ACS Omega
·
2025
·
IF 4.3
Mingmin Li,Liang Qi,Jin Huang,Haonan Li,Wei Cheng,Zihan Shi,Xianxing Jiang,Yifeng Zhou,Wanxiang Jiang
Liver fibrosis can progress to cirrhosis and hepatocellular carcinoma. Currently, there is no effective drug for liver fibrosis. The peptide 6 (T6) is an endogenous peptide derived from human intrauterine adhesion tissues and has antifibrotic potential. Here, to improve the long-term efficacy and activity of T6, we conducted the rational modified of T6 through studying structure–activity, and synthesized a series of analogues. Among them, S6 and S6-FA exhibited optimal antihepatic fibrosis activity, and S6-FA had a stronger long-acting effect than T6 and S6. The two analogues inhibited the expression of α-SMA and Collagen 1 in TGF-β-induced LX2 cells model and CCl4-induced mouse model of liver fibrosis. Besides, we discovered that S6 and S6-FA remarkably reduced the AST and ALT serum levels. Mechanistic studies have demonstrated that analogues inhibited liver fibrosis through inhibiting Erk, Smad and P65 pathways. This study provided that the novel peptide S6 and S6-FA is potential candidate compounds for treating liver fibrosis.
研究领域:
医学
·
药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MATERIALS SCIENCE & TECHNOLOGY
·
2024
·
IF 11.2
Yi Li,Shan Yu,Yuehan Cao,Yue Huang,Qiaohao Wang,Yuangang Duan,Lina Li,Kaibo Zheng,Ying Zhou
Maximizing ultrafast electron-transfer kinetics in semiconductor is pivotal but challenging for high-efficiency solar-to-energy during the photocatalytic reaction process due to the intrinsic property of photocatalysts with low surface electron density. Herein, a model photocatalyst CdS@Mo is synthesized through a typical hydrothermal method for modulating the ultrafast electron-transfer to enhance the surface electron density. X-ray absorption fine spectra (XAFS) reveal that Mo is coordinated with S atoms to form a Mo-S 6 configuration which is different from common MoS 2 and Mo foil structures. Based on the femtosecond transient absorption spectra (fs-TAS), it is found that the formation of Mo-S 6 configuration contributes to the fast decay of CdS signal and Mo-S 6 signal reactivation, illustrating the ultrafast electron-transfer (∼2.2 ps) from CdS to Mo-S 6 configuration, which achieves the enhanced electron density of photocatalyst surface. Finally, a holistic photocatalytic performance evaluation discloses that the growing of Mo-S 6 configuration obviously improves the photocatalytic hydrogen evolution (PHE) efficiency of CdS from 28.5 to 47.5 mmol g –1 h –1 with a solar-to-hydrogen (STH) efficiency of 0.10 % which is seldomly discussed in the system containing sacrificial agents. This work opens a new path to modulate the surface electron density by tuning the ultrafast electron-transfer for enhancing reaction efficiency in electron-density-dependent systems.
研究领域:
材料科学
·
物理化学
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Yang Xiaohua,Zhang Min,Lu Zhihong,Zhi Linping,Xue Huan,Liu Tao,Liu Mengmeng,Cui Lijuan,Liu Zhihong,He Peifeng,Liu Yunfeng,Zhang Yi
Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future.
研究领域:
药理学
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内分泌学
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糖尿病
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2020
·
IF 4.673
Junxin Zhao,Maomao Ma,Zheling Zeng,Ping Yu,Deming Gong,Shuguang Deng
A novel lipase, SCNL, was isolated from Staphylococcus caprae NCU S6 strain in the study. The lipase was purified to homogeneity with a yield of 6.13% and specific activity of 502.76 U/mg, and its molecular weight was determined to be approximately 87 kDa. SCNL maintained above 80% of its initial activity at a wide range of temperatures (20–50 °C) and pH values (6–11), with an optimal temperature at 40 °C and optimal pH at 9.0 with p-nitrophenyl palmitate as a substrate. SCNL exhibited a higher residual activity than the other staphylococcal lipases in the presence of common enzyme inhibitors and commercial detergents. The lipase activity was enhanced by organic solvents (isooctane, glycerol, DMSO and methanol) and metal ions (Na+, Ba2+, Ca2+, and Mn2+). The Km and Vmax values of SCNL were 0.695 mM and 262.66 s−1 mM−1, respectively. The enzyme showed a preference for p-NP stearate, tributyrin and canola oil. These biochemical features of SCNL suggested that it may be an excellent novel lipase candidate for industrial and biotechnological applications.
研究领域:
生物化学
·
酶学
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微生物学
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生物技术
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Su Jiyan,Chen Xiaohong,Xiao Yuanjie,Li Dan,Li Muxia,Li Hongfu,Huang Jiangjian,Lai Zhengquan,Su Ziren,Xie Yizhen,Zhu Dajiang,Chen Qianjun,Lu Hai,He Jingjin,Xia Chenglai
Triple-negative breast cancer (TNBC) has been acknowledged as an aggressive disease with worst prognosis, which requires endeavor to develop novel therapeutic agents. Bruceae fructus oil (BO), a vegetable oil derived from the fruit of Brucea javanica (L.) Merr., is an approved marketable drug for the treatment of cancer in China for several decades. Despite that the anti–breast cancer activity of several quassinoids derived from B. javanica has been found, it was the first time that the potential of BO against TNBC was revealed. Although BO had no cytotoxicity on TNBC cell lines in vitro, the oral administration of BO exhibited a gut microbiota–dependent tumor suppression without toxicity on the non-targeted organs in vivo. By metagenomics and untargeted metabolomics, it was found that BO not only altered the composition and amino acid metabolism function of gut microbiota but also regulated the host’s amino acid profile, which was in accordance with the metabolism alternation in gut microbiota. Moreover, the activity of mTOR in tumor was promoted by BO treatment as indicated by the phosphorylation of 4E-binding protein 1 (4E-BP1) and ribosomal protein S6, and hyper-autophagy was consequently restrained. By contrast, the failure of tumor suppression by BO under pseudo germ-free (PGF) condition came with indistinctive changes in autophagy and mTOR activity, implying the critical role of the gut microbiota in BO’s anticancer activity. The present study highlighted a promising application of BO against breast cancer with novel efficacy and safety.
研究领域:
肿瘤学
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药理学
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微生物学
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代谢组学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
Water Biology and Security
·
2023
·
IF 0
Chaolin Jiang,Xingchen Huo,Lingjie Tang,Meidi Hu,Chunrong Yang,Daji Luo,Jianguo Su
Grass carp hemorrhagic disease caused by grass carp reovirus (GCRV) results in significant economic losses to the global grass carp aquaculture industry. Oral vaccination is an ideal choice for disease precaution in aquaculture. However, oral vaccine can be degraded in the gut. Therefore, the selection of loading materials is essential. In this study, the S6 and S7 fragments (encoding the outer capsid protein VP4 and fibronectin VP56 of GCRV) and grass carp interferons (IFNs), including IFN1, IFN3, and IFNγ2 were used to create DNA vaccines and adjuvants based on pcDNA3.1, respectively. The oral DNA vaccine was encapsulated in poly(lactic-co-glycolic acid) (PLGA) and polyvinyl alcohol (PVA) with IFNs. The PLGA-PVA (PP) nano-microspheres were prepared by double emulsion-solvent evaporation technique. Using transmission electron microscopy and dynamic light scattering assays, it was determined the vaccines had a spherical structure with uniform particle size (643.5 ± 35.3 nm). The nano-microspheres possessed excellent encapsulation efficiency (81.6 ± 2.6%) and loading rate (0.54 ± 0.02%), and simultaneously exhibited negligible hemolytic activity and cell toxicity. The protection rate and tissue viral loads post-GCRV challenge in grass carp were assessed. The oral PP nano-microsphere with pVP4 + pIFN1 (PP41) vaccine increased protection rate by 44% compared with the control group and was correlated with relatively low viral loads in the spleen, head kidney, and hindgut. Further, three crucial serum biochemical indexes, total superoxide dismutase (TSOD), complement C3 (C3), and lysozyme (LZM), were also dramatically increased. Furthermore, mRNA expressions of representative immune-related genes (IgM, IFN1, IFNγ2, MHC-Ⅰ, and CD8α) in the head kidney and spleen were significantly enhanced. In addition, mRNA expression of IgT was significantly boosted in the hindgut. The results indicate that DNA vaccine capsulated with PP is effective against GCRV infection. The present study provides insights into a prospective strategy for oral vaccine development in aquaculture.
研究领域:
水产养殖
·
免疫学
·
病毒学
·
兽医学
✓ 已验证
DOI
PLoS Pathogens
·
2022
·Vol. 18
·期 9
·e1010808
·
IF 7.464
Pan-Pan Hong,Cang Li,Guo-Juan Niu,Xiao-Fan Zhao,Jin-Xing Wang
Previous studies have shown that the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has antiviral functions or is beneficial for viral replication, however, the detail mechanisms by which mTORC1 enhances viral infection remain unclear. Here, we found that proliferation of white spot syndrome virus (WSSV) was decreased after knockdown of mTor (mechanistic target of rapamycin) or injection inhibitor of mTORC1, rapamycin, in Marsupenaeus japonicus , which suggests that mTORC1 is utilized by WSSV for its replication in shrimp. Mechanistically, WSSV infects shrimp by binding to its receptor, polymeric immunoglobulin receptor (pIgR), and induces the interaction of its intracellular domain with Calmodulin. Calmodulin then promotes the activation of protein kinase B (AKT) by interaction with the pleckstrin homology (PH) domain of AKT. Activated AKT phosphorylates mTOR and results in the activation of the mTORC1 signaling pathway to promote its downstream effectors, ribosomal protein S6 kinase (S6Ks), for viral protein translation. Moreover, mTORC1 also phosphorylates eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which will result in the separation of 4EBP1 from eukaryotic translation initiation factor 4E (eIF4E) for the translation of viral proteins in shrimp. Our data revealed a novel pathway for WSSV proliferation in shrimp and indicated that mTORC1 may represent a potential clinical target for WSSV control in shrimp aquaculture.
White spot syndrome virus (WSSV) is the causative pathogen of white spot disease (WSD) and represents the most destructive viral disease of shrimp. The virus has evolved various strategies to escape from host defenses or exploit host biological pathways for its reproduction. Studies on viral immune-escape mechanisms can provide new strategies for disease prevention and control in shrimp aquaculture. Mechanistic target of rapamycin (mTOR) plays a central role in the regulation of cell growth and metabolism, which nucleates two distinct protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) with diverse functions at different levels of the signaling pathway. mTORC1 is reported to be exploited by viruses in their reproduction. However, the detail mechanism remains unclear. In this study, we identified a new mechanism of mTOR being hijacked by WSSV in shrimp ( Marsupenaeus japonicus ). WSSV infects shrimp by its receptor, pIgR and induces the interaction of the intracellular domain of pIgR with Calmodulin. Calmodulin subsequently promotes the activation of AKT by interaction with the pleckstrin homology domain of the kinase. Activated AKT phosphorylates mTOR and results in the activation of the mTORC1 signaling pathway to promote its downstream effectors, S6Ks, for viral protein synthesis. Moreover, mTORC1 also phosphorylates 4EBP1, which results in the separation of 4EBP1 from eIF4E for the translation of viral proteins in shrimp. Our study reveals a novel strategy for WSSV proliferation in shrimp and indicates that the components of mTORC1 may represent potential clinical targets for WSSV control in shrimp aquaculture.
研究领域:
水产养殖
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病毒学
·
分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science China-Life Sciences
·
2024
·
IF 8
Zheng Cheng,Song Lanlan,Yu Chang,Zhu Lingye,Zhang Jing,Wang Ning,Liu Mengchu,Li Shini,Wang Liangxing,Shen Zhifa,Huang Xiaoying
Chemotherapy is regarded as a widely used and effective treatment strategy for lung cancer, although most conventional chemotherapeutics cause severe toxic side-effects due to their indiscriminate attacks on both cancerous and normal cells. Although nucleic acid nanomaterials are emerging as a promising drug delivery strategy, their clinical applications are limited by rapid degradation by nucleases and difficulties in targeting cancer cells. In this study, we have developed a Rhein-loaded aptamer-based DNA nanotube (DNT-S6@Rhein) for the targeted and efficient therapy of non-small cell lung cancer. Through the palindrome segments, two specified oligonucleotides were hybridized and folded into the well-defined nanotubes (DNT-S6), with the S6 aptamer distributed outside. The obtained nanotubes exhibited excellent serum stability and targeting ability towards A549 cells due to the firm structure and decoration of the S6 aptamer. Rhein, as an antitumor drug and DNA intercalator, can be effectively inserted into the DNT-S6. The drug-loaded nanotubes rapidly disassembled in intracellular environment and then the released Rhein was found to activate cellular apoptotic process and significantly suppress proliferation, migration and invasion of A549 cells. Moreover, DNT-S6@Rhein could efficiently accumulate in tumor regions, offering compelling therapeutic efficacy and biocompatibility under both in vitro and in vivo settings. These findings of this study provide a promising strategy for mitigating the inevitable systemic side-effects of chemotherapy and expand the potential application of DNA nanostructure on targeted drug delivery.
研究领域:
癌症研究
·
纳米技术
·
药物递送系统
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分子生物学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2019
·Vol. 43
·期 12
·4908-4918
·
IF 3.069
Yitong Wang,Ling Wang,Luxuan Guo,Maiomiao Yan,Lei Feng,Shuli Dong,Jingcheng Hao
We report a multifunctional drug delivery platform (Au NR@SiO2/Ce@Dox@PDA@aptamer, abbreviated as PP-Dox nanocomposites) for enhancing non-small cell lung cancer (NSCLC) treatment with controlled drug release, magnetic targeting and specific cancer cell targeting. The platform is composed of polydopamine (PDA) as gatekeepers, gold nanorods (Au NRs) as local photothermal generators, S6 aptamers as targeting ligands and magnetic mesoporous silica nanoparticles (mSiO2) containing high payloads of Ce with cross-linking ligands as drug containers and magnetic targeting agents. Upon uptake into cells or stimulation under a near-infrared (NIR) laser, pH and photothermally triggered drug release was observed. When target cancer cells are absent, the cellular uptake of PP-Dox nanocomposites is suppressed and displays poor treatment effect. However, when target cancer cells are present, more PP-Dox nanocomposites enter into cells because of the specific recognition between aptamers and targeted cells, resulting in an excellent treatment effect. Furthermore, the magnetic field and photothermal effect also supply a more effective therapeutic outcome than chemotherapy alone. We believe that the PP-Dox multifunctional platform has great potential in targeted cancer therapy for enhancing therapeutic efficiency.
研究领域:
纳米技术
·
癌症研究
·
材料科学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-17
·
IF 40.8
Peng Fu,Liao Minru,Jin Wenke,Liu Wei,Li Zixiang,Fan Zhichao,Zou Ling,Chen Siwei,Zhu Lingjuan,Zhao Qian,Zhan Gu,Ouyang Liang,Peng Cheng,Han Bo,Zhang Jin,Fu Leilei
Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD + )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
研究领域:
心血管药理学
·
分子生物学
·
细胞生理学
✓ 已验证
DOI
高影响因子
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