MOLECULES
·
2023
·Vol. 28
·期 17
·6303
·
IF 4.6
Chuhong Chen,Ying Deng,Linyan Liu,Zhenyan Zou,Chenzhong Jin,Zhiyin Chen,Shuanghui Wang
Deltamethrin (DM), a Type II pyrethroid, is widely used worldwide in agriculture, household applications, and medicine. Recent studies have shown that DM exerts a variety of toxic effects on organs such as the kidney, heart muscle, and nerves in animals. However, little is known about the effects of high-dose DM on growth and development, and the mechanism of toxicity remains unclear. Using theCaenorhabditis elegansmodel, we found that high-dose DM caused a delay in nematode development. Our results showed that high-dose DM reduced the activation of the endoplasmic reticulum unfolded protein response (UPRER). Further studies revealed that high-dose DM-induced developmental toxicity and reduced capacity for UPRERactivation were associated with the IRE-1/XBP-1 pathway. Our results provide new evidence for the developmental toxicity of DM and new insights into the mechanism of DM toxicity.Keywords:deltamethrin;Caenorhabditis elegans;development;toxicity;endoplasmic reticulum unfolded protein response
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Hewen Qian,Yuanqing Ding,Xingyu Deng,Weiwei Huang,Zhenzhen Li,Fengling Liu,Jie Zhang,Lihui Wang,Junping Liu,Yaxia Yuan,Shurong Hou,Xiabin Chen,Lei Ma
Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c -Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC 50 = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC 50 = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis . Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001 . Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.
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PEST MANAGEMENT SCIENCE
·
2023
·
IF 4.1
Yifan Li,Shujun Ni,Yunping Wang,Ruichi Li,Hong Sun,Xuan Ye,Zhen Tian,Yalin Zhang,Jiyuan Liu
BACKGROUND Insecticide resistance continuously poses a threat to agricultural production. Chemosensory protein-mediated resistance is a new mechanism of insecticide resistance discovered in recent years. In-depth research on resistance mediated by chemosensory proteins (CSPs) provides new insight into aid insecticide resistance management. RESULTS Chemosensory protein 1 in Plutella xylostella ( PxCSP1 ) was overexpressed in the two indoxacarb-resistant field populations and PxCSP1 has a high affinity with indoxacarb. PxCSP1 was upregulated when exposed to indoxacarb and the knockdown of this gene elevated sensitivity to indoxacarb, which demonstrate that PxCSP1 is involved in the indoxacarb resistance. Considering that CSPs may confer resistance in insects via binding or sequestering, we explored the binding mechanism of indoxacarb in PxCSP1 -mediated resistance. Using molecular dynamics simulations and site-directed mutation, we found that indoxacarb forms a solid complex with PxCSP1 mainly through van der Waals interactions and electrostatic interactions. Between these, the electrostatic interaction provided by the Lys100 side chain in PxCSP1 , and especially the hydrogen bonding between the NZ atom and the O of the carbamoyl carbonyl group of indoxacarb, are the key factors for the high affinity of PxCSP1 to indoxacarb. CONCLUSIONS The overexpression of PxCPS1 and its high affinity to indoxacarb is partially responsible for indoxacarb resistance in P. xylostella . Modification of indoxacarb's carbamoyl group has the potential to alleviate indoxacarb resistance in P. xylostella . These findings will contribute to solving chemosensory protein-mediated indoxacarb resistance and provide a better understanding of the insecticide resistance mechanism. © 2023 Society of Chemical Industry.
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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
·
2022
·Vol. 120
·期 1
·e2209339120
·
IF 12.779
Fei Qiao,Yuedong He,Yuhao Zhang,Xuefei Jiang,Hanqing Cong,Zhiming Wang,Huapeng Sun,Yibei Xiao,Yucheng Zhao,Peter Nick
Cephalotaxines harbor great medical potential, but their natural source, the endemic conifer Cephalotaxus is highly endangered, creating a conflict between biotechnological valorization and preservation of biodiversity. Here, we construct the whole biosynthetic pathway to the 1-phenethylisoquinoline scaffold, as first committed compound for phenylethylisoquinoline alkaloids (PIAs), combining metabolic modeling, and transcriptome mining of Cephalotaxus hainanensis to infer the biosynthesis for PIA precursor. We identify a novel protein, ChPSS, driving the Pictet–Spengler condensation and show that this enzyme represents the branching point where PIA biosynthesis diverges from the concurrent benzylisoquinoline-alkaloids pathway. We also pinpoint ChDBR as crucial step to form 4-hydroxydihydrocinnamaldehyde diverging from lignin biosynthesis. The elucidation of the early PIA pathway represents an important step toward microbe-based production of these pharmaceutically important alkaloids resolving the conflict between biotechnology and preservation of biodiversity.
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JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
·
2018
·Vol. 18
·期 4
·2601-2608
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IF 1.354
Lin Jinrui,Ni Xiuyuan
In this study, a photochemical polymerization using graphene oxide (GO) as an initiator generated a new composite film with poly(1-vinylimidazole) (PVI) covered the GO sheets. Atomic force microscopy and infrared spectroscopy revealed the uniform layering of the PVI on the sheets. An
ITO/GO–PVI/Cu device was fabricated from this synthesized film, and it exhibited a write-once-read-many-times (WORM) memory functionality with resistance switching under an applied voltage of −3.2 V. The ON/OFF current ratio of the device reached 106. An analysis of the current–voltage
characteristics of the device indicated that the ON-state charge transport followed Ohmic conduction with metallic behavior, while the OFF-state charge transport was dominated by a trap-limited space charge limited conduction.
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BIOSCIENCE REPORTS
·
2018
·Vol. 38
·期 2
·
IF 2.899
Wang Qian,He Yuan,Lu Rui,Wang Wen-Ming,Yang Ke-Wu,Fan Hai Ming,Jin Yi,Blackburn G. Michael
The New Delhi metallo-β-lactamase (NDM-1) is an important clinical target for antimicrobial research, but there are insufficient clinically useful inhibitors and the details of NDM-1 enzyme catalysis remain unclear. The aim of this work is to provide a thermodynamic profile of NDM-1 catalysed hydrolysis of β-lactams using an isothermal titration calorimetry (ITC) approach and to apply this new method to the identification of new low-molecular-weight dicarboxylic acid inhibitors. The results reveal that hydrolysis of penicillin G and imipenem by NDM-1 share the same thermodynamic features with a significant intrinsic enthalpy change and the release of one proton into solution, while NDM-1 hydrolysis of cefazolin exhibits a different mechanism with a smaller enthalpy change and the release of two protons. The inhibitory constants of four carboxylic acids are found to be in the micromolar range. The compounds pyridine-2,6-dicarboxylic acid and thiazolidine-2,4-dicarboxylic acid show the best inhibitory potency and are confirmed to inhibit NDM-1 using a clinical strain of Escherichia coli. The pyridine compound is further shown to restore the susceptibility of this E. coli strain to imipenem, at an inhibitor concentration of 400 μM, while the thiazoline compound also shows a synergistic effect with imipenem. These results provide valuable information to enrich current understanding on the catalytic mechanism of NDM-1 and to aid the future optimisation of β-lactamase inhibitors based on these scaffolds to tackle the problem of antibiotic resistance.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2017
·
IF 3.743
Xiong Pan,Saige Wang,Nan Shi,Hua Fang,Yunlong Yu
The application of the herbicide chlorimuron-ethyl has a lasting toxic effect on some succession crops. Here, a bacterium capable of utilizing chlorimuron-ethyl as the sole source of nitrogen was isolated from the contaminated soil and was identified as Enterobacter ludwigii sp. CE-1, and its detoxification and degradation of the herbicide were then examined. The biodegradation of chlorimuron-ethyl by the isolate CE-1 was significantly accelerated with increasing concentration (1–10 mg/l) and temperature (20–40 °C). The optimal pH for the degradation of chlorimuron-ethyl by the isolate CE-1 was pH 7.0. A pathway for the biodegradation of chlorimuron-ethyl by the isolate CE-1 was proposed, in which it could be first converted into 2-amino-4-chloro-6-methoxypyrimidine and an intermediate product by the cleavage of the sulfonylurea bridge and then transformed into saccharin via hydrolysis and amidation. The plant height and fresh weight of corn that had been incubated in nutrient solution containing 0.2 mg/l of chlorimuron-ethyl significantly recovered to 83.9% and 83.1% compared with those in the uninoculated control, although the root growth inhibition of chlorimuron-ethyl could not be alleviated after inoculation for 14 d. The results indicate that the isolate CE-1 is a promising bacterial resource for the biodegradation and detoxification of chlorimuron-ethyl.
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Nature Communications
·
2024
·Vol. 15
·期 1
·1-12
·
IF 14.7
Ren Yuqi,Fu Yiwei,Li Naixu,You Changjun,Huang Jie,Huang Kai,Sun Zhenkun,Zhou Jiancheng,Si Yitao,Zhu Yuanhao,Chen Wenshuai,Duan Lunbo,Liu Maochang
H 2 O dissociation plays a crucial role in solar-driven catalytic CO 2 methanation, demanding high temperature even for solar-to-chemical conversion efficiencies <1% with modest product selectivity. Herein, we report an oxygen-vacancy (V o ) rich CeO 2 catalyst with single-atom Ni anchored around its surface V o sites by replacing Ce atoms to promote H 2 O dissociation and achieve effective photothermal CO 2 reduction under concentrated light irradiation. The high photon flux reduces the apparent activation energy for CH 4 production and prevents V o from depletion. The defects coordinated with single-atom Ni, significantly promote the capture of charges and local phonons at the Ni d -impurity orbitals, thereby inducing more effective H 2 O activation. The catalyst presents a CH 4 yield of 192.75 µmol/cm 2 /h, with a solar-to-chemical efficiency of 1.14% and a selectivity ~100%. The mechanistic insights uncovered in this study should help further the development of H 2 O-activating catalysts for CO 2 reduction and thereby expedite the practical utilization of solar-to-chemical technologies.
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2025
·Vol. 55
·期 3
·1-14
·
IF 5.8
Yixuan Ma,Yimin Huang,Xuyang Liu,Liwu Jiao,Hongtao Zhu,Zhiye Chen,Zhuojin Wu,Yuanzhong Shen,Kehan Lin,Feng Hu,Kai Shu
The present study investigated the mechanisms by which aquaporin 1 (AQP1) influences microglial polarization and neuroinflammatory processes in traumatic brain injury (TBI). A model of TBI was generated in AQP1‑knockout mice to assess the impact of AQP1 deletion on inflammatory cytokine release, neuronal damage and cognitive function. Immunofluorescence, reverse transcription‑quantitative PCR, western blotting and enzyme‑linked immunosorbent assay were employed to evaluate pro‑inflammatory and anti‑inflammatory markers. Behavioral assessments, including the Barnes maze, were performed to determine cognitive outcomes. Moreover, AQP1 knockout inhibited the activation of inflammation‑related signaling pathways, including nuclear factor‑κB, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3‑kinase/protein kinase B and extracellular signal‑regulated kinase/mitogen‑activated protein kinase pathways. Further studies indicated that the AQP1 inhibitor m‑phenylenediacrylic acid demonstrated significant neuroprotective effects in a mouse model of TBI. These findings suggested that AQP1 may be essential in post‑TBI inflammatory responses and neuronal injury, establishing a theoretical foundation for future therapies aimed at AQP1.
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JOURNAL OF NEUROCHEMISTRY
·
2015
·Vol. 134
·期 5
·904-914
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IF 4.281
Zhuang Wu,Linlang Li,Long-Tai Zheng,Zhihong Xu,Lin Guo,Xuechu Zhen
Recent studies have shown that sigma-1 receptor orthodox agonists can inhibit neuroinflammation. SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 agonist, has been recently identified as a potent allosteric modulator of sigma-1 receptor. Here, we investigated the anti-inflammatory effects of SKF83959 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Our results indicated that SKF83959 significantly suppressed the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and inhibited the generation of reactive oxygen species. All of these responses were blocked by selective sigma-1 receptor antagonists (BD1047 or BD1063) and by ketoconazole (an inhibitor of enzyme cytochrome c 17 to inhibit the synthesis of endogenous dehydroepiandrosterone, DHEA). Additionally, we found that SKF83959 promoted the binding activity of DHEA with sigma-1 receptors, and enhanced the inhibitory effects of DHEA on LPS-induced microglia activation in a synergic manner. Furthermore, in a microglia-conditioned media system, SKF83959 inhibited the cytotoxicity of conditioned medium generated by LPS-activated microglia toward HT-22 neuroblastoma cells. Taken together, our study provides the first evidence that allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. SKF83959 is a potent allosteric modulator of sigma-1 receptor. Our results indicated that SKF83959 enhanced the activity of endogenous dehydroepiandrosterone (DHEA) in a synergic manner, and inhibited the activation of BV2 microglia and the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS).
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CHINESE JOURNAL OF CATALYSIS
·
2015
·
IF 1.964
Xiaoming Zhang,Shengmei Lu,Mingmei Zhong,Yaopeng Zhao,Qihua Yang
Rh-PPh 3 -polymer@mesosilica composites were prepared by the polymerization of mixtures of divinylbenzene (DVB) and 4-vinyl-triphenylphosphine monomer in the nanopores of mesoporous silicas followed by coordination with Rh(acac)(CO) 2 (acac =acetylacetonate). These catalysts were characterized by XRD, N 2 sorption , TEM, FT-IR, and TG, and could efficiently catalyze the hydroformylation of 1-octene with higher activity than a pure polymer catalyst because of their high surface area and large pore volume, which were beneficial for the exposure of active sites and mass transport. Through the control of pore size and pore connectivity by using different mesoporous silica (MCM-41, SBA-15, and FDU-12), the activity and selectivity can be controlled. Rh-PPh 3 -polymer@FDU-12 with a cage-like mesostrucuture showed lower activity but slightly higher selectivity than the catalyst with a 2-D hexagonal mesostructure (Rh-PPh 3 -polymer@SBA-15 or Rh-PPh 3 -polymer@MCM-41). By varying the polymer content in the nanopores of the mesosilica, the activity and selectivity (92%–96%) can also be tuned. The solid composite catalyst can be recycled without loss of activity, but a decrease in selectivity was observed.
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RSC Advances
·
2016
·Vol. 6
·期 113
·112445-112450
·
IF 3.289
Shanni Hong,Na Sun,Min Liu,Jine Wang,Renjun Pei
Galectin-1 is closely related with immune systems, and its overexpression may cause tumor metastasis. Owing to the better stability of antisense oligonucleotides than siRNA, we constructed a chimera of aptamer–antisense oligonucleotide (Apt–AS) for silencing the galectin-1 gene specifically. For studying the endocytosis pathways of Apt–AS by aptamer targeted delivery, we marked the 3′ terminus of Apt–AS with Alexa Flour 488 (Apt–AS488) so as to trace the pathways through the confocal microscope. Furthermore, Apt–AS was used to silence the expression of galectin-1. The results showed Apt–AS entered cells by a caveolae mediated endocytosis pathway, and the aptamer–antisense chimeras did not impair the antisense gene silencing efficiency. Moreover Apt–AS could improve the cellular uptake and selectively entered cells.
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