Bioengineered
·
2021
·
IF 3.269
Shanzhi Wan,Zhimin Liu,Yang Chen,Zhitao Mai,Mingming Jiang,Qingguo Di,Baohua Sun
MicroRNA (miR)-140-3p has been proved to repress lung adenocarcinoma (LUAD), and our study aims to further evaluate the mechanism. Bioinformatic analyses were performed. The viability, proliferation, migration, invasion and angiogenesis of transfected LUAD cells were all determined via Cell Counting Kit-8, colony formation, Scratch, Transwell, and tube formation assays. The targeting relationship between miR-140-3p and thymidylate synthetase (TYMS) was confirmed by dual-luciferase reporter assay. Relative expressions of miR-140-3p, TYMS, epithelial-to-mesenchymal transition- (E-cadherin, N-cadherin, vimentin), angiogenesis- (vascular endothelial growth factor (VEGF)), and apoptosis-related factors (cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax)) were quantified by quantitative real-time polymerase chain reaction or Western blot. TYMS was high-expressed yet miR-140-3p was low-expressed in LUAD cells. Upregulation of miR-140-3p inhibited TYMS expression, viability, colony formation, migration, invasion, and tube length within LUAD cells, while downregulation of miR-140-3p did oppositely. Silenced TYMS, the downstream target gene of miR-140-3p, reversed the effects of miR-140-3p downregulation on TYMS expression, cell viability, colony formation, migration, invasion, and tube length as well as the metastasis-, apoptosis- and angiogenesis-related proteins in LUAD cells. Upregulation of miR-140-3p inhibited the proliferation, migration, invasion and angiogenesis of LUAD cells via targeting TYMS.
研究领域:
肿瘤学
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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
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2024
·
IF 3.3
Bo Cai,Zelin He,Dandan Liu,Yuping Zhang,Zikang Yin,Weijia Bao,Qiaoyi Le,Ju Shao,Hongyan Du,Ligang Jie
The elevated risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) have a higher mortality rate compared to the general population due to abnormal platelet activation. Thymidine phosphorylase (TYMP) plays a crucial role in platelet activation and thrombosis, following bridging the link between RA and CVD. Data from Gene Expression Omnibus (GEO) database exhibited that TYMP levels were highly expressed in synovial tissues, immune cells, and whole blood of RA patients especially those with high levels of inflammation. Platelet count (PLT) and plateletcrit (PCT) were positively correlated with the severity of inflammation in rheumatoid arthritis while platelet distribution width (PDW) and mean platelet volume (MPV) were adverse. Levels of CD62P and TYMP in platelets of patients with active RA were significantly elevated compared to patients in the inactive phase. In vivo experiments showed that reducing TYMP expression levels of platelets could relieve inflammation in Adjuvant-Induced Arthritis (AIA) mice. Platelet activation was significantly elevated in AIA model mice, along with increased levels of intracellular calcium (Ca 2+ ), reactive oxygen species (ROS), and decreased Mitochondrial Membrane Potential (ΔΨm). However, treatment with Tipiracil hydrochloride (TPI) or the utilization of Tymp −/− mice reversed these effects. In vitro stimulation of wild type (WT) mouse platelets with tumor necrosis factor-alpha (TNF-α) promoted platelet activation, elevated levels of intracellular Ca 2+ as well as ROS while decreased ΔΨm. Platelets of WT mice treated with TPI or platelets of Tymp −/− mice exhibited the adverse results. Our study illustrates the vital role of TYMP in promoting RA inflammation and platelet activation, suggesting that TYMP may be a potential therapeutic target for RA.
研究领域:
免疫学
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分子生物学
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风湿病学
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DOI
PubMed
高影响因子
Transboundary and Emerging Diseases
·
2024
·Vol. 2024
·期 1
·7063673
·
IF 3.5
Yuqian Jia,Zhiwan Zheng,Bingqing Yang,Haijie Zhang,Zhiqiang Wang,Yuan Liu
The dissemination of antimicrobial resistance (AMR) severely degrades the performance of antibiotics and constantly paralyzes the global health system. In particular, plasmid-mediated transfer of antibiotic resistance genes (ARGs) across bacteria is recognized as the primary driver. Therefore, antiplasmid transfer approaches are urgently warranted to resolve this intractable problem. Herein, we demonstrated the potential of azidothymidine (AZT), an FDA-approved anti-HIV drug, as a broad-spectrum horizontal transfer inhibitor to effectively prevent the transmission of multiple ARGs, including mcr-1 , bla NDM−5 , and tet (X4), both in vitro and in vivo . It was also noteworthy that the inhibitory effect of AZT was proved to be valid within and across bacterial genera under different mating conditions. Mechanistic studies revealed that AZT dissipated bacterial proton motive force, which was indispensable for ATP synthesis and flagellar motility. In addition, AZT downregulated bacterial secretion systems involving general and type IV secretion systems (T4SS). Furthermore, the thymidine kinase, which is associated with DNA synthesis, turned out to be the potential target of AZT. Collectively, our work demonstrates the broad inhibitory effect of AZT in preventing ARGs transmission, opening new horizons for controlling AMR.
研究领域:
微生物学
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药理学
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传染病学
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DOI
高影响因子
BRITISH JOURNAL OF CANCER
·
2022
·Vol. 128
·期 2
·219-231
·
IF 9.075
Yang Bingxue,Xie Xinran,Lv Dazhao,Hu Jiajun,Chen Yuyun,Wu Zhaoyu,Luo Shuyue,Zhang Shiyi
Background Hand-foot syndrome (HFS) is a serious dose-limiting cutaneous toxicity of capecitabine-containing chemotherapy, leading to a deteriorated quality of life and negative impacts on chemotherapy treatment. The symptoms of HFS have been widely reported, but the precise molecular and cellular mechanisms remain unknown. The metabolic enzyme of capecitabine, thymidine phosphorylase (TP) may be related to HFS. Here, we investigated whether TP contributes to the HFS and the molecular basis of cellular toxicity of capecitabine. Methods TP-/- mice were generated to assess the relevance of TP and HFS. Cellular toxicity and signalling mechanisms were assessed by in vitro and in vivo experiments. Results TP-/- significantly reduced capecitabine-induced HFS, indicating that the activity of TP plays a critical role in the development of HFS. Further investigations into the cellular mechanisms revealed that the cytotoxicity of the active metabolite of capecitabine, 5-DFUR, was attributed to the cleavage of GSDME-mediated pyroptosis. Finally, we demonstrated that capecitabine-induced HFS could be reversed by local application of the TP inhibitor tipiracil. Conclusion Our findings reveal that the presence of elevated TP expression in the palm and sole aggravates local cell cytotoxicity, further explaining the molecular basis underlying 5-DFUR-induced cellular toxicity and providing a promising approach to the therapeutic management of HFS.
研究领域:
肿瘤学
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药理学
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细胞生物学
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毒理学
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DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2023
·
IF 4.4
Jun-Hu Cheng,Xinxue Zhang,Ji Ma,Da-Wen Sun
Tropomyosin (TM) is the main allergen in shellfish. Developing a novel, simple and accurate method to track and detect TM in food products is necessary. In this work, a label-free fluorescent aptasensor based on polythymidine (poly(T))-templated copper nanoclusters (CuNCs) was designed for sensitive detection of TM in processed shrimp products. Magnetic beads (MBs), aptamer and cDNA were used to construct an MBs-aptamer@cDNA complex as a detection probe, and with the presence of TM, the poly(T)-templated CuNCs attached at the end of the cDNA as the fluorescent signal was released from the complex to turn on the fluorescence. Under optimal conditions, the poly(T)-templated CuNCs aptasensor achieved a linear range from 0.1 to 50 μg/mL (R 2 = 0.9980), a low limit of detection of 0.0489 μg/mL and an excellent recovery percentage of 105.29%-108.91% in the complex food matrix, providing a new approach for food safety assurance.
研究领域:
食品科学
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纳米技术
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分析化学
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过敏原检测
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DOI
PubMed
高影响因子
Synthetic and Systems Biotechnology
·
2025
·
IF 4.4
Dandan Feng,Tianshu Zhang,Guan Zhou,Yanli Cao,Quan Luo,Huifang Xu,Xuefeng Lu
2′-Deoxy-2′-fluoroadenosine (2′-F-dA) is a nucleoside analogue used as a key building block for oligonucleotide drugs. It can be biosynthesized from a low-cost 2′-deoxy-2′-fluorouridine via one-pot transglycosylation catalyzed by a thymidine phosphorylase (TP) and a purine nucleoside phosphorylase (PNP). However, reliance on purified enzymes and low space-time yields present challenges for industrial application of the process. Here, we develop a whole-cell-based biocatalytic system employing TP and PNP from Escherichia coli , which demonstrates high catalytic efficiency and operational simplicity in scaled-up reaction. In particular, a thermal pretreatment of TP- and PNP-expressing whole cells, determined as 50 °C for 3 h, effectively suppressed endogenous deamination side reaction while enhancing 2′-F-dA yield. Subsequent optimization of enzyme and substrate loadings and their relative ratios achieved an unprecedented space-time yield of 1.22 g/L/h with 88.1 g/L product titer in a 500 mL scaled-up reaction, manifesting a highest total conversion of 68.2 %. An integrated purification process yielded gram-scale solid powder of 2′-F-dA with 98.0 % chemical purity and 85.0 % recovery. This novel whole-cell biocatalytic process demonstrates significant industrial potential for the production of 2′-F-dA.
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高影响因子
Small
·
2016
·Vol. 12
·期 43
·5944-5953
·
IF 8.315
Qianwen Ding,Qiuqiang Zhan,Xiaoming Zhou,Tao Zhang,Da Xing
Remote optical detection and imaging of specific tumor-related biomarkers and simultaneous activation of therapy according to the expression level of the biomarkers in tumor site with theranostic probes should be an effective modality for treatment of cancers. Herein, an upconversion nanobeacon (UCNPs-MB/Dox) is proposed as a new theranostic nanoprobe to ratiometrically detect and visualize the thymidine kinase 1 (TK1) mRNA that can simultaneously trigger the Dox release to activate the chemotherapy accordingly. UCNPs-MB/Dox is constructed with the conjugation of a TK1 mRNA-specific molecular beacon (MB) bearing a quencher (BHQ-1) and an alkene handle modified upconversion nanoparticle (UCNP) through click reaction and subsequently loading with a chemotherapy drug (Dox). With this nanobeacon, quantitative ratiometric upconversion detection of the target with high sensitivity and selectivity as well as the target triggered Dox release in vitro is demonstrated. The sensitive and selective ratiometric detection and imaging of TK1 mRNA under the irradiation of near infrared light (980 nm) and the mRNA-dependent release of Dox for chemotherapy in the tumor MCF-7 cells and A549 cells are also shown. This work provides a smart and robust platform for gene-related tumor theranostics.
研究领域:
纳米技术
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癌症生物学
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分子影像
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治疗诊断学
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DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2022
·
IF 9.231
Yi Wu,Minhua Zong,Zhenhui Zhang,Yongtai Wu,Lin Li,Xia Zhang,Hong Wu,Bing Li
Advanced glycation end-products (AGEs) are a chemically heterogeneous set of modifications widely found in processed foods. Due to uncertain bioavailability, dietary AGEs regulate energy homeostasis through mechanisms that largely remain unclear. In this study, selective transmembrane transport of AGEs with different modification types from glycated β-casein digest were identified and compared. The results showed that only a few types of free and peptide-bound AGEs can easily cross the Caco-2 monolayers and thus exert their effects. A combination of biochemical assays, mitochondrial analyses, and comparative experiments identified that the effect of AGEs on cellular energy homeostasis comes mainly from their free fractions. Mechanistically, free AGEs arrest the mitochondrial differentiation and mtDNA repair by intervening in the function of thymidine phosphorylase, and interfering with mitochondrial energy production by inhibiting the activation of AMPK-SIRT6 signaling pathway. These results demonstrate mechanisms by which processed foods cause mitochondrial dysfunction and lead to dysfunctional energy homeostasis.
研究领域:
营养学
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细胞生物学
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代谢学
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食品科学
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DOI
PubMed
高影响因子
BIOTECHNOLOGY LETTERS
·
2017
·Vol. 39
·期 12
·1903-1910
·
IF 1.73
Liu Ke,Zhou Youzhi,Zhang Jinsong,Chu Jianlin,Zhang Yewei,He Bingfang
Objective To isolate a thermostable pyrimidine nucleoside phosphorylase (PyNP) from mesophilic bacteria by gene mining. Results
Bb PyNP from Brevibacillus borstelensis LK01 was isolated by gene mining. Bb PyNP had a highest 60% identity with that of reported PyNPs. Bb PyNP could catalyze the phosphorolysis of thymidine, 2′-deoxyuridine, uridine and 5-methyuridine. Bb PyNP had good thermostability and retained 73% of its original activity after 2 h incubation at 50 °C. Bb PyNP had the highest activity at an optimum alkaline pH of 8.5. Bb PyNP was stable from pH 7 to 9.8. Under preliminary optimized conditions, the biosynthesis of various 5-halogenated pyrimidine nucleosides by Bb PyNP reached the yield of 61–84%. Conclusion An efficient approach was estimated in isolating thermostable PyNP from mesophilic bacteria.
研究领域:
生物化学
·
酶学
·
生物技术
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PubMed
高影响因子
WORLD JOURNAL OF MICROBIOLOGY & BIOTECHNOLOGY
·
2023
·Vol. 39
·期 10
·1-9
·
IF 4.1
Xu Lian,Li Hui-Min,Lin Juan
2’-deoxyguanosine is a key medicinal intermediate that could be used to synthesize anti-cancer drug and biomarker in type 2 diabetes. In this study, an enzymatic cascade using thymidine phosphorylase from Escherichia coli ( Ec TP) and purine nucleoside phosphorylase from Brevibacterium acetylicum ( Ba PNP) in a one-pot whole cell catalysis was proposed for the efficient synthesis of 2’-deoxyguanosine. Ba PNP was semi-rationally designed to improve its activity, yielding the best triple variant Ba PNP-Mu3 (E57A/T189S/L243I), with a 5.6-fold higher production of 2’-deoxyguanosine than that of wild-type Ba PNP ( Ba PNP-Mu0). Molecular dynamics simulation revealed that the engineering of Ba PNP-Mu3 resulted in a larger and more flexible substrate entrance channel, which might contribute to its catalytic efficiency. Furthermore, by coordinating the expression of Ba PNP-Mu3 and Ec TP, a robust whole cell catalyst W05 was created, capable of producing 14.8 mM 2’-deoxyguanosine (74.0% conversion rate) with a high time-space yield (1.32 g/L/h) and therefore being very competitive for industrial applications.
研究领域:
生物技术
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药物化学
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酶学
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分子生物学
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DOI
PubMed
高影响因子
Inorganic Chemistry Frontiers
·
2020
·Vol. 7
·期 5
·1220-1228
·
IF 5.958
Xiao-Jing Ding,Ran Zhang,Rui-Ping Liu,Xue-Qing Song,Xin Qiao,Cheng-Zhi Xie,Xiu-He Zhao,Jing-Yuan Xu
A series of Pt(IV) compounds comprising a special short-chain fatty acid (a histone deacetylase inhibitor) and 5-FU (a thymidylate synthase inhibitor) were prepared and bio-evaluated for their antiproliferative activity using the MTT assay. The assembled compounds 11–15, as triple-prodrugs, exhibited a potent anti-cancer activity. In particular, compounds 14 and 15 both with valproic acid (VPA) showed higher potent cytotoxicity against the tested cancer cells, whereas lower cytotoxicity toward normal human umbilical vein endothelial cells than the free drugs involved. Compound 14, as a representative for further study, rapidly enhanced the cellular accumulation in a time-dependent manner, significantly induced the DNA-damage, cell cycle blocking at the S phase, and cell apoptosis as well as suppressed migration in HeLa. Most strikingly, compound 14 simultaneously regulated the TS, HDAC and γH2AX factors, suggesting a synergistic action of 5-FU, VPA and CDDP to increase the drug effects.
研究领域:
药理学
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肿瘤学
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化学
·
分子生物学
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DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 6.054
Ran Zhang,Xue-Qing Song,Rui-Ping Liu,Zhong-Ying Ma,Jing-Yuan Xu
As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of “dual-prodrug” by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10–17, named Fuplatin, exhibited much higher cytotoxicity against the tested cancer cells while lower cytotoxicity toward the human normal lung cells than free drugs or their combinations. Among them, 14 enhanced cellular accumulation with 62- and 825-fold amount of oxaliplatin and 8 at 9 h, respectively, significantly induced DNA damage and cell apoptosis, and inhibited migration and invasion in HCT-116 cells. Compound 14 arrested the cell cycle at S and G2 phases and up-regulated thymidylate synthase and p53, consistent with the results of the combination, suggesting 14 adopted a collaborative mode of 5-FU and oxaliplatin to kill cancer cells. In vivo, compound 14 showed high antitumor effect and no observable toxicity in NOD/SCID mice bearing HCT-116 tumors.
研究领域:
肿瘤学
·
药理学
·
化疗
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）