INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2016
·
IF 3.994
Yuan Sheng,Yiwen You,Yun Chen
The extended use of doxorubicin (DOX) could be limited due to the emergence of drug resistance associated with its treatment. In addition to the overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), other mechanisms including apoptosis evasion and tumor cell survival may also be important contributor to drug resistance. Within this context, targeting extracellular signal-regulated kinases (ERK), one of the principle protein molecules in cell apoptosis has emerged as an attractive therapeutic concept. In this study, a dual-targeting hybrid peptide HAIYPRHGGCGMPKKKPTPIQLNP (T10-ERK), which is composed of ERK peptide inhibitor MPKKKPTPIQLNP, a thiol spacer ( i.e ., GGCG) and transferrin receptor (TfR)-binding peptide HAIYPRH, was designed. Then, this thiol-modified hybrid peptide was conjugated to DOXO-EMCH (6-maleimidocaproyl) hydrazone of DOX), forming a novel peptide-DOX conjugate T10-ERK-DOX. The structure and properties of this conjugate were characterized using 1 H NMR, mass spectrometry and HPLC. Using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of T10-ERK-DOX to reverse drug resistance was accessed as compared with free DOX and T10-DOX. As a result, T10-ERK-DOX demonstrated a much lower in vitro IC 50 (20.8 ± 1.1 μM) and its in vivo extent of inhibition in mice was more evident (72.2 ± 4.6%). Induction of various apoptosis pathways was also observed. Furthermore, the potency of ERK peptide inhibitor to reverse drug resistance was individually assessed, given the pronounced efficacy of T10-DOX indicated by our previous work. The results provided evidence of its additive effect with T10-DOX, which leads to greater efficacy and less susceptibility to drug resistance. Finally, the success of multi-targeting strategy in the present study implied that multi-target drugs with rational design could be more promising in cancer therapy.
研究领域:
药理学
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肿瘤学
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分子生物学
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化疗
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药物递送系统
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2014
·
IF 3.163
Xiude Hua,Xiaofeng Liu,Wei Yin,Yazhong Xia,Qiujun Zhou,Yiwen Lu,Wei Li,Haiyan Shi,Fengquan Liu,Minghua Wang
A sensitive monoclonal antibody-based enzyme monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) was developed to detect bifenthrin in a chemical soil barrier for termite control. LBc ((2-methyl[1,1-biphenyl]-3-methoxy) carbonyl propionic acid) was conjugated to bovine serum albumin (BSA) for producing monoclonal antibody. After optimization, the IC 50 and limit of detection (LOD, IC 10 ) were 0.05 mg L − 1 and 0.004 mg L − 1 , respectively. The sensitivity was improved 40-fold compared to polyclonal antibody-based ELISA reported earlier. No cross-reactivity was measured for the other analogues such as cyhalothrin, cyhalothric acid, cypermethrin, deltamethrin, fenpropathrin, fenvalerate, ethofenprox and tetramethrin except 2-methyl-3-biphenylmethyanol. Spiked recoveries were between 83.5% and 104.7% for the detection of bifenthrin in loess, red soil and black soil. All the relative standard deviations (RSDs) were less than or equal to 15.0%. Moreover, the ELISA for authentic samples showed reliability and high correlation with gas chromatography. The developed ELISA is an alternative tool for simple, sensitive and accurate monitoring of bifenthrin in chemical soil barriers.
研究领域:
分析化学
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环境科学
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害虫控制
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2022
·
IF 3.571
Xiaofang Li,Liqiang Liu,Lingling Guo,Liguang Xu,Hua Kuang,Chuanlai Xu
Nicotine (NCT) is commonly contained in e-cigarette oils, and long-term nicotine intake can exacerbate cardiovascular disease, neurodegenerative disease , and lung cancer. Therefore, there is a need to develop a fast and sensitive method for detecting NCT in e-cigarette oils. We prepared anti-NCT monoclonal antibodies (mAbs), which belong to the IgG2 subclass. The optimum mAb had a half-maximal inhibitory concentration (IC 50 ) of 6.81 ng/mL for NCT. We developed a colloidal gold immunochromatographic strip (CG-ICS) to detect NCT content with a visual cut-off and limit of detection of 20 ng/mL and 0.40 ng/mL, respectively. The recovery rates of NCT from spiked samples ranged between 100.36% and 109.96% based on CG-ICS. These results were consistent with those obtained from high performance liquid chromatography (HPLC). We confirmed the reliability of CG-ICS using NCT-positive samples. Therefore, CG-ICS represents an effective and rapid on-site screening tool for the detection of NCT in e-cigarette oils.
研究领域:
分析化学
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毒理学
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公共卫生
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Chenxing Xu,Nan Wang,Tao Ma,Shengrong Pei,Meiting Wang,Jinpeng Yu,Dongting Zhangsun,Xiaopeng Zhu,Sulan Luo
α 3 β 4, a vital subtype of neuronal nicotinic acetylcholine receptors (nAChRs), is widely distributed in the brain, ganglia, and adrenal glands, associated with addiction and neurological diseases. However, the lack of specific imaging tools for α 3 β 4 nAChRs has hindered the investigation of their tissue distribution and functions. [D11A]LvIA, a peptide derived from marine cone snails, demonstrates high affinity and potency for α 3 β 4 nAChRs, making it a valuable pharmacological tool for studying this receptor subtype. In this study, three fluorescent conjugates of [D11A]LvIA were synthesized using 6-TAMRA-SE (R), Cy3-NHS-ester (Cy3), and BODIPY-FL NHS ester (BDP) dyes. The electrophysiological activities were assessed in Xenopus laevis oocytes by two-electrodes voltage clamp (TEVC). [D11A]LvIA-Cy3 and [D11A]LvIA-BDP show improved selectivity and affinity, with IC 50 values of 512.70 nM and 343.50 nM, respectively, and [D11A]LvIA-Cy3 exhibits better stability in cerebrospinal fluid. Utilizing [D11A]LvIA-Cy3, we successfully visualized the distribution of α 3 β 4 nAChRs in rat trigeminal ganglia, retina, adrenal glands, and various brain regions. This novel fluorescent peptide provides a significant pharmacological tool for the exploration and visualization in-situ distribution of α 3 β 4 nAChRs in different tissues and also assists in clarifying the function.
研究领域:
神经科学
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药理学
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成像技术
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DOI
PubMed
高影响因子
FOOD AND AGRICULTURAL IMMUNOLOGY
·
2014
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IF 0.984
Xinlin Wei,Yaru Zhao,Baoqin Wang,Yuanfeng Wang
Two kinds of new immunogens and coating antigens had been designed and synthesised by methods of lively ester (DCC) and carbodiimide (EDC), respectively. Preliminary immunosorbent assays indicated that the two target conjugates presented good inhibition ratio against the haptens of cypermethrin in vivo. The results showed that the best efficient titres of anti-cypermethrin rabbit serum in methods of DCC and EDC were 1:32000 and 1:64000, the IC50 of them were 18.907µg/L and 16.877µg/L against the haptens of cypermethrin, respectively. The data indicated that the anti-cypermethrin antibodies in method of EDC had higher sensitivity and higher selectivity than the anti-cypermethrin antibodies in method of DCC. Thus, we can synthesise antigens and anti-bodies with method of EDC. The antibodies of high quality can be effectively used in the field of the rapid detection of pyrethroid pesticide residues in the research of the reagent strips.
研究领域:
分析化学
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环境科学
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毒理学
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农业科学
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DOI
高影响因子
Food & Function
·
2022
·Vol. 14
·期 1
·171-180
·
IF 6.317
Xinlin Chen,Ying Wu,Yucheng Gu,Jianguang Luo,Lingyi Kong
A great deal of attention has been paid to the seeds of Paeoniae lactiflora pall., an underutilized food resource, since its extract exhibits excellent α-glucosidase (GAA) inhibitory activity. In the present study, to gain further insight into this plant and find out potent GAA inhibitors, we established a novel ligand fishing strategy by introducing a competitive inhibitor as an indicator. After the successful establishment of this approach was verified by a series of methods, including kinetic assay, fluorescence determination, and HPLC, the newly developed ligand fishing method was applied to acquire potent GAA inhibitors from P. lactiflora seeds. Nine bioactive compounds were captured, and seven of them were identified as suffruticosol A, suffruticosol B, resveratrol, vitisin E, luteolin, trans-δ-viniferin, and ampelopsin E. The data of their GAA inhibitory activity demonstrated that these constituents were vigorously active against GAA with IC50 values of 1.67–30.47 μM, while such value of 1-DNJ was 228.77 μM. Among them, vitisin E and ampelopsin E were reported to show such inhibitory activity for the first time. Collectively, our findings provide valuable clues for the further utilization of P. lactiflora seeds as a functional food, and offer a new avenue for acquiring potent inhibitors from natural resources.
研究领域:
药理学
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天然产物化学
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生物化学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2024
·
IF 5.1
Zhengming Xu,Kseniya Hileuskaya,Aliaksandr Kraskouski,Yujiao Yang,Zhe Huang,Zhengang Zhao
A diet containing natural active compounds that can inhibit the hydrolytic activity of α-glucosidase on carbohydrates and intestinal glucose absorption is an effective means of controlling postprandial hyperglycemia. Phlorizin and polydatin as phenolic glycosides had a high affinity to the catalytic site of α-glucosidase, but exhibited unsatisfactory competitive inhibitory capacity, with IC50 of 0.97 and > 2 mM, respectively. However, dodecyl-acylated derivatives of phlorizin and polydatin exerted α-glucosidase inhibitory capacity, with IC50 of 55.10 and 70.95 µM, respectively, which were greatly enhanced and much stronger than that of acarbose with IC50 of 2.46 mM. Both dodecyl phlorizin and dodecyl polydatin reduced the catalytic ability of α-glucosidase by reversible noncompetitive and uncompetitive mixed inhibition, which bind noncovalently to the allosteric site 2 through hydrogen bonds and hydrophobic interactions, thereby inducing the secondary structure unfolding and intrinsic fluorescence quenching of α-glucosidase. Confocal microscopy detection visually showed the significant inhibitory effects on FITC-labeled glucose uptake in intestinal Caco-2 cells by phlorizin, polydatin, dodecyl phlorizin and dodecyl polydatin. In addition, based on the differentiated Caco-2 cell monolayer model, dodecyl phlorizin and dodecyl polydatin suppressed intestinal glucose transport more effectively than phlorizin and polydatin, suggesting that they were promising in vivo hypoglycemic active compounds.
研究领域:
药理学
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生物化学
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分子生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
Natural Product Communications
·
2020
·
IF 0.468
Ling-Li Zheng,Guan Wen,Yun-Xin Yao,Xiao-Huan Li,Feng Gao
Based on the strong activity dependence of paclitaxel (PTX; Taxol) or docetaxel (Taxotere) on the C-13 side chain, a small library of dehydroepiandrosterone, cholesterol, vitamin D2, and alkaloids talatisamine and songorine-PTX hybrids have been synthesized and evaluated for in vitro anticancer activity by MTT assay against human breast (MCF-7), colon (HCT116), lung carcinoma (A549), and renal adenocarcinoma (786-0) cancer cell lines. Most hybrids (11b, 12b, 13b, 15b, and 18b) reduced the growth of MCF-7 and 786-0 cells with low PTX sensitivity in vitro. Among the synthesized compounds, hybrid 11b was better in inhibiting the growth of the 4 cells than PTX. A relatively low IC50 value of compound 11b (8.16 ± 0.04 μM) was also examined after exposure for 48 hours. Hybrid 11b showed a proapoptotic effect in HCT116 cells evaluated by Annexin V/propidium iodide binding assay. The level of hybrid 11b leading to protective cell death in HCT116 cells was detected using western blot and not easily observed in our basic examinations.
研究领域:
药理学
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肿瘤学
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药物化学
·
细胞生物学
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产品关联
DOI
高影响因子
Biomed Research International
·
2013
·
IF 0
Li Lv,Yuanyuan Shen,Min Li,Xiaofen Xu,Mingna Li,Shengrong Guo,Shengtang Huang
A novel 4-arm poly(ethylene glycol)-block-poly(anhydride-esters) amphiphilic copolymer (4-arm PEG-b-PAE) was synthesized by esterization of 4-arm poly(ethylene glycol) and poly(anhydride-esters) which was obtained by melt polycondensation of α-, ω-acetic anhydride terminated poly(L-lactic acid). The obtained 4-arm PEG-b-PAE was characterized by 1H-NMR and gel permeation chromatography. The critical micelle concentration of 4-arm PEG-b-PAE was 2.38 μg/mL. The curcumin-loaded 4-arm PEG-b-PAE micelles were prepared by a solid dispersion method and the drug loading content and encapsulation efficiency of the micelles were 7.0% and 85.2%, respectively. The curcumin-loaded micelles were spherical with a hydrodynamic diameter of 151.9 nm. Curcumin was encapsulated within 4-arm PEG-b-PAE micelles amorphously and released from the micelles, faster in pH 5.0 than pH 7.4, presenting one biphasic drug release pattern with rapid release at the initial stage and slow release later. The hemolysis rate of the curcumin-loaded 4-arm PEG-b-PAE micelles was 3.18%, which was below 5%. The IC50 value of the curcumin-loaded micelles against Hela cells was 10.21 μg/mL, lower than the one of free curcumin (25.90 μg/mL). The cellular uptake of the curcumin-loaded micelles in Hela cell increased in a time-dependent manner. The curcumin-loaded micelles could induce G2/M phase cell cycle arrest and apoptosis of Hela cells.
研究领域:
药学
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材料科学
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纳米技术
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
PEST MANAGEMENT SCIENCE
·
2023
·Vol. 79
·期 5
·1922-1930
·
IF 4.1
Zhi Ma,Shuo Qiu,Dong Zhang,Xinying Guo,Yuele Lu,Yongxian Fan,Xiaolong Chen
BACKGROUND Succinate dehydrogenase inhibitor (SDHI) fungicides are an important class of agricultural fungicides with the advantages of high efficiency and a broad bactericidal spectrum. To pursue novel SDHIs, a series of N -substituted dithiin tetracarboximide derivatives were designed, synthesized, and characterized by 1 H NMR, 13 C NMR, and high resolution mass spectrum (HRMS). RESULTS These engineered compounds displayed potent fungicidal activity against phytopathogens, including Sclerotinia sclerotiorum , Botrytis cinerea , and Rhizoctonia solani , comparable with that of the commercial SDHI fungicide boscalid . In particular, compound 18 stood out with prominent activity against S. sclerotiorum with a half-maximal effective concentration (EC 50 ) value of 1.37 μg ml −1 . Compound 1 exhibited the most potent antifungal activity against B. cinerea with EC 50 values of 5.02 μg ml −1 . As for R. solani , 12 and 13 exhibited remarkably inhibitory activity with EC 50 values of 4.26 and 5.76 μg ml −1 , respectively. In the succinate dehydrogenase (SDH) inhibition assay, 13 presented significant inhibitory activity with a half-maximal inhibitory concentration (IC 50 ) value of 15.3 μ m , which was approximately equivalent to that of boscalid (14.2 μ m ). Furthermore, molecular docking studies revealed that 13 could anchor in the binding site of SDH. CONCLUSION Taken together, results suggested that the dithiin tetracarboximide scaffold possessed a huge potential to be developed as novel fungicides and SDHIs. © 2023 Society of Chemical Industry.
研究领域:
农业化学
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药物化学
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植物病理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Miao Jiefei,Meng Chi,Wu Hongmei,Shan Wenpei,Wang Haoran,Ling Changchun,Zhang Jinlin,Yang Tao
A novel hybrid CHC was designed and synthesized by conjugating β-carboline with an important active fragment N-hydroxyacrylamide of histone deacetylase (HDAC) inhibitor by an amide linkage to enhance antitumor efficacy/potency or even block drug resistance. CHC displayed high antiproliferative effects against drug-sensitive SUMM-7721, Bel7402, Huh7, and HCT116 cells and drug-resistant Bel7402/5FU cells with IC50 values ranging from 1.84 to 3.27 μM, which were two-to four-fold lower than those of FDA-approved HDAC inhibitor SAHA. However, CHC had relatively weak effect on non-tumor hepatic LO2 cells. Furthermore, CHC exhibited selective HDAC1/6 inhibitory effects and simultaneously augmented the acetylated histone H3/H4 and α-tubulin, which may make a great contribution to their antiproliferative effects. In addition, CHC also electrostatically interacted with CT-DNA, exerted remarkable cellular apoptosis by regulating the expression of apoptosis-related proteins and DNA damage proteins in Bel7402/5FU cells, and significantly accumulated cancer cells at the G2/M phase of the cell cycle by suppressing CDK1 and cyclin B protein with greater potency than SAHA-treated groups. Finally, CHC displayed strong inhibitory potency to drug-resistant hepatic tumors in mice. Our designed and synthetic hybrid CHC could be further developed as a significant and selective anticancer agent to potentially treat drug-resistant hepatocellular carcinoma.
研究领域:
药理学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
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2021
·
IF 3.534
Zifei Qin,Peile Wang,Shuyi Duan,Xiaoying Wan,Han Xing,Jing Yang,Xiaojian Zhang,Zhihong Yao,Xinsheng Yao
Isobavachalcone, a naturally occurring chalcone in Psoralea corylifolia , posses many biological properties including anticancer, antiplatelet, and antifungal. However, its glucuronidation, glucuronides excretion, and drug-drug interaction (DDI) involving in human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) enzymes, and efflux transporters (BCRP and MRPs) remains unclear so far. After incubation, three glucuronides were produced by HLM and HIM with total intrinsic clearance ( CL int ) of 236.71 and 323.40 μL/min/mg, respectively. Reaction phenotyping proved UGT1A1, 1A3, 1A7, 1A8, and 1A9 played important roles in glucuronidation with total CL int values of 62.69–143.00 μL/min/mg. Activity correlation analysis indicated UGT1A1 and UGT1A3 participated more in the glucuronidation. In addition, the glucuronidation showed marked species differences, and rabbits and dogs were probably appropriate model animals to investigate the in vivo glucuronidation. Furthermore, BCRP , MRP1, and MRP4 transporters were identified as the most important contributors to glucuronides excretion in HeLa1A1 cells based on gene silencing method. Moreover, isobavachalcone demonstrated broad-spectrum inhibitory effects against CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6 , CYP2E1 , UGT1A1, UGT1A9, UGT2B7 with IC 50 values of 1.08–9.78 μM. Except CYP2B6 and CYP2D6, the calculated [I]/ K i values for other enzymes were all greater than 0.1, indicating the inhibition of systemic metabolism or elimination for these enzyme substrates seems likely. Taken together, we summarized metabolic fates of isobavachalcone including glucuronidation and efflux transport as well as inhibitory effects involving in human CYP and UGT enzymes.
研究领域:
药理学
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生物化学
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药学
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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）