JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yabing Xin,Can Xiao,Nan Wang,Huidan Wu,Wenjing Kang,Xuetao Chen,Chihong Liu,Qidong You,Zhengyu Jiang,Xiaoke Guo
Acute myeloid leukemia (AML) patients usually exhibit suboptimal responses after receiving single target drug therapy. Simultaneously targeting multiple oncogenic pathways is a promising strategy for cancer treatment. Herein, based on the synergistic antiproliferative capacity of the PIM inhibitor C28 and the HDAC inhibitor SAHA in MV4–11 cells, we developed a series of novel dual PIM/HDAC inhibitors. Among them, compound 22 exhibited potent antiproliferative activity in MV4–11 cells, along with robust inhibitory effects against both PIM1 and HDAC6. Flow cytometry analysis showed that 22 dose-dependently induced apoptosis in MV4–11 cells. Mechanistically, treatment with 22 remarkably induced the cleavage of PARP, thereby initiating apoptosis. Furthermore, 22 demonstrated significant anticancer efficacy (TGI = 81.3%; 50 mg/kg, QD) in the MV4–11 xenograft model without notable toxicity. In conclusion, our study established the therapeutic potential of dual PIM/HDAC inhibitors and provided a tool to elucidate synergistic mechanisms underlying the combined inhibition of these targets.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Gas Science and Engineering
·
2024
·
IF 0
Jintang Wang,Bo Liao,Lei Liu,Longqiao Chen,Yaowei Huang,Ke Zhao,Xiaohui Sun,Kaihe Lv,Yuxuan Zheng,Jinsheng Sun
Based on the existing components of drilling fluids, the construction of a multi-component hydrate inhibitor system is essential for building a high-performance hydrate drilling fluid system and reducing production costs. The constant rate cooling method are performed to investigate the effect of different inhibitor systems on hydrate formation . The results indicate that thermodynamic inhibitors exhibit enhanced effectiveness in inhibiting hydrate formation at higher mass concentrations. In contrast, kinetic inhibitors demonstrate superior performance at lower mass concentrations, and their inhibitory efficacy does not scale up with concentration. Kinetic inhibitors can synergize with other components of the drilling fluid that have thermodynamic inhibitor effects. In particular, the ternary composite system has better synergistic effects compared to the binary composite system. It is of great significance for the construction of efficient hydrate drilling fluid systems in the future.
研究领域:
石油工程
·
化学工程
✓ 已验证
DOI
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Yahui Huang,Na Liu,Zhizhi Pan,Zhuang Li,Chunquan Sheng
Breast cancer is susceptible to Candida infections, and candidiasis has an enhancing effect on the progression and metastasis of tumor. Breast cancer and concurrent candidiasis represent a significant challenge in clinical therapy. Herein, a series of novel small molecule inhibitors simultaneously targeting bromodomain and extra-terminal (BET) and histone deacetylase (HDAC) were designed for combinational treatment of breast cancer and resistant Candida albicans infections. Among them, compounds 13c and 17b exhibited excellent and balanced inhibitory activity against both BET family proteins BRD4 and HDAC1. As compared with BRD4 or HDAC1 inhibitors, dual inhibitors 13c and 17b displayed improved in vivo antitumor efficacy in MDA-MB-231 breast cancer xenograft models. Notably, they synergized with fluconazole (FLC) to effectively reduce the kidney fungal burden in a murine model of disseminated candidiasis. Thus, the BET–HDAC dual inhibitors represented a novel therapeutic strategy for combinational treatment of breast cancer and concurrent candidiasis.
研究领域:
肿瘤学
·
医学微生物学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2024
·
IF 7
Jun Dai,Zihan Liu,Lei Ma,Chunliu Yang,Ligai Bai,Dandan Han,Qi Song,Hongyuan Yan,Zhiqiang Wang
This study examined the suppressive effects of 16 selected plant-based foods on α-glucosidase and pancreatic lipase and their antioxidant properties. Among these, the bark of Cinnamomum cassia (Cinnamon, WLN-FM 15) showed the highest inhibitory activity against α-glucosidase and the highest antioxidant activity. Additionally, WLN-FM 15 showed promising results in the other tests. To further identify the bioactive constituents of WLN-FM 15, a multi-bioactivity-labeled molecular networking approach was used through a combination of GNPS-based molecular networking, DPPH-HPLC, and affinity-based ultrafiltration-HPLC. A total of nine procyanidins were identified as antioxidants and inhibitors of α-glucosidase and pancreatic lipase in WLN-FM 15. Subsequently, procyanidins A1, A2, B1, and C1 were isolated, and their efficacy was confirmed through functional assays. In summary, WLN-FM 15 has the potential to serve as a functional food ingredient with the procyanidins as its bioactive constituents. These results also suggest that the multi-bioactivity-labeled molecular networking approach is reliable for identifying bioactive constituents in plant-based foods.
研究领域:
植物化学
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食品科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Hongbo Xie,Haixia Wen,Denan Zhang,Lei Liu,Bo Liu,Qiuqi Liu,Qing Jin,Kehui Ke,Ming Hu,Xiujie Chen
Alzheimer's disease is a multifactorial neurodegenerative disorder with many drug targets contributing to its etiology. Despite the devastating effects of this disease, therapeutic methods for treating Alzheimer's disease remain limited. The multifactorial nature of Alzheimer's disease strongly supports a multi-target rationale as a drug design strategy. Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 have been identified as being involved in the pathological hyperphosphorylation of tau proteins, which leads to the formation of neurofibrillary tangles and causes Alzheimer's disease. In this study, using a molecular docking method to screen a virtual library, we discovered molecules that can simultaneously inhibit Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 as lead compounds for the treatment of Alzheimer's disease. The docking results revealed the key residues in the substrate binding sites of both Glycogen synthase kinase-3 beta and cyclin-dependent kinase 5. A receiver operating characteristic curve indicated that the docking model consistently and selectively scored the majority of active compounds above decoys. The pre-treatment of cells with screened compounds protected them against A β 25-35 - induced cell death by up to 80%. Collectively, these findings suggest that some compounds have potential to be promising multifunctional agents for Alzheimer's disease treatment.
研究领域:
药理学
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神经科学
·
计算生物学
✓ 已验证
DOI
PubMed
高影响因子
DESALINATION
·
2021
·
IF 9.501
Yuxuan Zheng,Yuhua Gao,Haihua Li,Meifang Yan,Junping Zhao,Zhenfa Liu
A biodegradable and non-phosphorus chitosan derivative (CTS-AA-PSI) was synthesized with chitosan, acrylic acid and polysuccinimide, which can be used as a new environmentally friendly scale and corrosion inhibitor . The structure of CTS-AA-PSI was confirmed by FTIR , 1 H NMR and 13 C NMR. The CTS-AA-PSI showed outstanding scale inhibition performance with a scale inhibition rate of 87.96% at the concentration of 25 mg/L. The electrochemical impedance results indicated that CTS-AA-PSI showed a significant corrosion inhibition effect in a 3.5% NaCl solution with a corrosion inhibition rate of 71.17% when the dosage was 500 mg/L. In addition, the biodegradability experiment showed that its degradation rate was 72.32% on the 28th day. It was demonstrated that the CTS-AA-PSI is a readily biodegradable material . The possible scale inhibition mechanism was explored by SEM, XRD , XPS and EEM. The results indicated that the excellent scale inhibition performance of CTS-AA-PSI was related to its chelating and lattice-distortion ability, which inhibited the formation and precipitation of CaCO 3 crystal. These findings suggest that CTS-AA-PSI is a quite promising candidate for an environmentally friendly scale and corrosion inhibitor.
研究领域:
材料科学
·
环境科学
✓ 已验证
DOI
高影响因子
Cell Death & Disease
·
2021
·Vol. 12
·期 1
·1-18
·
IF 8.469
Fang Shaohong,Wan Xin,Zou Xiaoyi,Sun Song,Hao Xinran,Liang Chenchen,Zhang Zhenming,Zhang Fangni,Sun Bo,Li Hulun,Yu Bo
Inducing autophagy and inhibiting apoptosis may provide a therapeutic treatment for atherosclerosis (AS). For the treatment of progressive AS, arsenic trioxide (ATO) has been used to coat vascular stents. However, the effect of ATO on autophagy of macrophages is still unknown. Therefore, the aims of this study were to characterize the effects and the mechanism of actions of ATO on autophagy in macrophages. Our results showed that ATO-induced activation of autophagy was an earlier event than ATO-induced inhibition of the expression of apoptosis markers in macrophages and foam cells. Nuclear transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy and promoting lysosomal biogenesis. Here, we report that ATO triggered the nuclear translocation of TFEB, which in turn promoted autophagy and autophagosome-lysosome fusion. Both the latter events were prevented by TFEB knockdown. Moreover, ATO decreased the p-AKT and p-mTOR in the PI3K/AKT/mTOR signaling pathway, thus inducing autophagy. Correspondingly, treatment with the autophagy inhibitor 3-methyladenine (3-MA) abolished the autophagy-inducing effects of ATO. Meanwhile, PI3K inhibitor (LY294002) and mTOR inhibitor (rapamycin) cooperated with ATO to induce autophagy. Furthermore, reactive oxygen species (ROS) were generated in macrophages after treatment with ATO. The ROS scavenger N-acetyl-1-cysteine (NAC) abolished ATO-induced nuclear translocation of TFEB, as well as changes in key molecules of the AKT/mTOR signaling pathway and downstream autophagy. More importantly, ATO promoted autophagy in the aorta of ApoE −/− mice and reduced atherosclerotic lesions in early AS, which were reversed by 3-MA treatment. In summary, our data indicated that ATO promoted ROS induction, which resulted in nuclear translocation of TFEB and inhibition of the PI3K/AKT/mTOR pathway. These actions ultimately promoted macrophage autophagy and reduced atherosclerotic lesions at early stages. These findings may provide a new perspective for the clinical treatment of early-stage atherosclerosis and should be further studied.
研究领域:
心血管疾病
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药理学
·
细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Future Medicinal Chemistry
·
2021
·Vol. 13
·期 13
·
IF 3.808
Xin Lu,Yijun Liu,Nan Qin,Hongyu Yang,Yuting Qiao,Xueyang Jiang,Yao Chen,Feng Feng,Wenyuan Liu,You Zhou,Haopeng Sun
Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.
研究领域:
神经科学
·
药物化学
·
老年医学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2021
·Vol. 26
·期 23
·7293
·
IF 4.412
Xu Wang,Dai-Yan Zhang,Shi-Jun Yin,Hui Jiang,Min Lu,Feng-Qing Yang,Yuan-Jia Hu
In this study; a spectrum–effect relationship analysis combined with a high-performance liquid chromatography–mass spectrometry (LC–MS) analysis was established to screen and identify active components that can inhibit thrombin and factor Xa (THR and FXa) in Salviae Miltiorrhizae Radix et Rhizoma–Chuanxiong Rhizoma (Danshen–Chuanxiong) herbal pair. Ten potential active compounds were predicted through a canonical correlation analysis (CCA), and eight of them were tentatively identified through an LC–MS analysis. Furthermore; the enzyme inhibitory activity of six available compounds; chlorogenic acid;Z-ligustilide; caffeic acid; ferulic acid; tanshinone I and tanshinone IIA; were tested to verify the feasibility of the method. Among them; chlorogenic acid was validated to possess a good THR inhibitory activity with IC50of 185.08 µM. Tanshinone I and tanshinone IIA are potential FXa inhibitors with IC50of 112.59 µM and 138.19 µM; respectively. Meanwhile; molecular docking results show that tanshinone I and tanshinone IIA; which both have binding energies of less than −7.0 kcal·mol−1; can interact with FXa by forming H-bonds with residues of SER214; GLY219 and GLN192. In short; the THR and FXa inhibitors in the Danshen–Chuanxiong herbal pair have been successfully characterized through a spectrum–effect relationship analysis and an LC–MS analysis.Keywords:Danshen–Chuanxiong herbal pair;thrombin inhibitors;factor Xa inhibitors;spectrum–effect relationship analysis
研究领域:
中药学
·
生物化学
·
药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DESALINATION
·
2020
·
IF 7.098
Weiwei Zhang,Hui-Jing Li,Liwei Chen,Jiani Sun,Xingyi Ma,Yunfei Li,Chao Liu,Xu Han,Boyi Pang,Yan-Chao Wu
An environment-friendly scaling–corrosion inhibitor composed of 10-methylacridinium iodide (MAI) and sodium citrate (SC) was developed, whose scale inhibition performance were studied through weight loss, electrochemical techniques , static tests and surface analysis techniques (SEM, SECM , XPS , XRD). The optimum mass ratio of MAI and SC corrosion inhibition was found to be 1:2, and the optimum mass ratio of scale inhibition was 1:3. The experimental results showed that MAI–SC mixture as mixed-type scaling–corrosion inhibitor with excellent corrosion ( η w = 92.7%) and scale inhibition performance ( η Ca = 98.3%). The electrochemical stability of the inhibitor film was investigated by chronoamperometry (CA). SEM and XRD simulations indicated that the MAI–SC mixture inhibitor can distort and disperse the crystal lattice of calcium carbonate without forming scale, and it plays a dominant role in the inhibition of calcite (110) surface growth. The structure-activity relationship between the molecule structure of the MAI–SC mixture and its scale–corrosion inhibition performance was discussed based on the quantum chemistry calculation.
研究领域:
材料科学
·
化学工程
·
环境科学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF MATERIALS SCIENCE
·
2024
·Vol. 59
·期 8
·3604-3623
·
IF 3.5
Wang Xintong,Yang Jiang,Chen Xu,Wang Yefei,Yang Zhen,Ding Wei
To mitigate CO 2 corrosion in the oil and gas industry, a green non-toxic β -N-butyl amino propionic acid (BAA) was synthesized using a low-energy and zero-waste one-pot method. The effectiveness of BAA as a corrosion inhibitor for N80 steel in CO 2 -saturated brine water was investigated through experimental measurements and theoretical modeling. The results demonstrate that BAA functions as an effective mixed-type corrosion inhibitor. BAA molecules interact with F (1 1 0) with the–COO– and–NH 2 + -moiety in the hydrophilic head group, and the hydrophobic groups are adsorbed on the steel surface in a configuration 45° away from the steel surface. The adsorption is a mixture of physical and chemical processes and is consistent with the Langmuir isothermal adsorption formula. When the concentration is greater than 50 ppm, a complete corrosion inhibitor film with high hydrophobicity can be adsorbed on the steel surface, which can effectively impede the diffusion of corrosive species from brine to the steel surface. Graphical abstract
研究领域:
腐蚀科学
·
材料工程
·
环境化学
·
石油天然气工业
✓ 已验证
DOI
高影响因子
Journal of Chemical Information and Modeling
·
2015
·
IF 3.738
Lu Cui,Yu Wang,Zhihong Liu,Hongzhuan Chen,Hao Wang,Xinxin Zhou,Jun Xu
Myasthenia gravis (MG) is a neuromuscular disease that is conventionally treated with acetylcholinesterase (AChE) inhibitors, which may not fully remove the symptom for many reasons. When AChE inhibitors do not work, Chinese patients turn to Chinese medicine, such as the Buzhongyiqi decoction (BD), to treat MG. By elucidating the relations between the herbs of the Buzhongyiqi decoction recipe and AChE inhibitors with structure-based and ligand-based drug design methods and chemoinformatics approaches, we have found the key active components of BD. Using these key active components as templates, we have discovered five new AChE inhibitors through virtual screening of a commercial compound library. The new AChE inhibitors have been confirmed with Ellman assays. This study demonstrates that lead identification can be inspired by elucidating Chinese medicine. Since BD is a mixture, further studies against other drug targets are needed.
研究领域:
药理学
·
化学信息学
·
中药学
✓ 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）