybrid achieves an improved ability to remove Cr 6+ at an initial concentration of 20 mg L −1 in three consecutive batches due to the synergistic effect. The FeS is the main active component for rapid chemical reduction of Cr 6+ because of its highly reducible Fe 2+ and S 2- , and rGO acts as the bridge to accelerate electron transfer from the applied electrode to MR-1 cells. Then, the MR-1 cells use the obtained electrons for FeS regeneration, which in turn reduces Cr 6+ again, resulting in the precipitation of less toxic Cr 3+ [Cr(OH) 3 and Cr 2 O 3 ] in the biohybrid. This study provides a feasible route for removal of toxic Cr 6+ from water lacking organic electron donor by in-situ synthesis of biohybrid with external electricity supply.
研究领域:
环境科学
·
微生物学
✓ 已验证
DOI
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2022
·
IF 14.224
Huilei Wang,Yilin Le,Jianzhong Sun
Widespread application of synthetic dyes could generate colored wastewaters causing a range of serious environmental problems. Due to the complex nature of effluents from textile industries , it is difficult to obtain satisfactory treatment of dyes-contaminated wastewater using one single method. Biohybrids coupling of photocatalysts and biocatalysts have great potential in environmental purification. However, how to select suitable organisms and enhance the hybrid’s catalytic activities remain challenging. Here, a novel biohybrid system ( Clostridium thermocellum -CdS), created for light-driven biodecolorization under thermophilic treatment by using non-photosynthetic microorganism C. thermocellum self-photosensitized with CdS nanoparticles was established. The biohybrids exhibited remarkable decolorization effects on triphenylmethane dyes. The highest decolorization rate was 0.206 min −1 . More importantly, enhanced catalytic activities of cadmium sulfide (CdS)-based biohybrids by controlling the particle sizes of semiconductors were demonstrated. Biohybrids systems ( Clostridium thermocellum -CdS) through the self-precipitation of CdS with different particle sizes not only showed dramatic changes in the optical properties but also exhibited a very different decolorization rate. This work can not only further broaden targeted applications of CdS-based biohybrids but also demonstrate a promising route for improving biohybrids corresponding photocatalytic capabilities through in situ precipitation CdS with different particle sizes.
研究领域:
环境科学
·
微生物学
·
光催化
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2020
·
IF 2.463
Meng-qiu Song,Wei Min,Jing Wang,Xin-Xin Si,Xiu-Jun Wang,Yu-Wei Liu,Da-Hua Shi
Twelve carbazole-coumarin hybrids were synthesized and biologically evaluated as dual binding site acetylcholinesterase inhibitors. The structures of the carbazole-coumarin hybrids were confirmed by IR, NMR, HRMS and single-crystal X-ray diffraction studies. The compound 3j had the crystal system of triclinic and the space group of P-1. The cholinesterase inhibitory activity of synthesized compounds was measured using colorimetric Ellman's method. Compound 3h exhibited good acetylcholinesterase (AChE) inhibitory activity (IC 50 value of 6.72 μ M) and a high selectivity over butyrylcholinesterase (BuChE). Compound 3k showed the best BuChE inhibitory activity with the IC 50 of 0.50 μM. The SAR studies revealed that the linker length played a crucial role in determining AChE inhibitory activity and the structure of the coumarin moieties affected the BuChE-inhibition activities of the hybrids. Molecular docking study of compound 3h indicated that it interacts with the crucial amino acids present at the catalytic active site and peripheral anionic site of AChE. Compound 3h would be a promising drug candidate to treat AD as a selective and dual binding site inhibitor of AChE.
研究领域:
药物化学
·
神经科学
·
有机化学
✓ 已验证
DOI
高影响因子
POLYMERS FOR ADVANCED TECHNOLOGIES
·
2016
·Vol. 27
·期 10
·1376-1382
·
IF 1.823
Naipu He,Yue Wang,Zhenwu Lu
The temperature-responsive poly (N, N-diethylacrylamide) (pDEAAm) with narrower molecular weight distribution was prepared by the atom transfer radical polymerization and characterized by 1 HNMR and gel permeation chromatography. The temperature-responsive “tadpole-shaped” BSA–pDEAAm hybrids were fabricated via a free Cys-34 residue of bovine serum albumin (BSA) site specifically binding to the end group disulfide bonds of pDEAAm and characterized by native-polyacrylamide gel electrophoresis (Native-PAGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry. Their temperature-responsive behaviors were measured by ultraviolet-visible spectra (UV-Vis). The lower critical solution temperature (LCST) of the pDEAAm was identified as 28°C, and the LCST of BSA–pDEAAm hybrids was identified as 31°C. The morphologies of BSA–pDEAAm hybrids self-assembled in the aqueous solutions with two different temperatures at 25 °C and 40°C were investigated by transmission electron microscopy. Below the LCST of BSA–pDEAAm hybrids, the separate spherical nanoparticles were observed. In contrast, bundles and clusters were observed above the LCST of BSA–pDEAAm hybrids. The results suggested that the self-assembly morphology of BSA–pDEAAm hybrids depended upon the pDEAAm block in BSA–pDEAAm hybrids, and the morphology transitions were effected by the LCST of BSA–pDEAAm hybrids. It would be expected to be used in biomedicine and materials science. Copyright © 2016 John Wiley & Sons, Ltd.
研究领域:
高分子化学
·
材料科学
·
生物医学工程
✓ 已验证
DOI
高影响因子
STRUCTURE
·
2023
·
IF 5.7
Jin Dong,Han Xiao,Jia-Nan Chen,Bai-Feng Zheng,Yu-Ling Xu,Meng-Xi Chen,Wen-Chao Yang,Hong-Yan Lin,Guang-Fu Yang
4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and α7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.
研究领域:
药理学
·
药物化学
·
结构生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2021
·Vol. 26
·期 5
·1303
·
IF 4.412
Yingda Zang,Ke Liu,Weiping Wang,Chuangjun Li,Jie Ma,Jingzhi Yang,Xinyi Chen,Xiaoliang Wang,Dongming Zhang
The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63–4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore,6bdcould cross the blood–brain barrier in vitro. More importantly, compared to edaravone,6bdhad stronger free-radical scavenging activity. Molecular docking studies revealed that6bdcould interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate6bdas a leading structure worthy of further investigation.Keywords:Alzheimer’s disease;Claulansine F–donepezil hybrids;AChE inhibitory activity;free-radical scavenging activity;neuroprotective effects
研究领域:
药理学
·
神经科学
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2019
·
IF 6.35
Wei Li,Qi Zhang,Yijia Wang,Yanyan Ma,Zhanchen Guo,Zhen Liu
Molecularly imprinted polymers (MIPs) and aptamers, as effective mimics of antibodies, can overcome only some drawbacks of antibodies. Since they have their own advantages and disadvantages, the combination of MIPs with aptamers could be an ideal solution to produce hybrid alternatives with improved properties and desirable features. Although quite a few attempts have been made in this direction, a facile and controllable approach for the preparation of aptamer–MIP hybrids still remains lacking. Herein, we present a new approach for facile and controllable preparation of aptamer–MIP hybrids for high-specificity and high-affinity recognition toward proteins. An aptamer that can bind the glycoprotein alkaline phosphatase (ALP) with relative weak affinity and specificity was used as a ligand, and controllable oriented surface imprinting was carried out with an in-water self-polymerization system of dopamine. A thin layer of polydopamine was formed to cover the template to an appropriate thickness. After removing the template from the polymer, an aptamer–MIP hybrid with apparently improved affinity and specificity toward ALP was obtained, giving cross-reactivity of 3.2–5.6% and a dissociation constant of 1.5 nM. With this aptamer–MIP hybrid, a plasmonic immunosandwich assay (PISA) was developed. Reliable detection of ALP in human serum by the PISA was demonstrated.
研究领域:
生物材料
·
分析化学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2022
·
IF 3.461
Peng Liu,Maojun Cheng,Jie Guo,Duanyuan Cao,Jinchong Luo,Yang Wan,Yuanying Fang,Yi Jin,Sai-Sai Xie,Jing Liu
Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer’s disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE ( hu BuChE IC 50 = 1.20 μM, hu AChE IC 50 = 177.49 μM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for hu BuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs.
研究领域:
药理学
·
神经科学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Feiyu Li,Peipei Zhu,Bingzhu Zheng,Zijie Lu,Chao Fang,Yike Fu,Xiang Li
Intrinsic characteristics of microorganisms, including non-specific metabolism sites, toxic byproducts and uncontrolled proliferation constrain their exploitation in medical applications such as tumor therapy. Here, we report an engineered biohybrid that can efficiently target cancerous sites through a pre-determined metabolic pathway to enable precise tumor ablation. In this system, DH5α Escherichia coli is engineered by the introduction of hypoxia-inducible promoters and lactate oxidase genes, and further surface-armored with iron-doped ZIF-8 nanoparticles. This bioengineered E. coli can produce and secrete lactate oxidase to reduce lactate concentration in response to hypoxic tumor microenvironment, as well as triggering immune activation. The peroxidase-like functionality of the nanoparticles extends the end product of the lactate metabolism, enabling the conversion of hydrogen peroxide (H 2 O 2 ) into highly cytotoxic hydroxyl radicals. This, coupled with the transformation of tirapazamine loaded on nanoparticles to toxic benzotriazinyl, culminates in severe tumor cell ferroptosis. Intravenous injection of this biohybrid significantly inhibited tumor growth and metastasis. This article is protected by copyright. All rights reserved
研究领域:
生物技术
·
癌症治疗
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2021
·
IF 15.881
Jia-Wei Wang,Qi-Wen Chen,Guo-Feng Luo,Zi-Yi Han,Wen-Fang Song,Juan Yang,Wei-Hai Chen,Xian-Zheng Zhang
The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is Shewanella oneidensis MR-1 and MDH is MIL-101 metal–organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed via the integration of doxorubicin (DOX)-loaded metal–organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe3+, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe3+ to Fe2+ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe2+ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe3+, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.
研究领域:
生物技术
·
癌症治疗
·
纳米技术
·
生物化学
·
药学
✓ 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）