ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2021
·Vol. 413
·期 13
·3493-3499
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IF 4.157
Cao Xiuping,Shang Xinxin,Guo Yingshu,Zheng Xiaofei,Li Wenxin,Wu Di,Sun Li,Mu Shanliang,Guo Chuanen
In the process of drug carrier design, lysosome degradation in cells is often neglected, which makes a considerable number of drugs not play a role. Here, we have constructed a tumor treatment platform (Apn/siRNA/NLS/HA/Apt) with unique lysosomal escape function and excellent cancer treatment effect. Apoferritin (Apn) has attracted more and more attention because of its high uniformity, modifiability, and controllability. Meanwhile, its endogenous nature can avoid the risk of immune response being eliminated. We used aptamer modified iron deficient protein nanocages (Apn) to tightly encapsulate the combination of siRNA and NLS (siRNA/NLS) with influenza virus hemagglutinin (HA peptide). After Apn/siRNA/NLS/HA/Apt was targeted into cells, the acidic environment of lysosome led to the cleavage of Apn nanocages, and the release of siRNA/NLS and HA peptide. HA peptide can destroy lysosome membrane, make siRNA/NLS escape lysosome, and enter the nucleus under the action of NLS, resulting in efficient gene silencing effect. This kind of cancer treatment strategy based on Apn nanocage shows high biocompatibility and unique lysosome escape property, which significantly improves the drug delivery and treatment efficiency. Graphical abstract
Lysosomal escape protein nanocarriers for nuclear-targeted siRNA delivery
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ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·121-132
·
IF 6.15
Zhao Ze-an,Jiang Yu,Chen Yan-yu,Wu Ting,Lan Qun-sheng,Li Yong-mei,Li Lu,Yang Yang,Lin Cui-ting,Cao Ying,Zhou Ping-zheng,Guo Jia-yin,Tian Yuan-xin,Pang Jian-xin
Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [ 14 C]-uric acid in URAT1-expressing HEK293 cells with an IC 50 value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC 50 value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC 50 value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg −1 · d −1 ) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg −1 · d −1 ) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.
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Environmental Chemistry Letters
·
2021
·Vol. 19
·期 4
·3511-3515
·
IF 9.027
Si Huimin,Che Mingda,Chen Zhiguo,Qiu Sha,Cui Mei,Huang Renliang,Qi Wei,He Zhimin,Su Rongxin
Chloroform is an harmful chlorinated hydrocarbon which is hardly degraded using actual dechlorination methods. Alternatively, carboxymethyl cellulose/zero-valent iron appears promising to degrade chlorinated hydrocarbons in water, yet actually carboxymethyl cellulose cannot inhibit the oxidation and sedimentation of iron ions under alkaline condition. Here, polyethylene glycol, a green and low-cost non-ionic polymer, was used as a stabilizer to synthesize polyethylene glycol-stabilized Fe/Ni nanoparticles (PEG-Fe/Ni) for removing chloroform from water in a wide range of pH, from 3 to 11. PEG-Fe/Ni was prepared by a stepwise liquid-phase chemical reduction, then added into groundwater to remove chloroform. Results show that polyethylene glycol can both reduce the particle size from 106.9 to 79.6 nm and prevent the oxidation and sedimentation of iron ions under alkaline condition. The removal efficiency of chloroform increased from 86.3 to 100% at pH 6 in the presence of polyethylene glycol, and slightly decreased to 95.4% at pH 11. The calculated rate constant ( k ) indicates that chloroform removal follows pseudo-first-order kinetics. Furthermore, the PEG-Fe/Ni also removed chloroform from real groundwater at pH 8 with an efficiency of 90.1% in 4 h, which is higher than that for Fe/Ni nanoparticles, of 41.7%.
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ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·96-110
·
IF 6.15
Liu Xue-qi,Jiang Ling,Li Yuan-yuan,Huang Yue-bo,Hu Xue-ru,Zhu Wei,Wang Xian,Wu Yong-gui,Meng Xiao-ming,Qi Xiang-ming
Diabetic kidney disease (DKD) is one of the microvascular complications of diabetes mellitus and a major cause of end-stage renal disease with limited treatment options. Wogonin is a flavonoid derived from the root of Scutellaria baicalensis Georgi, which has shown a potent renoprotective effect. But the mechanisms of action in DKD are not fully elucidated. In this study, we investigated the effects of wogonin on glomerular podocytes in DKD using mouse podocyte clone 5 (MPC5) cells and diabetic mice model. MPC5 cells were treated with high glucose (30 mM). We showed that wogonin (4, 8, 16 μM) dose-dependently alleviated high glucose (HG)-induced MPC5 cell damage, accompanied by increased expression of WT-1, nephrin, and podocin proteins, and decreased expression of TNF-α, MCP-1, IL-1β as well as phosphorylated p65. Furthermore, wogonin treatment significantly inhibited HG-induced apoptosis in MPC5 cells. Wogonin reversed HG-suppressed autophagy in MPC5 cells, evidenced by increased ATG7, LC3-II, and Beclin-1 protein, and decreased p62 protein. We demonstrated that wogonin directly bound to Bcl-2 in MPC5 cells. In HG-treated MPC5 cells, knockdown of Bcl-2 abolished the beneficial effects of wogonin, whereas overexpression of Bcl-2 mimicked the protective effects of wogonin. Interestingly, we found that the expression of Bcl-2 was significantly decreased in biopsy renal tissue of diabetic nephropathy patients. In vivo experiments were conducted in STZ-induced diabetic mice, which were administered wogonin (10, 20, 40 mg · kg −1 · d −1 , i.g.) every other day for 12 weeks. We showed that wogonin administration significantly alleviated albuminuria, histopathological lesions, and p65 NF-κB-mediated renal inflammatory response. Wogonin administration dose-dependently inhibited podocyte apoptosis and promoted podocyte autophagy in STZ-induced diabetic mice. This study for the first time demonstrates a novel action of wogonin in mitigating glomerulopathy and podocytes injury by regulating Bcl-2-mediated crosstalk between autophagy and apoptosis. Wogonin may be a potential therapeutic drug against DKD.
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ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2021
·Vol. 413
·期 20
·4939-4945
·
IF 4.157
Guan Shulin,Yue Jing,Sun Weihan,Xu Weiqing,Liang Chongyang,Xu Shuping
A highly sensitive trypsin sensing system in serum was developed by using an anodic alumina oxide (AAO)-based, trypsin substrate-decorated hybrid ion permeation membrane. Owing to the trypsin-triggered peptide hydrolyzation reaction, the surface electrical feature of the peptide-decorated hybrid ion membrane changed. The electric double layer effect reduces the effective ion current diameter in the AAO nano unit, so that the ion current rectification ratio will be enhanced, realizing the quantitative detection of trypsin. The lowest detection concentration can be achieved as low as 0.1 pM. This method is no need for sample pre-preparation, easy to operate, highly sensitive, and also applicable to other enzyme evaluation systems by changing corresponding substrates. This study provides a new idea for selective measurements of proteases in complex biological samples. Graphical abstract
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Nature Communications
·
2021
·Vol. 12
·期 1
·1-10
·
IF 14.919
Li Zishuai,Cheng Simin,Lin Qiaohong,Cao Wenbo,Yang Jing,Zhang Minmin,Shen Aijun,Zhang Wenpeng,Xia Yu,Ma Xiaoxiao,Ouyang Zheng
Single-cell analysis is critical to revealing cell-to-cell heterogeneity that would otherwise be lost in ensemble analysis. Detailed lipidome characterization for single cells is still far from mature, especially when considering the highly complex structural diversity of lipids and the limited sample amounts available from a single cell. We report the development of a general strategy enabling single-cell lipidomic analysis with high structural specificity. Cell fixation is applied to retain lipids in the cell during batch treatments prior to single-cell analysis. In addition to tandem mass spectrometry analysis revealing the class and fatty acyl-chain for lipids, batch photochemical derivatization and single-cell droplet treatment are performed to identify the C=C locations and sn -positions of lipids, respectively. Electro-migration combined with droplet-assisted electrospray ionization enables single-cell mass spectrometry analysis with easy operation but high efficiency in sample usage. Four subtypes of human breast cancer cells are correctly classified through quantitative analysis of lipid C=C location or sn -position isomers in ~160 cells. Most importantly, the single-cell deep lipidomics strategy successfully discriminates gefitinib-resistant cells from a population of wild-type human lung cancer cells (HCC827), highlighting its unique capability to promote precision medicine.
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Biomass Conversion and Biorefinery
·
2021
·Vol. 13
·期 9
·8115-8121
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IF 4.987
Ren Dezhang,Jiang Xuelei,Zhang Nahui,Duo Jia,Norinaga Koyo,Huo Zhibao
Production of pyridine derivatives from bio-based feedstocks instead of fossil fuels is a promising strategy. The development of effective heterogeneous catalysts and mild reaction systems for pyridinization of renewable biomass derivatives remains a huge challenge. In this article, a direct and environment-friendly method was reported to produce 3-hydroxypyridine from bio-based furfural in water over a Raney Fe catalyst. Raney Fe exhibited an efficient catalytic performance for activation of the aldehyde group of furfural and afforded an 18.2% yield of 3-hydroxypyridine at 120 °C with ammonia as N source. The polymerization of furfural on the catalyst in hot water was the main cause of deactivation, which was verified by the scanning electron microscope (SEM), X-ray diffraction (XRD), and N 2 adsorption and desorption analysis. A possible mechanism for this reaction was also proposed. This study provides a new way for academia and industry to realize the synthesis of nitrogen-containing chemicals from biomass and its derivatives.
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FUNCTIONAL & INTEGRATIVE GENOMICS
·
2021
·Vol. 21
·期 5
·557-570
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IF 3.41
Sun Shouxiang,Cao Xiaojuan,Castro L. Filipe C.,Monroig Óscar,Gao Jian
Obesity is a rapidly growing health pandemic, underlying a wide variety of disease conditions leading to increases in global mortality. It is known that the phosphorylation of various proteins regulates sterol regulatory element-binding transcription factors 1 ( srebf1 ), a key lipogenic transcription factor, to cause the development of obesity. To detect the key protein kinases for regulating srebf1 in lipid deposition, we established the srebf1 knockout model in zebrafish (KO, srebf1 −/− ) by CRISPR/Cas9. The KO zebrafish exhibited a significant reduction of total free fatty acid content (fell 60.5%) and lipid deposition decrease compared with wild-type (WT) zebrafish. Meanwhile, srebf1 deletion in zebrafish eliminated lipid deposition induced by high-fat diet feeding. Compared with WT zebrafish, a total of 697 differentially expressed proteins and 316 differentially expressed phosphoproteins with 439 sites were identified in KO by differential proteomic and phosphoproteomic analyses. A significant number of proteins identified were involved in lipid and glucose metabolism. Moreover, some protein kinases critical for regulating srebf1 in lipid deposition, including Cdk2, Pkc, Prkceb, mTORC1, Mapk12, and Wnk1, were determined by network analyses. An in vitro study was performed to verify the network analysis results. Our findings provide potential targets (kinases) for human obesity treatments.
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MICROCHIMICA ACTA
·
2021
·Vol. 188
·期 8
·1-11
·
IF 5.833
Feng Jun,Lu Hao,Yang Yu,Huang Wenyi,Cheng Hao,Kong Hongxing,Li
Lijun
By in situ synthesis of gold nanoparticles (AuNPs) within the acid-etched (AE) MIL-101 (Cr) framework, AE-MIL-101 (Cr) nanocomposites embedded with AuNPs (AuNP/AE-MIL-101 (Cr)) were prepared as surface-enhanced Raman scattering (SERS) substrate. AuNPs are uniformly distributed and stabilized inside the metal-organic framework (MOF), thus forming more SERS hotspots. The SERS performance of AuNP/AE-MIL-101 (Cr) was evaluated using 4-mercaptophenylboronic acid (4-MPBA), 4-mercaptobenzoic acid (4-MBA), benzidine, and rhodamine 6G (R6G). The SERS substrate displays satisfying stability with very low background signal. When benzidine is used as the Raman reporter, the limit of detection (LOD) can reach 6.7 × 10 −13 mol·L −1 , and the relative standard deviation (RSD) of the intra- and inter-batch repetitive tests is less than 5.2%. On this basis, we developed a method for the detection of human carboxylesterase 1 (hCE 1) in human serum using AuNP/AE-MIL-101 (Cr) nanocomposite as SERS substrate and enzyme-linked immunosorbent assay (ELISA) colorimetric substrate as SERS marker. This method was used to determine hCE 1 in clinical serum samples without complicated sample pretreatment, and the detection results were consistent with the data determined by ELISA. In the concentration range 0.1–120 ng·mL −1 , the SERS signal intensity of benzidine at 1609 cm −1 gradually decreases with the increase of hCE 1 concentration (R 2 = 0.9948). The average recoveries of hCE 1 in human serum are in the range 84 to 108%, with RSDs lower than 7.7%. Graphical abstract
By using AuNP/acid etching-MIL-101(Cr) metal organic framework (MOF) as SERS substrate and enzyme-linked immunosorbent assay (ELISA) colorimetric substrate as the SERS marker, a rapid and sensitive method for the determination of human carboxylesterase 1 (hCE1) in human serum samples has been developed.
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CHINESE JOURNAL OF POLYMER SCIENCE
·
2021
·Vol. 39
·期 8
·994-1003
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IF 3.603
Zhang Wan-Bin,Luo Jie,Wang Yan-Meng,Zhu Xiu-Zhong,Zhang Ce,Liu Jing,Ni Mei-Le,Zhang Guang-Hua
A series of hydroxyl-terminated polyethylenes (HTPE) bearing various functional side groups ( e.g. carboxyl, ester and butane groups) were synthesized by the combination of ring-opening metathesis polymerization (ROMP) and visible light photocatalytic thiol-ene reaction. The products are named as α, ω -dihydroxyl-poly[(propionyloxythio)methinetrimethylene] (HTPE carboxyl ), α, ω -dihydroxyl-poly[(methylpropionatethio) methinetrimethylene] (HTPE ester ) and α, ω -dihydroxyl-poly[(butylthio) methinetrimethylene] (HTPE butane ), respectively. The investigation of ROMP indicated that the molecular weight of resultant hydroxyl-terminated polybutadiene (HTPB) can be tailored by varying the feed ratios of monomer to chain transfer agent (CTA). The exploration of the photocatalytic thiol-ene reaction between HTPB precursor and methyl 3-mercaptopropionate revealed that blue light as well as oxygen accelerated the reaction. 1 H-NMR and 13 C-NMR results verified all the double bonds in HTPB can be modified, and the main chain of resultant polymer can be considered as polyethylene. Subsequently, relationship between the structure of side groups and the thermal properties of functional PEs was studied. And the results suggested that the T g was in the order of HTPE butane
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IONICS
·
2021
·Vol. 27
·期 7
·3099-3108
·
IF 2.817
Cheng Yu,Zhan Yanhu,Ran JiaJia,Wang Zhanhua,Agnoli Stefano,Xia Hesheng,Granozzi Gaetano
Hybrid MXene/reduced graphene oxide aerogel microspheres (MXene/rGOAMs),where MXenes are two-dimensional (2D) transition metal carbides, with abundant macro/meso/micro multi-scale pores and self-supporting structure, are prepared by electrospraying followed by freeze-drying and then thermal annealing. A center-diverging structure with well-aligned microchannels is formed within each microsphere, which can be maintained after thermal reduction. Such highly ordered 3D hybrid mesoporous network has been tested for the hydrogen evolution reaction (HER) because it may prevent the stacking of the 2D layers, thus enhancing the mass transfer. Actually, in the case of Ti 3 C 2 T x /rGOAMs, obtained with an optimized MXene:GO mass ratio and after a thermal treatment at 400 °C, a better HER performance with respect to the bulk Ti 3 C 2 T x aerogel or the MXene/GO composite is observed ( η 10 = -336 mV), suggesting an accelerated mass transfer through different inter-sheets when the 3D mesoporous microsphere networks are created. The Ti 3 C 2 T x /rGOAMs also exhibit enhanced HER activity compared to rGOAMs, suggesting that the MXene plays a key role due to the presence of titanium atoms with a low valence state. Graphical abstract
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MEDICINAL CHEMISTRY RESEARCH
·
2021
·Vol. 30
·期 6
·1240-1248
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IF 1.965
Shi Bo-Ya,Wang Ze-Hao,Zhang Ning,Xie Yin-Rong,Sun Xiu-Li,Yang Hao-Nan,Wu Yi-Long,Zi Cheng-Ting,Wang Xuan-Jun,Sheng Jun
Novel glucosylated (-)-epigallocatechin-3-gallate derivatives 10 – 13 having the EGCG analogs conjugated to the d -glucosyl azide were synthesized by carrying out the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, and were evaluated for their cytotoxicities against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) using MTT assays. Compounds 10 and 11 showed the highest levels of cytotoxicity against the HL-60 cells with IC 50 values of 4.57 and 3.78 μM, respectively, and showed moderate selectivity toward cancer cell lines. Compound 11 was also shown to induce apoptosis in HL-60 cells. Most notably, inclusion of the perbutyrylated glucose residue in an EGCG derivative was concluded to lead to increased anticancer activity.
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