CHEMISTRY & BIODIVERSITY
·
2022
·Vol. 19
·期 11
·e202200414
·
IF 2.745
Xin-Yu Lei,Shao-Huan Liu,Ya-Xian Zhao,Meng-Jia Guo,Ling Tao,Xiang-Chun Shen,Nen-Ling Zhang
A pair of new lignan conformers ( 1 – 2 ), one new flavonoid glycoside ( 3 ), as well as nineteen known compounds were purified from the twigs and leaves of Cajanus cajan (L.) Millsp.. The planar structures of the unknown compounds were determined via NMR and high-resolution mass spectrometry, while their absolute configurations were elucidated via comparison between their experimental and calculated electronic circular dichroism (ECD) values. All the isolated compounds were assayed for their α -glucosidase inhibitory activities. The results demonstrated that compounds 8 – 12 , 15 – 16 , 18 – 19 , 21 – 22 had strong inhibition activities, with compound 10 (IC 50 =0.4±0.21 μM) most active. The structure-activity relationships were preliminarily summarized. Enzyme kinetics showed that compounds 8 , 9 , 15 – 16 , 18 – 19 , 21 – 22 were non-competitive inhibitors and compounds 10 – 12 were anti-competitive ones. Graphical
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Drug Design Development and Therapy
·
2022
·
IF 4.319
Nianxiu Tian,Yanbin Gao,Xiaolei Wang,Xiaoming Wu,Dawei Zou,Zhiyao Zhu,ZheJi Han,Tao Wang,Yimin Shi
Background Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown.Aim This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK–eIF2α pathway.Methods KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopathology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time PCR were used to detect gene and protein expression both in vivo and in vitro.Results The results showed that emodin treatment ameliorated urine albumin, serum creatinine, and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes apoptosis and endoplasmic reticulum stress markers (GRP78) were significantly reduced upon emodin treatment. Furthermore, emodin treatment decreased the expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (P-PERK), phosphorylated P-eIF2α, ATF4, and CHOP. In vitro, emodin treatment was further found to decrease the GRP78 level induced by high glucose or tunicamycin (TM). Besides, emodin and PERK knockdown inhibited the apoptosis of podocytes cultured in high glucose by counteracting the upregulation of phosphorylated PERK, phosphorylated eIF2α, ATF4, and CHOP.Conclusion Overall, the findings indicate that emodin mitigates podocytes apoptosis by inhibiting the PERK-eIF2α signaling pathway in vivo and in vitro, and, therefore, exerts a protective action on podocytes in DN.
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MOLECULES
·
2022
·Vol. 27
·期 22
·7971
·
IF 4.927
Yijing Liao,Xi Mai,Xiaqing Wu,Xing Hu,Xiaoqiao Luo,Guowen Zhang
This study investigated the inhibitory mechanism of quercetin in acetylcholinesterase (AChE) and its neuroprotective effects on β-amyloid25–35-induced oxidative stress injury in PC12 cells. Quercetin inhibited AChE in a reversible mixed manner with an IC50of 4.59 ± 0.27 µM. The binding constant of quercetin with AChE at 25 °C was (5.52 ± 0.05) × 104L mol−1. Hydrogen bonding and van der Waals forces were the main interactions in forming the stable quercetin–AChE complex. Computational docking revealed that quercetin was dominant at the peripheral aromatic site in AChE and induced enzymatic allosterism; meanwhile, it extended deep into the active center of AChE and destabilized the hydrogen bond network, which caused the constriction of the gorge entrance and prevented the substrate from entering the enzyme, thus resulting in the inhibition of AChE. Molecular dynamics (MD) simulation emphasized the stability of the quercetin–AChE complex and corroborated the previous findings. Interestingly, a combination of galantamine hydrobromide and quercetin exhibited the synergistic inhibition effect by binding to different active sites of AChE. In a β-amyloid25–35-induced oxidative stress injury model in PC12 cells, quercetin exerted neuroprotective effects by increasing the glutathione level and reducing the malondialdehyde content and reactive oxygen species levels. These findings may provide novel insights into the development and application of quercetin in the dietary treatment of Alzheimer’s disease.Keywords:acetylcholinesterase;quercetin;inhibitory mechanism;computational docking;oxidative stress
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PHYTOMEDICINE
·
2022
·
IF 6.656
Chang-Long He,Yong Tang,Xue Chen,Tao Long,Yan-Ni He,Jing Wei,Jian-Ming Wu,Cai Lan,Lu Yu,Fei-Hong Huang,Cong-Wei Gu,Jian Liu,Chong-Lin Yu,Vincent Kam-Wai Wong,Betty Yuen-Kwan Law,Da-Lian Qin,An-Guo Wu,Xiao-Gang Zhou
Background Protein aggregates are considered key pathological features in neurodegenerative diseases (NDs). The induction of autophagy can effectively promote the clearance of ND-related misfolded proteins. Objective In this study, we aimed to screen natural autophagy enhancers from traditional Chinese medicines (TCMs) presenting potent neuroprotective potential in multiple ND models. Methods The autophagy enhancers were broadly screened in our established herbal extract library using the transgenic Caenorhabditis elegans ( C. elegans ) DA2123 strain. The neuroprotective effects of the identified autophagy enhancers were evaluated in multiple C. elegans ND models by measuring Aβ-, Tau-, α-synuclein-, and polyQ40-induced pathologies. In addition, PC-12 cells and 3 × Tg-AD mice were employed to further validate the neuroprotective ability of the identified autophagy enhancers, both in vitro and in vivo . Furthermore, RNAi bacteria and autophagy inhibitors were used to evaluate whether the observed effects of the identified autophagy enhancers were mediated by the autophagy-activated pathway. Results The ethanol extract of Folium Hibisci Mutabilis (FHME) was found to significantly increase GFP::LGG-1-positive puncta in the DA2123 worms. FHME treatment markedly inhibited Aβ , α-synuclein, and polyQ40, as well as prolonging the lifespan and improving the behaviors of C. elegans , while siRNA targeting four key autophagy genes partly abrogated the protective roles of FHME in C. elegans . Additionally, FHME decreased the expression of AD-related proteins and restored cell viability in PC-12 cells, which were canceled by cotreatment with 3-methyladenine (3-MA) or bafilomycin A1 (Baf). Moreover, FHME ameliorated AD-like cognitive impairment and pathology, as well as activating autophagy in 3 × Tg-AD mice. Conclusion FHME was successfully screened from our natural product library as a potent autophagy enhancer that exhibits a neuroprotective effect in multiple ND models across species through the induction of autophagy. These findings offer a new and reliable strategy for screening autophagy inducers, as well as providing evidence that FHME may serve as a possible therapeutic agent for NDs.
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PHYTOMEDICINE
·
2022
·
IF 6.656
Xun Sun,Xinyu Zhang,Hui Yan,Hongfei Wu,Shijian Cao,Wenchen Zhao,Ting Dong,An Zhou
Background Hepatolenticular degeneration (HLD) is an autosomal recessive disorder concerning copper metabolism . Copper overload is also accompanied by iron overload in HLD patients , which can lead to ferroptosis . Curcumin , the active component in turmeric, has the potential to inhibit ferroptosis. Purpose The current study proposed a systematic investigation of the protective effects of curcumin against HLD and the underlying mechanisms. Methods The protective effect of curcumin on toxic milk (TX) mice was studied. Liver tissue was observed via hematoxylin-eosin (H&E) staining and the ultrastructure of the liver tissue was observed through transmission electron microscopy . Copper levels in the tissues, serum, and metabolites were measured by atomic absorption spectrometry (AAS). In addition, serum and liver indicators were evaluated. In cellular experiments, the effect of curcumin on the viability of rat normal liver cells (BRL-3A) was determined via the 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay. Cell and mitochondrial morphology were observed in curcumin-mediated HLD model cells. The intracellular copper ion fluorescence intensity was observed via fluorescence microscopy , and intracellular copper iron content was detected using AAS. Further, oxidative stress indicators were evaluated. Cellular reactive oxygen species (ROS) and cellular mitochondrial membrane potential were examined via flow cytometry. Furthermore, the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) were determined via western blotting (WB). Results The histopathology of the liver confirmed the hepatoprotective effects of curcumin. Curcumin improved copper metabolism in TX mice. Both serum liver enzyme markers and antioxidant enzyme levels indicated the protective effect of curcumin against HLD-related liver injury. The MTT assay results showed that curcumin was protective against excess copper-induced injury. Curcumin improved the morphology of HLD model cells and their mitochondrial morphology. The Cu 2+ fluorescent probe and the AAS results indicated that curcumin reduced Cu 2+ content in HLD hepatocytes. In addition, curcumin improved oxidative stress levels and prevented the decline of mitochondrial membrane potential in HLD model cells. The ferroptosis inducer Erastin reversed these effects of curcumin. WB revealed that curcumin promoted Nrf2, HO-1, and GPX4 protein expression in HLD model cells, and the Nrf2 inhibitor ML385 reversed the effects of curcumin. Conclusion Curcumin demonstrates a protective role by expelling copper and inhibiting ferroptosis, activating the Nrf2/HO-1/GPX4 signaling pathway in HLD.
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ACS Omega
·
2022
·
IF 4.132
Xiudi Zhou,Qiang Chen,Chunjing Guo,Yanguo Su,Huimin Guo,Min Cao,Zhongxin Liu,Dandan Zhang,Ningning Diao,Huaying Fan,Daquan Chen
For the therapy attenuating renal ischemia–reperfusion (IR) injury, a novel drug delivery system was urgently needed, which could precisely deliver drugs to the pathological renal tissue. Here, we have prepared new nanomaterials with a reactive oxygen species (ROS)-responsive hydrogen sulfide (H2S) donor and hyaluronic acid that targets CD44 receptor. The novel material was synthesized and characterized via related experiments. Then, rapamycin was loaded, which inhibited kidney damage. In the in vitro study, we found that the micelles had ROS-responsiveness, biocompatibility, and cell penetration. In addition, the experimental results showed that the intracellular H2S concentration after administration was threefold higher than that of the control group. The western blot assay revealed that they have anti-inflammatory effects via H2S donor blocking the NF-κB signaling pathway. Consequently, the rising CD44 receptor-targeting and ROS-sensitive H2S donor micelles would provide a promising way for renal IR injury. This work provides a strategy for improving ischemia/reperfusion injury for pharmaceuticals.
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Advanced Materials Technologies
·
2022
·Vol. 8
·期 5
·2201559
·
IF 8.856
Qingli Qu,Weixia Cheng,Xiaoli Zhang,Hossein Ravanbakhsh,Guosheng Tang,Aying Zhou,Dong Pei,Ranhua Xiong,Chaobo Huang
Enzymatic cascade reactions are essential for metabolic pathway and biological signal transduction in living cells. More and more attention has been paid to artificial microreactors, which mimic these efficient, methodical, and selective biological cascade catalytic systems in cells. Natural hydrogels such as alginate and chitosan are thought of as suitable materials for matching the chemical, physical, and mechanical properties with extracellular matrix. Inspired by the structures of eukaryotic cells, alginate/chitosan multicompartment microcapsules for enzymatic cascade reaction are developed using an oil-free gas-shearing method. Multiple enzymes as biocatalysts are encapsulated in the particles to resemble complex physiological reactions. Biocatalysts, including glucose oxidase and peroxidase in alginate Janus core as a model, sense the external hyperglycemic environment, resulting in insulin release following chitosan shell protonation. The microcapsules show an excellent recyclability, room-temperature long-term and anti-proteolysis stability. The microreactor approach leads to the development of a multi-enzymatic cascade reaction system and provides an ideal carbohydrate platform to further understand the biomimetic metabolic function of organelles and organs.
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ULTRASONICS SONOCHEMISTRY
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2022
·
IF 9.336
Na Li,Ke-Xin Zhang,Jia-Yi Du,Zhi-Feng Tan,Yun-Peng Xu,Xiao-Yang Liu,Da-Yong Zhou,De-Yang Li
The effects of high-intensity ultrasound on the physicochemical and gelling properties of Litopenaeus vannamei ( L. vannamei ) myofibrillar protein (MP) were investigated. MP solutions were subjected to ultrasound treatment (power 100 W, 300 W, and 500 W). It was found that the carbonyl and free amino contents of MP increased significantly with increasing ultrasound power, accompanied by enhanced emulsification properties. The increase of free radical and carbonyl content indicated that ultrasound induced the oxidation of MP. With the increase of ultrasound power, it was found that the total sulfhydryl content of the shrimp MP decreased, but the surface hydrophobicity increased significantly, which might be closely related to the conformational changes of MP. Meanwhile, a significant increase of β-sheet but a decrease of α-helix in the secondary structure of MP was observed with increasing ultrasound power, indicating that ultrasound treatment induced the stretching and flexibility of MP molecules. SDS-PAGE showed that L. vannamei MP consisted of myosin heavy chain, actin, myosin light chain, paramyosin and tropomyosin. Ultrasound treatment could lead to some degree of oxidative aggregation of MP. The results of rheological properties indicated that ultrasound treatment enhanced the viscoelasticity of MP and further improved the gel strength of MP gel. This study can provide a theoretical basis for the functional modification of shrimp MP and the processing of its surimi products.
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Chemosensors
·
2022
·Vol. 10
·期 11
·443
·
IF 4.229
Luyi Zhu,Qinan Zhou,Wenqing Shao,Zhenbo Wei,Jun Wang
A novel Co-based organic frameworks/carbon nanotubes/silicon dioxide (Co-MOF/CNTs/SiO2)-modified Au electrode was fabricated and taken as a platform for gallic acid (GA) detection. The composite combined the advantages of Co-MOF, CNTs and SiO2, and higher electrochemical response of Co-MOF/CNTs/SiO2-modified electrode indicated that the composite material exhibited satisfied the catalytic activity towards GA. Moreover, the electrochemical oxidation process of GA was deeply investigated on the surface of electrode based on computational investigations. Hirshfeld charges and condensed Fukui functions of each atom in GA were calculated. Besides, the catalysis of Co-MOF to GA was further investigated based on density functional theory. The quantitative determination of GA was carried out and showed a linear range between 0.05–200 μM, with low limit of detection. The sensitivity value of the self-assembled electrochemical sensor was calculated to be 593.33 μA cm−2mM−1, and the selectivity, reproducibility and stability of the gallic acid sensor were also confirmed in the study.Keywords:gallic acid;electrochemical;electro-oxidation;detection;density functional theory
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MOLECULES
·
2022
·Vol. 27
·期 20
·6929
·
IF 4.927
Lei Yang,Mohammad Javad Afshari,Jianxian Ge,Dandan Kou,Lei Chen,Dandan Zhou,Cang Li,Shuwang Wu,Leshuai Zhang,Jianfeng Zeng,Jian Zhong,Roland H. Stauber,Mingyuan Gao
Hypoxia is a common biological condition in many malignant solid tumors that plays an imperative role in regulating tumor growth and impacting the treatment’s therapeutic effect. Therefore, the hypoxia assessment is of great significance in predicting tumor development and evaluating its prognosis. Among the plenty of existing tumor diagnosis techniques, magnetic resonance imaging (MRI) offers certain distinctive features, such as being free of ionizing radiation and providing images with a high spatial resolution. In this study, we develop a fluorescent traceable and hypoxia-sensitiveT1-weighted MRI probe (Fe3O4-Met-Cy5.5) via conjugating notable hypoxia-sensitive metronidazole moiety and Cy5.5 dye with ultrasmall iron oxide (Fe3O4) nanoparticles. The results of in vitro and in vivo experiments show that Fe3O4-Met-Cy5.5 has excellent performance in relaxivity, biocompatibility, and hypoxia specificity. More importantly, the obvious signal enhancement in hypoxic areas indicates that the probe has great feasibility for sensing tumor hypoxia viaT1-weighted MRI. These promising results may unlock the potential of Fe3O4nanoparticles asT1-weighted contrast agents for the development of clinical hypoxia probes.Keywords:tumor hypoxia;ultrasmall iron oxide nanoparticles;magnetic resonance imaging;metronidazole
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FOOD RESEARCH INTERNATIONAL
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2022
·
IF 7.425
Wen-Juan Pan,Lu-Lu Shi,Yu-Ru Ren,Cheng-Ying Yao,Yong-Ming Lu,Yan Chen
Age-associated increase in intestinal permeability is known to relate with gut microbiota dysbiosis and loss of epithelial tissue integrity. To improve healthy aging and prevent age-associated chronic disabilities, the protective potential of polysaccharides from Oudemansiella raphanipes (ORP-1) against age-associated intestinal epithelial barrier dysfunction in d -galactose-induced Caco-2 cells monolayer was investigated. In-vitro results demonstrated that ORP-1 can restore a healthy gut microbial population to handle age-related gut microbiota dysbiosis mainly by facilitating the proliferation and adhesion of probiotics Lactobacillus acidophilus ( L. acidophilus ) and Bifidobacterium bifidum ( B. bifidum ) to compete with intestinal pathogenic Escherichia coli ( E. coli ) for ecological niches and nutrition. Meanwhile, ORP-1 strengthened the intestinal structural integrity primarily by abolishing the aggravation of apoptosis and the age-associated alterations of tight junction (TJ) proteins expression in intestine. These findings highlighted that ORP-1 could be a potential functional food component with preventive utility against age-associated intestinal barrier injury.
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Asian Journal of Pharmaceutical Sciences
·
2022
·
IF 9.273
Gaofeng Shu,Lin Shen,Jiayi Ding,Junchao Yu,Xiaoxiao Chen,Xiaoju Guo,Enqi Qiao,Yaning Chen,Chenying Lu,Zhongwei Zhao,Yongzhong Du,Minjiang Chen,Jiansong Ji
The development of novel theranostic agents with outstanding diagnostic and therapeutic performances is still strongly desired in the treatment of hepatocellular carcinoma (HCC). Here, a fucoidan-modified mesoporous polydopamine nanoparticle dual-loaded with gadolinium iron and doxorubicin (FMPDA/Gd 3+ /DOX) was prepared as an effective theranostic agent for magnetic resonance imaging (MRI)-guided chemo-photothermal therapy of HCC. It was found that FMPDA/Gd 3+ /DOX had a high photothermal conversion efficiency of 33.4% and excellent T 1 −MRI performance with a longitudinal relaxivity (r 1 ) value of 14.966 mM −1 · s − 1 . Moreover, the results suggested that FMPDA/Gd 3+ /DOX could effectively accumulate into the tumor foci by dual-targeting the tumor-infiltrated platelets and HCC cells, which resulted from the specific interaction between fucoidan and overexpressed p-selectin receptors. The excellent tumor-homing ability and MRI-guided chemo-photothermal therapy therefore endowed FMPDA/Gd 3+ /DOX with a strongest ability to inhibit tumor growth than the respective single treatment modality. Overall, our study demonstrated that FMPDA/Gd 3+ /DOX could be applied as a potential nanoplatform for safe and effective cancer theranostics
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