Frontiers in Plant Science
·
2017
·
IF 4.291
Su Ping,Guan Hongyu,Zhang Yifeng,Wang Xing,Gao Linhui,Zhao Yujun,Hu Tianyuan,Zhou Jiawei,Ma Baowei,Tu Lichan,Tong Yuru,Huang Luqi,Gao Wei
Tripterygium wilfordii produces not only ent-kaurene, which is an intermediate of gibberellin (GA) biosynthesis in flowering plants, but also 16α-hydroxy-ent-kaurane, whose physiological role has not been characterized. The two compounds are biosynthesized from the universal diterpenoid precursor (E,E,E)-geranylgeranyl diphosphate (GGPP) by diterpene synthases, which have been discovered and functionally characterized in T. wilfordii. Here, we described the functional characterization of four cytochrome P450 reductases (TwCPR) and one ent-kaurene oxidase (TwKO). Four TwCPRs were found to have relatively ubiquitous expression in T. wilfordii root, stem, leaf, and flower tissues. Co-expression of both a TwCPR and TwKO in yeast showed that TwCPR3 has a slightly better activity for providing the electrons required for these reactions, indicating that TwCPR3 is more suitable for use in the functional analysis of other cytochrome P450 monooxygenases. TwKO catalyzed the three-step oxidation of the C4α methyl of the tetracyclic diterpene intermediate ent-kaurene to form ent-kaurenoic acid as an early step in GA biosynthesis. Notably, TwKO could also convert 16α-hydroxy-ent-kaurane to 16α-hydroxy-ent-kaurenoic acid, indicating an important function of 16α-hydroxy-ent-kaurane in the anti-HIV principle tripterifordin biosynthetic pathway in planta. Homology modeling and molecular docking were used to investigate the unknown crucial active amino acid residue involved in the catalytic reaction of TwKO, and one key residue (Leu387) contributed to the formation of 16α-hydroxy-ent-kaurenoic acid, most likely by forming hydrogen bonds with the hydroxyl group (-OH) of 16α-hydroxy-ent-kaurane, which laid the basis for further investigation of the multifunctional nature of KO catalysis. Also, our findings paved the way for the complete biosynthesis of the anti-HIV principle tripterifordin.
研究领域:
植物生物化学
·
酶学
·
分子生物学
·
生药学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2020
·
IF 8.579
Yue Kuai,Hao Liu,Dongyu Liu,Yunlong Liu,Ye Sun,Jiansheng Xie,Jiachun Sun,Yong Fang,Hongming Pan,Weidong Han
Long-term inflammatory stimulation is considered one of the most important causes of colorectal cancer. Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, can inhibit a variety of inflammatory responses. However, the systemic toxicity of DPI limits its clinical application. Whether DPI can inhibit colitis-associated colorectal cancer (CAC) at ultralow concentrations remains unknown. Methods : CAC was induced by azoxymethane (AOM) injection followed by treatment with dextran sulfate sodium (DSS), and DPI was intraperitoneally injected (i.p.) in the first cycle for 21 days. Colon tissue was collected and analyzed by western blotting. Immune cell infiltration and macrophage polarization were examined by immunohistochemistry, immunofluorescence, or real-time polymerase-chain reaction (PCR). Reactive oxygen species (ROS) production was measured by flow cytometry. Results : Ultralow dose DPI significantly ameliorated the DSS-induced colitis and attenuated the colon tumorigenesis in the mouse model of AOM/ DSS-induced CAC. Mechanistically, an ultralow dose of DPI inhibited the production of pro-inflammatory cytokines, (tumor necrosis factor (TNF)-α and interleukin (IL)-6), reduced the macrophage infiltration and classical polarization, and induced the ROS generation. These effects were found to be related to the inhibition of the phosphorylation of signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF -κB). Conclusion : The present study revealed that an ultralow dose of DPI, with no significant systemic toxicity involved, may be an effective way to prevent the occurrence and development of CAC.
研究领域:
肿瘤学
·
免疫学
·
药理学
·
胃肠病学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Tianyuan Lei,Lefei Han,Yunan Zhang,Ningning Jiang,Dingding Deng,Xiu Wang,Qingqing Wang,Xuliang Guo
The heterogeneous characteristics of cancer determine that monotherapeutic strategies is difficult to deal with various sub-populations of cancer cells, leading to tumor recrudescence and dissemination. The combination of reactive oxygen species (ROS) mediated apoptosis in photodynamic therapy (PDT) and lipid peroxides induced ferroptosis exhibits remarkable potential in overcoming tumor heterogeneity-driven therapeutic resistance. However, the intracellular antioxidant systems involve the glutathione (GSH), reduced thioredoxin (Trx(SH) 2 ), and ubiquinol (CoQ 10 H 2 ) can reduce the potency of interactive therapy. Here, we reported a nitroimidazole-bearing hypoxia-responsive polymeric micelles to deliver model photosensitizer Chlorin e6 (Ce6) for selective ROS induced apoptosis in PDT sensitization and ferroptosis boosting. Upon light irradiation, the hypoxia-responsive micelles encapsulated with Ce6 produced ROS for apoptotic cell death. The ROS could also decrease intracellular concentrations of GSH and hence ferroptotic cell death. Leveraging the hypoxic tumor micro-environment characterized by elevated nitroreductase expression, nitroimidazole moieties undergo a reduction process, leading to a marked depletion in nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) levels. This would further decline the intracellular abundance of GSH, Trx(SH) 2 , and CoQ 10 H 2 attributed to NADPH's critical role in regenerating these vital antioxidants, and then boost ferroptotic cell death. The interactive sensitization of apoptosis and ferroptosis induced by ROS and the depletion of NADPH, GSH, Trx(SH) 2 , and CoQ 10 H 2 was subsequently validated in vivo using the 4T1 tumor xenograft murine model. The present study establishes an innovative strategy for the concurrent sensitization of ROS-driven apoptosis and ferroptosis to achieve efficacious cancer treatment.
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DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Ying Huang,Huisi Zhao,Yu Zhang,Chuanqi Zhao,Jinsong Ren,Xiaogang Qu
The nanozyme with NADPH oxidase (NOX)-like activity can promote the consumption of NADPH and the generation of free radicals. In consideration of that the upregulation of glucose-6-phosphate dehydrogenase (G6PD) would accelerate the compensation production of NADPH, for inhibition of G6PD activity, our designed bioorthogonal nanozyme can in situ catalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone (DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined platform can disrupt NADPH homeostasis, leading to the collapse of the antioxidant defense system in the tumor cells. The enzyme-like activity of PdCuFe is further enhanced when irradiated by NIR-II light. The destruction of NADPH homeostasis can promote ferroptosis and, in turn, facilitate mild photothermal therapy. Our design can realize NADPH depletion and greatly improve the therapeutic effect through metabolic regulation, which may provide inspiration for the design of bioorthogonal catalysis
研究领域:
癌症治疗
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生物医学工程
·
纳米技术
·
生物化学
·
诊疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Translational Psychiatry
·
2025
·
IF 6.2
He Dian,Guo Si-Yi,Yang Yi-Chun,Wang Hai-Yang,Zhang Yi,Mo Xiao-Long,Liu Lan-Xiang,Qin Zheng-Hong,Xie Peng
Our study investigated the role of nicotinamide adenine dinucleotide phosphate (NADPH) in neuroinflammation-associated depression-like behaviors. Using a lipopolysaccharide (LPS)-induced mouse model of depression, we found that NADPH significantly alleviated depressive-like behaviors, including reduced immobility time and increased sucrose preference. Mechanistic exploration revealed that NADPH suppressed microglial activation, downregulated pro-inflammatory cytokine expression (e.g., IL-1β, TNF-α, IFN-γ), and mitigated oxidative stress in the hippocampus, thereby ameliorating neuroinflammation. Furthermore, NADPH preserved myelin integrity, inhibited microglial phagocytosis of myelin and synapses, and preserved synaptic integrity. These findings provide experimental evidence supporting NADPH as a potential antidepressant agent and highlight its critical role in modulating neuroinflammation via dual suppression of cytokine release and microglial hyperactivation.
研究领域:
神经科学
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免疫精神病学
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分子生物学
·
神经药理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Ruiyang Yu,Hui Qiao,Gengcheng Liao,Zongyu Huang,Qiaoliang Bao,Xiang Qi
Here, a photoelectrochemical (PEC) photodetector with good flexibility and high photoresponsivity was successfully fabricated in a vertical structure, where the MXene (Ti2CTx) nanosheet and carbon black electrode were separated by adenosine triphosphate/nicotinamide adenine dinucleotide phosphate (ATP/NADPH)-incorporated solid-state electrolyte. The photocurrent and photoresponsivity can reach 1.84 μA/cm2 and 8.89 μA/W, respectively, under a light intensity of 90 mW/cm2 at a bias potential of 0.6 V, which are approximately 2.3 times those of Ti2CTx nanosheets. The addition of ATP and NADPH to the electrolyte also leads to a large decrease of the rise time from 0.76 to 0.26 s. Furthermore, the photodetector can continue to function and maintain stability under 45° bending and after 500 cycles of bending, indicating a robust device structure and great flexibility. The performance enhancement of the PEC photodetector can be attributed to the synergistic effect of electrolyte additives on Ti2CTx nanosheets, where ATP and NADPH greatly enhance the circulation and utilization of photogenerated carriers. This work suggests that the incorporation of chloroplast-inspired carrier circulation with two-dimensional nanosheets could achieve efficient light-current conversion, providing a new strategy to improve the performance of PEC-type photodetectors.
研究领域:
材料科学
·
光电器件
·
生物启发设计
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2018
·
IF 3.487
Zhengying Su,Zhaoquan Li,Chunmiao Wang,Wei Tian,Fu Lan,Dandan Liang,Junying Li,Danrong Li,Huaxin Hou
Radiation resistance and recurrent have become the major factors resulting in poor prognosis in the clinical treatment of patients with nasopharyngeal carcinoma (NPC). New strategies to enhance the efficacy of radiotherapy have been focused on the development of radiosensitizers and searching for directly targets that modulated tumor radiosensitivity. A novel potential radiosensitizer 1,8-Dihydroxy −3-(2′-(4″-methylpiperazin-1″-yl) ethyl-9,10-anthraquinone −3-carboxylate (RP-4) was designed and synthesized based on molecular docking technology, which was expected to regulate the radiosensitivity of tumor cells through targeting Rac1. In order to assess the radiosensitization activity of RP-4 on NPC cells, the highly differentiated CNE1 and poorly differentiated CNE2 cells NPC lines were employed. According to the results, RP-4 showed higher binding affinity toward the interaction with Rac1 than lead compounds. We found that RP-4 could inhibit cell viability and proliferation in CNE1 and CNE2 cells and significantly induced apoptosis after non-toxic concentration of RP-4 combined with 2Gy irradiation. RP-4 could effectively modulated the radiosensitivity both CNE1 cells and CNE2 cells through activating Rac1/NADPH signaling pathway and its downstream JNK/AP-1 pathway. What's more, Rac1/NADPH signaling pathway were significantly activated in Rac1-overexpressed CNE1 and CNE2 cells after treated with RP-4. Taken together, Rac1 and its downstream pathway may probably be the direct targets of RP-4 in regulating radiosensitivity of NPC cells, our finding provided a novel strategy for the development of therapeutic agents in response to tumorous radiation resistance.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
放射生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Hongbiao Li,Shuai Zhang,Zilong Dong,Xiaoyu Shan,Jingwen Zhou,Weizhu Zeng
Dihydroquercetin is a vital flavonoid compound with a wide range of physiological activities. However, factors, such as metabolic regulation, limit the heterologous synthesis of dihydroquercetin in microorganisms. In this study, flavanone 3-hydroxylase (F3H) and flavanone 3′-hydroxylase (F3′H) were screened from different plants, and their co-expression in Saccharomyces cerevisiae was optimized. Promoter engineering and redox partner engineering were used to optimize the corresponding expression of genes involved in the dihydroquercetin synthesis pathway. Dihydroquercetin production was further improved through multicopy integration pathway genes and systems metabolic engineering. By increasing NADPH and α-ketoglutarate supply, the catalytic efficiency of F3’H and F3H was improved, thereby effectively increasing dihydroquercetin production (235.1 mg/L). Finally, 873.1 mg/L dihydroquercetin titer was obtained by fed-batch fermentation in a 5-L bioreactor, which is the highest dihydroquercetin production achieved through de novo microbial synthesis. These results established a pivotal groundwork for flavonoids synthesis.
研究领域:
生物化学
·
合成生物学
·
代谢工程
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Weiyong Tao,Xiaodan Wu,Jiaqi Li,Feige Wu,Chen Chen,Ting Jiang,Cunjing Xu,Shangtong Jiang,Jianglin Wang,Bo Xiao,Yingying Du,Shengmin Zhang
The anti-cancer effect of selenite (SeO 3 2− ) is limited by its short half-life and narrow therapeutic window. Peroxynitrite (ONOO − ), the most active reactive nitrogen species (RNS) derived from nitric oxide (NO) reacting with superoxide anion (O 2 •− ), is still not fully exploited in the combination therapy against cancers. Herein, an injectable hydrogel is developed to trigger intracellular reactive oxygen species (ROS)/RNS bursts and disrupt nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis via an innovative SeO 3 2− -based strategy. Calcium selenite/ L -Arginine ( L -Arg) nanospheres (SL NPs) are synthesized as the donor of NO and SeO 3 2− . The injectable Alg@SLGA sol composed of SL NPs, glucose oxidase (GOx), 6-aminonicotinamide (6-AN, an inhibitor of the pentose phosphate pathway (PPP)), and sodium alginate (Alg) can convert to gel in a physiological environment. Peritumoral injection of Alg@SLGA hydrogel is performed for safe and targeted treatment. The loaded GOx catalyzes glucose oxidation to produce acidic H 2 O 2 , initiating the release of NO and SeO 3 2− from Alg@SLGA. SeO 3 2− reacts with intracellular GSH and H 2 O 2 to generate •OH and O 2 •− , which further interacts with NO to form ONOO − . The SeO 3 2− and 6-AN synergistically trigger intracellular NADPH exhaustion by promoting cystine metabolism-mediated NADPH consumption and inhibiting NADPH generation, respectively. Moreover, Alg@SLGA effectively induces immunogenic cell death (ICD) of tumor cells, further provoking systemic antitumor immune responses. As a consequence, the injectable Alg@SLGA hydrogel achieves enhanced ROS/RNS-mediated combination therapy by synergistically disrupting NADPH homeostasis and improving antitumor immunity.
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Li Qiao,Jing Zhang,Yongjian Jiang,Bianqin Ma,Haomin Chen,Peng Gao,Pengfei Zhang,Anming Wang,Roger A. Sheldon
Effective photolytic regeneration of the NAD( P )H cofactor in enzymatic reductions is an important and elusive goal in biocatalysis. It can, in principle, be achieved using a near-infrared light (NIR) driven artificial photosynthesis system employing H 2 O as the sacrificial reductant. To this end we utilized TiO 2 /reduced graphene quantum dots (r-GQDs), combined with a novel rhodium electron mediator, to continuously supply NADPH in situ for aldo-keto reductase (AKR) mediated asymmetric reductions under NIR irradiation. This upconversion system, in which the Ti-O-C bonds formed between r-GQDs and TiO 2 enabled efficient interfacial charge transfer, was able to regenerate NADPH efficiently in 64 % yield in 105 min. Based on this, the pharmaceutical intermediate ( R )-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol was obtained, in 84 % yield and 99.98 % ee, by reduction of the corresponding ketone. The photo-enzymatic system is recyclable with a polymeric electron mediator, which maintained 66 % of its original catalytic efficiency and excellent enantioselectivity (99.9 % ee) after 6 cycles.
研究领域:
生物化学
·
光催化
·
合成生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 16
·8871
·
IF 4.9
Rui Feng,Juyi Zhao,Xiaochen Li,Sijun Dong,Dan Ma
Polyacrylamide (PAM) is a high-molecular-weight polymer with extensive applications. However, the inefficient natural degradation of PAM results in environmental accumulation of the polymer. Biodegradation is an environmentally friendly approach in the field of PAM treatment. The first phase of PAM biodegradation is the deamination of PAM, forming the product poly(acrylic acid) (PAA). The second phase of PAM biodegradation involves the cleavage of PAA into small molecules, which is a crucial step in the degradation pathway of PAM. However, the enzyme that catalyzes the degradation of PAA and the molecular mechanism remain unclear. Here, a novel monooxygenase PCX02514 is identified as the key enzyme for PAA degradation. Through biochemical experiments, the monooxygenase PCX02514 oxidizes PAA with the participation of NADPH, causing the cleavage of carbon chains and a decrease in the molecular weight of PAA. In addition, the crystal structure of the monooxygenase PCX02514 is solved at a resolution of 1.97 Å. The active pocket is in a long cavity that extends from the C-terminus of the TIM barrel to the protein surface and exhibits positive electrostatic potential, thereby causing the migration of oxygen-negative ions into the active pocket and facilitating the reaction between the substrates and monooxygenase PCX02514. Moreover, Arg10-Arg125-Ser186-Arg187-His253 are proposed as potential active sites in monooxygenase PCX02514. Our research characterizes the molecular mechanism of this monooxygenase, providing a theoretical basis and valuable tools for PAM bioremediation.
研究领域:
环境科学
·
生物化学
·
分子生物学
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2020
·Vol. 48
·期 5
·345-352
·
IF 3.231
Xiaohua Zhao,Hong Ma,Qiusha Pan,Haiyi Wang,Xingkai Qian,Peifang Song,Liwei Zou,Mingqing Mao,Shuyue Xia,Guangbo Ge,Ling Yang
Doxophylline (DOXO) and theophylline are widely used as bronchodilators for treating asthma and chronic obstructive pulmonary disease, and DOXO has a better safety profile than theophylline. How DOXO’s metabolism and disposition affect its antiasthmatic efficacy and safety remains to be explored. In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative analysis of DOXO metabolism in human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metabolism of DOXO began with a cytochrome P450 (P450)–mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 production was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metabolism in vivo, by non-P450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP+/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metabolism in human.
研究领域:
药理学
·
生物化学
✓ 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）