机械工程学报

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里送审, 胡春华

, doi: rhnk.1013934/rhnk2021.0003

[摘要](17) [PDF 0KB](0)

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探讨基于Caprini 风险评估模型进行 DVT风险评估，并根据风险程度分级实施预见性护理方案在中重度烧伤患者中的应用价值。方法以2019年1至6月收治的40例中重度烧伤住院患者为对照组，实施烧伤患者常规护理及一般 DVT 预防措施；以 2019年7至12月收治的 42 例中重度烧伤住院患者为观察组，采用Caprini评估量表进行DVT风险分级，并实施相应的预见性护理。比较两组干预效果。结果观察组患者DVT疾病知识掌握程度、疾病健康行为均优于对照组，差异有统计学意义；观察组预见性护理措施落实率为92%高于对照组，差异有统计学意义；干预后观察组发生血液淤滞1例，对照组发生2例DVT及6例血流淤滞，观察组效果优于对照组，差异均有统计学意义。结论基于Caprini量表DVT风险评估的预见性护理方案能够提高中重度烧伤住院患者DVT疾病知识掌握程度及预防措施落实率，降低DVT发生率，有效提高护理满意度。

极区电离层对流速度的浅层神经网络建模与分析

胡大大

, doi: rhnk.1013934/rhnk2019-0015

[摘要](8) [PDF 0KB](0)

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555

基于贝叶斯网络的老旧小区改造项目风险管理研究——以重庆市红育坡片区老旧小区改造项目为例

胡春华初

, doi: rhnk.1013934/rhnk2019-0048

[摘要](10) [PDF 0KB](0)

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测试

皮下脂肪来源干细胞抑制正畸源性牙根吸收的实验研究

张丹, 杨春先, 胥鹏, 唐娜娜, 肖顺娥, 张疆弢

, doi: 10.7507/1002-1892.202309030

[摘要](23) [HTML全文](20) [PDF 0KB](0)

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目的

探讨人皮下脂肪来源干细胞（human subcutaneous adipose-derived stem cells，hADSCs）局部移植对正畸源性牙根吸收（orthodontically induced root resorption，OIRR）的影响，为临床应用hADSCs抑制OIRR提供实验依据。

方法

取40只8周龄雄性SD大鼠随机分为实验组和对照组，每组20只，建立大鼠右侧上颌第1磨牙近中牙正畸牙移动（orthodontic tooth movement，OTM）模型。实验组大鼠于建模第1、4、8、12天注射25 μL含2.5×10⁵个hADSCs的细胞悬液，对照组注射25 μL PBS。在加力前及加力7、14 d后获取大鼠上颌模型，于加力7、14 d后两组各处死10只大鼠并取材。体式显微镜测量OTM距离，扫描电镜观察压力侧牙根形态及测定牙根吸收面积比，HE染色观察压力侧牙根吸收及牙周组织改建并计算牙根吸收指数，抗酒石酸酸性磷酸酶染色计数压力侧牙周组织破牙骨质细胞和破骨细胞数量。

结果

两组OTM距离均随加力时间延长而增加（P<0.05）；加力7、14 d实验组和对照组比较OTM距离差异无统计学意义（P>0.05）。扫描电镜观察示加力7 d，实验组和对照组牙根表面见小而浅的散在吸收陷窝，两组牙根吸收面积比差异无统计学意义（P>0.05）；加力14 d，两组牙根吸收陷窝加深变大，实验组牙根吸收面积比显著小于对照组（P<0.05）。实验组牙根吸收范围小于对照组、深度浅于对照组，加力14 d实验组牙根吸收指数显著小于对照组（P<0.05）。加力7、14 d实验组破牙骨质细胞计数均显著少于对照组（P<0.05）；加力14 d实验组破骨细胞计数显著少于对照组（P<0.05）。

结论

hADSCs 局部移植可能通过降低大鼠OTM过程中破牙骨质细胞和破骨细胞的数量来减小牙根吸收面积和深度，从而抑制OIRR。

, doi: 10.59717/j.xinn-geo.2023.100029

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, doi: 10.37188/lam.2023.022

[摘要](23) [HTML全文](19) [PDF 0KB](0)

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气候变暖背景下麦田沟金针虫爆发性发生为害的研究

徐庆涛, 任三学, 赵花荣, 齐月, 田晓丽, 杨超, 胡丽丽

, doi: rhnk.1013934/2022005

[摘要](52) [PDF 22KB](0)

摘要:
沟金针虫是我国北方旱作农田的重要地下害虫。近年来华北地区大面积推行保护性耕作措施和作物秸秆粉碎还田，冬小麦+夏玉米一年两熟连续轮作种植，为沟金针虫创造了有利的取食和栖息的环境。地处华北北部的固城站2018—2019年秋、冬、春三季气温出现了冷暖交替，尤其最低气温显著偏高，诱发麦田沟金针虫爆发性发生为害。据春季麦田挖土调查，虫口密度最高达144头/m²；虫口重量最重达18.764g/m²。58个调查点达防治指标5头/m²占98.27%。拔节～收获期调查虫口密度：孕穗期最高、拔节期次之、收获期最低。老熟幼虫虫体最长34.68mm，最宽4.90mm，最长增长4.68mm，最宽增大0.90mm。冬小麦+夏玉米禾本科作物连作种植田间虫口密度达35.3～40.4头/m²，显著高于前茬大豆、玉米、冬小麦休闲地，且花生地、春玉米地比大豆地虫口密度高5倍多，虫口重量高10倍以上。成熟期虫害麦田测产：籽粒减产36.8%，虫口密度增加10头/m²籽粒减产率增加4.824%，虫口重量增加1g/m²籽粒减产率增加3.871%，植株虫害率增加10%籽粒减产率增加11.587%。

51

续作在, 徐庆涛, 休会后

, doi: rhnk.1234/23-595

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Active DNA demethylation regulates MAMP-triggered immune priming in Arabidopsis

Mengling Huang, Ying Zhang, Ying Wang, Jiatao Xie, Jiasen Cheng, Yanping Fu, Daohong Jiang, Xiao Yu, Bo Li

, doi: 10.1016/j.jgg.2022.02.021

[摘要](69) [PDF 0KB](0)

摘要:
Plants recognize microbe-associated molecular patterns (MAMPs) to activate immune responses and defense priming to defend against pathogen infections. Transcriptional regulation of gene expression is crucial for plant immunity and is mediated by multiple factors, including DNA methylation. However, it remains unknown whether and how DNA demethylation contributes to immune responses in MAMP-triggered immunity. Here, we report that active DNA demethylation is required for MAMP-triggered immunity to bacterial pathogens. The rdd-2 triple mutant carrying mutations in ROS1, DML2, and DML3 that encode DNA glycosylases, which are key DNA demethylation enzymes, exhibits compromised immune responses triggered by the MAMPs flg22 and elf18. Genome-wide methylome analysis reveals that flg22 induces rapid and specific DNA demethylation in an RDD-dependent manner. The expression levels of salicylic acid signaling-related and phytoalexin biosynthesis-related genes are tightly associated with the flg22-induced promoter demethylation. The compromised accumulation of priming compounds and antimicrobial metabolites ultimately leads to a defense priming defect in the rdd-2 mutant. Our results reveal the critical role of active DNA demethylation in the MAMP-triggered immune response and provide unique insight into the molecular mechanism of flg22-modulated DNA demethylation.

Phosphorylation of an ethylene response factor by MPK3/MPK6 mediates negative feedback regulation of pathogen-induced ethylene biosynthesis in Arabidopsis

Xiaoyang Wang, Huicong Meng, Yuxi Tang, Yashi Zhang, Yunxia He, Jinggeng Zhou, Xiangzong Meng

, doi: 10.1016/j.jgg.2022.04.012

[摘要](73) [PDF 0KB](0)

摘要:
Plants under pathogen attack produce high levels of the gaseous phytohormone ethylene to induce plant defense responses via the ethylene signaling pathway. The 1-aminocyclopropane-1-carboxylate synthase (ACS) is a critical rate-limiting enzyme of ethylene biosynthesis. Transcriptional and post-translational upregulation of ACS2 and ACS6 by the mitogen-activated protein kinases MPK3 and MPK6 are previously shown to be crucial for pathogen-induced ethylene biosynthesis in Arabidopsis. Here, we report that the fungal pathogen Botrytis cinerea-induced ethylene biosynthesis in Arabidopsis is under the negative feedback regulation by ethylene signaling pathway. The ethylene response factor ERF1A is further found to act downstream of ethylene signaling to negatively regulate the B. cinerea-induced ethylene biosynthesis via indirectly suppressing the expression of ACS2 and ACS6. Interestingly, ERF1A is shown to also upregulate defensin genes directly and therefore promote Arabidopsis resistance to B.cinerea. Furthermore, ERF1A is identified to be a substrate of MPK3 and MPK6, which phosphoactivate ERF1A to enhance its functions in suppressing ethylene biosynthesis and inducing defensin gene expression. Taken together, our data reveal that ERF1A and its phosphorylation by MPK3/MPK6 not only mediate the negative-feedback regulation of the B.cinerea-induced ethylene biosynthesis, but also upregulate defensin gene expression to increase Arabidopsis resistance to B. cinerea.

Two plant NLR proteins confer strain-specific resistance conditioned by an effector from Pseudomonas syringae pv. actinidiae

Xiaojuan Zheng, Zhaoyang Zhou, Zhen Gong, Meijuan Hu, Ye Jin Ahn, Xiaojuan Zhang, Yan Zhao, Guoshu Gong, Jian Zhang, Jianru Zuo, Guan-Zhu Han, Sohn Kee Hoon, Jian-Min Zhou

, doi: 10.1016/j.jgg.2022.06.006

[摘要](69) [PDF 0KB](0)

摘要:
Pseudomonas syringae pv. actinidiae (Psa) causes bacterial canker, a devastating disease threatening the Actinidia fruit industry. In a search for non-host resistance genes against Psa, we find that the nucleotide-binding leucine-rich repeat receptor (NLR) protein ZAR1 from both Arabidopsis and Nicotiana benthamiana (Nb) recognizes HopZ5 and triggers cell death. The recognition requires ZED1 in Arabidopsis and JIM2 in Nb plants, which are members of the ZRK pseudokinases and known components of the ZAR1 resistosome. Surprisingly, Arabidopsis ZAR1 and RPM1, another NLR known to recognize HopZ5, confer disease resistance to HopZ5 in a strain-specific manner. Thus, ZAR1, but not RPM1, is solely required for resistance to P.s. maculicola ES4326 (Psm) carrying hopZ5, whereas RPM1 is primarily required for resistance to P.s. tomato DC3000 (Pst) carrying hopZ5. Furthermore, the ZAR1-mediated resistance to Psm hopZ5 in Arabidopsis is insensitive to SOBER1, which encodes a deacetylase known to suppress the RPM1-mediated resistance to Pst hopZ5. In addition, hopZ5 enhances P.syringae virulence in the absence of ZAR1 or RPM1 and that SOBER1 abolishes such virulence function. Together the study suggests that ZAR1 may be used for improving Psa resistance in Actinidia and uncovers previously unknown complexity of effector-triggered immunity and effector-triggered virulence.

Functional characterization of powdery mildew resistance gene MlIW172, a new Pm60 allele and its allelic variation in wild emmer wheat

Qiuhong Wu, Yongxing Chen, Beibei Li, Jing Li, Panpan Zhang, Jingzhong Xie, Huaizhi Zhang, Guanghao Guo, Ping Lu, Miaomiao Li, Keyu Zhu, Wenling Li, Tzion Fahima, Eviatar Nevo, Hongjie Li, Lingli Dong, Zhiyong Liu

, doi: 10.1016/j.jgg.2022.01.010

[摘要](74) [PDF 0KB](0)

摘要:
Wild emmer wheat (Triticum dicoccoides, WEW) is an immediate progenitor of both the cultivated tetraploid and hexaploid wheats and it harbors rich genetic diversity against powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt). A powdery mildew resistance gene MlIW172 originated from WEW accession IW172 (G-797-M) is fine mapped in a 0.048 centimorgan (cM) genetic interval on 7AL, corresponding to a genomic region spanning 233kb, 1Mb and 800kb in Chinese Spring, WEW Zavitan, and T.urartu G1812, respectively. MlIW172 encodes a typical NLR protein NLR^IW172 and physically locates in an NBS-LRR gene cluster. NLR is subsequently identified as a new allele of Pm60, and its function is validated by EMS mutagenesis and transgenic complementation. Haplotype analysis of the Pm60 alleles reveals diversifications in sequence variation in the locus and presence and absence variations (PAV) in WEW populations. Four common single nucleotide variations (SNV) are detected between the Pm60 alleles from WEW and T.urartu, indicative of speciation divergence between the two different wheat progenitors. The newly identified Pm60 alleles and haplotypes in WEW are anticipated to be valuable for breeding powdery mildew resistance wheat cultivars via marker-assisted selection.

The molecular mechanism of plasma membrane H⁺-ATPases in plant responses to abiotic stress

Jing Li, Yan Guo, Yongqing Yang

, doi: 10.1016/j.jgg.2022.05.007

[摘要](94) [PDF 0KB](0)

摘要:
Plasma membrane H⁺-ATPases (PM H⁺-ATPases) are critical proton pumps that export protons from the cytoplasm to the apoplast. The resulting proton gradient and difference in electrical potential energize various secondary active transport events. PM H⁺-ATPases play essential roles in plant growth, development, and stress responses. In this review, we focus on recent studies of the mechanism of PM H⁺-ATPases in response to abiotic stresses in plants, such as salt and high pH, temperature, drought, light, macronutrient deficiency, acidic soil and aluminum stress, as well as heavy metal toxicity. Moreover, we discuss remaining outstanding questions about how PM H⁺-ATPases contribute to abiotic stress responses.

Nitric oxide negatively regulates gibberellin signaling to coordinate growth and salt tolerance in Arabidopsis

Lichao Chen, Shuhao Sun, Chun-Peng Song, Jian-Min Zhou, Jiayang Li, Jianru Zuo

, doi: 10.1016/j.jgg.2022.02.023

[摘要](54) [PDF 0KB](0)

摘要:
In response to dynamically altered environments, plants must finely coordinate the balance between growth and stress responses for their survival. However, the underpinning regulatory mechanisms remain largely elusive. The phytohormone gibberellin promotes growth via a derepression mechanism by proteasomal degradation of the DELLA transcription repressors. Conversely, the stress-induced burst of nitric oxide (NO) enhances stress tolerance, largely relying on NO-mediated S-nitrosylation, a redox-based posttranslational modification. Here, we show that S-nitrosylation of Cys-374 in the Arabidopsis RGA protein, a key member of DELLAs, inhibits its interaction with the F-box protein SLY1, thereby preventing its proteasomal degradation under salinity condition. The accumulation of RGA consequently retards growth but enhances salt tolerance. We propose that NO negatively regulates gibberellin signaling via S-nitrosylation of RGA to coordinate the balance of growth and stress responses when challenged by adverse environments.

Plants response to light stress

Yafei Shi, Xiangsheng Ke, Xiaoxia Yang, Yuhan Liu, Xin Hou

, doi: 10.1016/j.jgg.2022.04.017

[摘要](200) [PDF 0KB](0)

摘要:
Plants require solar energy to grow through oxygenic photosynthesis; however, when light intensity exceeds the optimal range for photosynthesis, it causes abiotic stress and physiological damage in plants. In response to high light stress, plants initiate a series of signal transduction from chloroplasts to whole cells and from locally stressed tissues to the rest of the plant body. These signals trigger a variety of physiological and biochemical reactions intended to mitigate the deleterious effects of high light intensity, such as photodamage and photoinhibition. Light stress protection mechanisms include chloroplastic Reactive oxygen species (ROS) scavenging, chloroplast and stomatal movement, and anthocyanin production. Photosynthetic apparatuses, being the direct targets of photodamage, have also developed various acclimation processes such as thermal energy dissipation through nonphotochemical quenching (NPQ), photorepair of Photosystem II (PSII), and transcriptional regulation of photosynthetic proteins. Fluctuating light is another mild but persistent type of light stress in nature, which unfortunately has been poorly investigated. Current studies, however, suggest that state transitions and cyclic electron transport are the main adaptive mechanisms for mediating fluctuating light stress in plants. Here, we review the current breadth of knowledge regarding physiological and biochemical responses to both high light stress and fluctuating light stress.

OsMPK4 promotes phosphorylation and degradation of IPA1 in response to salt stress to confer salt tolerance in rice

Meiru Jia, Nan Luo, Xiangbing Meng, Xiaoguang Song, Yanhui Jing, Liquan Kou, Guifu Liu, Xiahe Huang, Yingchun Wang, Jiayang Li, Bing Wang, Hong Yu

, doi: 10.1016/j.jgg.2022.06.009

[摘要](72) [PDF 0KB](0)

摘要:
Salt stress adversely affects plant growth, development, and crop yield. Rice (Oryza sativa L.) is one of the most salt-sensitive cereal crops, especially at the early seedling stage. Mitogen-activated protein kinase (MAPK/MPK) cascades have been shown to play critical roles in salt response in Arabidopsis. However, the roles of the MPK cascade signaling in rice salt response and substrates of OsMPK remain largely unknown. Here, we report that the salt-induced OsMPK4-Ideal Plant Architecture 1 (IPA1) signaling pathway regulates the salt tolerance in rice. Under salt stress, OsMPK4 could interact with IPA1 and phosphorylate IPA1 at Thr180, leading to degradation of IPA1. Genetic evidence shows that IPA1 is a negative regulator of salt tolerance in rice, whereas OsMPK4 promotes salt response in an IPA1-dependent manner. Taken together, our results uncover an OsMPK4-IPA1 signal cascade that modulates the salt stress response in rice and sheds new light on the breeding of salt-tolerant rice varieties.

Emerging roles of phosphoinositide-associated membrane trafficking in plant stress responses

Feng Lin, Junming Zheng, Yanhua Xie, Wen Jing, Qun Zhang, Wenhua Zhang

, doi: 10.1016/j.jgg.2022.05.003

[摘要](70) [PDF 0KB](0)

摘要:
Eukaryotic cells are confined by membranes that create hydrophobic barriers for substance and information exchange between the inside and outside of the cell. These barriers are formed by assembly of lipids and protein in aqueous environments. Lipids not only serve as building blocks for membrane construction, but also possess regulatory functions in cellular activities. These regulatory lipids are non-uniformly distributed in membrane systems; their temporal and spatial accumulation in specific membranes decodes environmental cues and changes cellular activity accordingly. Phosphoinositides (PIs) are phospholipids that exert regulatory effects. In recent years, research on PIs roles in regulating plant growth, development, and responses to environmental stress is increasing. Several reviews have been published on the composition of PIs, intermolecular transferring of PIs by lipid kinases (phosphatases) or PI-PLCs, subcellular localization, and specially their functions in plant developments. Herein, we review the crucial regulatory functions of PIs in plant stress responses, with a particular focus on PIs involved in membrane trafficking.

Function of hydroxycinnamoyl transferases for the biosynthesis of phenolamides in rice resistance to Magnaporthe oryzae

Hong Fang, Fan Zhang, Chongyang Zhang, Dan Wang, Shuangqian Shen, Feng He, Hui Tao, Ruyi Wang, Min Wang, Debao Wang, Xionglun Liu, Jie Luo, Guo-Liang Wang, Yuese Ning

, doi: 10.1016/j.jgg.2022.02.008

[摘要](62) [PDF 0KB](0)

摘要:
Phenolamide (PA) metabolites play important roles in the interaction between plants and pathogens. The putrescine hydroxycinnamoyl transferase genes OsPHT3 and OsPHT4 positively regulate rice cell death and resistance to Magnaporthe oryzae. The bZIP transcription factor APIP5, a negative regulator of cell death and rice immunity, directly binds to the OsPHT4 promoter to regulate putrescine-derived PAs. Whether other hydroxycinnamoyl transferase (HT) genes also participate in APIP5-mediated immunity remains unclear. Surprisingly, we find that genes encoding agmatine hydroxycinnamoyl transferases OsAHT1 and OsAHT2, tryptamine hydroxycinnamoyl transferases OsTBT1 and OsTBT2, and tyramine hydroxycinnamoyl transferases OsTHT1 and OsTHT2, responsible for the biosynthesis of polyamine-derived PAs are all up-regulated in APIP5-RNAi transgenic plants compared with segregated wild-type rice. Furthermore, both OsAHT1/2 and OsTBT1/2 are induced during M.oryzae infection, showing expression patterns similar to those previously reported for OsTHT1/2 and OsPHT3/4. Transgenic plants overexpressing either OsAHT2-GFP or OsTBT1-GFP show enhanced resistance against M.oryzae and accumulated more PA metabolites and lignin compared with wild-type plants. Interestingly, as demonstrated for OsPHT4, APIP5 directly binds to the promoters of OsAHT1/2, OsTBT1/2, and OsTHT1/2, repressing their transcription. Together, these results indicate that the HT genes are common targets of APIP5 and that PAs play critical roles in rice immunity.

Abiotic stress-triggered oxidative challenges: Where does H₂S act?

Linda de Bont, Xiujie Mu, Bo Wei, Yi Han

, doi: 10.1016/j.jgg.2022.02.019

[摘要](50) [PDF 0KB](0)

摘要:
Hydrogen sulfide (H₂S) was once principally considered the perpetrator of plant growth cessation and cell death. However, this has become an antiquated view, with cumulative evidence showing that the H₂S serves as a biological signaling molecule notably involved in abiotic stress response and adaptation, such as defense by phytohormone activation, stomatal movement, gene reprogramming, and plant growth modulation. Reactive oxygen species (ROS)-dependent oxidative stress is involved in these responses. Remarkably, an ever-growing body of evidence indicates that H₂S can directly interact with ROS processing systems in a redox-dependent manner, while it has been gradually recognized that H₂S-based posttranslational modifications of key protein cysteine residues determine stress responses. Furthermore, the reciprocal interplay between H₂S and nitric oxide (NO) in regulating oxidative stress has significant importance. The interaction of H₂S with NO and ROS during acclimation to abiotic stress may vary from synergism to antagonism. However, the molecular pathways and factors involved remain to be identified. This review not only aims to provide updated information on H₂S action in regulating ROS-dependent redox homeostasis and signaling, but also discusses the mechanisms of H₂S-dependent regulation in the context of oxidative stress elicited by environmental cues.

From plant immunity to crop disease resistance

Yan Zhao, Xiaobo Zhu, Xuewei Chen, Jian-Min Zhou

, doi: 10.1016/j.jgg.2022.06.003

[摘要](69) [PDF 0KB](0)

摘要:
Plant diseases caused by diverse pathogens lead to a serious reduction in crop yield and threaten food security worldwide. Genetic improvement of plant immunity is considered as the most effective and sustainable approach to control crop diseases. In the last decade, our understanding of plant immunity at both molecular and genomic levels has improved greatly. Combined with advances in biotechnologies, particularly clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-based genome editing, we can now rapidly identify new resistance genes and engineer disease-resistance crop plants like never before. In this review, we summarize the current knowledge of plant immunity and outline existing and new strategies for disease resistance improvement in crop plants. We also discuss existing challenges in this field and suggest directions for future studies.

Regulation and integration of plant jasmonate signaling: a comparative view of monocot and dicot

Shiwei Wan, Xiu-Fang Xin

, doi: 10.1016/j.jgg.2022.04.002

[摘要](102) [PDF 0KB](0)

摘要:
The phytohormone jasmonate plays a pivotal role in various aspects of plant life, including developmental programs and defense against pests and pathogens. A large body of knowledge on jasmonate biosynthesis, signal transduction as well as its functions in diverse plant processes has been gained in the past two decades. In addition, there exists extensive crosstalk between jasmonate pathway and other phytohormone pathways, such as salicylic acid (SA) and gibberellin (GA), in co-regulation of plant immune status, fine-tuning the balance of plant growth and defense, and so on, which were mostly learned from studies in the dicotyledonous model plants Arabidopsis thaliana and tomato but much less in monocot. Interestingly, existing evidence suggests both conservation and functional divergence in terms of core components of jasmonate pathway, its biological functions and signal integration with other phytohormones, between monocot and dicot. In this review, we summarize the current understanding on JA signal initiation, perception and regulation, and highlight the distinctive characteristics in different lineages of plants.

Author correction to “Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers” [Acta Pharmaceutica Sinica B 11 (2021) 355–372]

Tingting Jiang, Guan Wang, Yao Liu, Lu Feng, Meng Wang, Jie Liu, Yi Chen, Liang Ouyang

, doi: 10.1016/j.apsb.2022.02.028

[摘要](99) [PDF 0KB](0)

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Author correction to “A nanocleaner specifically penetrates the blood-brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer’s disease” [Acta Pharmaceutica Sinica B 12, (2021) 4032–4044]

Ting Lei, Zhihang Yang, Xue Xia, Yuxiu Chen, Xiaotong Yang, Rou Xie, Fan Tong, Xiaolin Wang, Huile Gao

, doi: 10.1016/j.apsb.2022.04.008

[摘要](75) [PDF 0KB](0)

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Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism

Haiming Xiao, Xiaohong Sun, Zeyuan Lin, Yan Yang, Meng Zhang, Zhanchi Xu, Peiqing Liu, Zhongqiu Liu, Heqing Huang

, doi: 10.1016/j.apsb.2021.12.023

[摘要](69) [PDF 0KB](0)

摘要:
The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH₂-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.

Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm

Wei Wang, Shuo Feng, Zhuyifan Ye, Hanlu Gao, Jinzhong Lin, Defang Ouyang

, doi: 10.1016/j.apsb.2021.11.021

[摘要](91) [PDF 0KB](0)

摘要:
Lipid nanoparticle (LNP) is commonly used to deliver mRNA vaccines. Currently, LNP optimization primarily relies on screening ionizable lipids by traditional experiments which consumes intensive cost and time. Current study attempts to apply computational methods to accelerate the LNP development for mRNA vaccines. Firstly, 325 data samples of mRNA vaccine LNP formulations with IgG titer were collected. The machine learning algorithm, lightGBM, was used to build a prediction model with good performance (R² > 0.87). More importantly, the critical substructures of ionizable lipids in LNPs were identified by the algorithm, which well agreed with published results. The animal experimental results showed that LNP using DLin-MC3-DMA (MC3) as ionizable lipid with an N/P ratio at 6:1 induced higher efficiency in mice than LNP with SM-102, which was consistent with the model prediction. Molecular dynamic modeling further investigated the molecular mechanism of LNPs used in the experiment. The result showed that the lipid molecules aggregated to form LNPs, and mRNA molecules twined around the LNPs. In summary, the machine learning predictive model for LNP-based mRNA vaccines was first developed, validated by experiments, and further integrated with molecular modeling. The prediction model can be used for virtual screening of LNP formulations in the future.

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma

Jiao Xue, Yining Zhu, Shuting Bai, Chunting He, Guangsheng Du, Yuandong Zhang, Yao Zhong, Wenfei Chen, Hairui Wang, Xun Sun

, doi: 10.1016/j.apsb.2021.11.020

[摘要](52) [PDF 0KB](0)

摘要:
Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core-shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

Peilu Song, Fan Zhao, Dahong Li, Jiqiang Qu, Miao Yao, Yuan Su, Hanxun Wang, Miaomiao Zhou, Yujie Wang, Yinli Gao, Feng Li, Dongmei Zhao, Fengjiao Zhang, Yu Rao, Mingyu Xia, Haitao Li, Jian Wang, Maosheng Cheng

, doi: 10.1016/j.apsb.2022.02.029

[摘要](68) [PDF 0KB](0)

摘要:
The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii

Lichan Tu, Xinbo Cai, Yifeng Zhang, Yuru Tong, Jian Wang, Ping Su, Yun Lu, Tianyuan Hu, Yunfeng Luo, Xiaoyi Wu, Dan Li, Luqi Huang, Wei Gao

, doi: 10.1016/j.apsb.2022.02.013

[摘要](66) [PDF 0KB](0)

摘要:
Tripterygium wilfordii is a valuable medicinal plant rich in biologically active diterpenoids, but there are few studies on the origins of these diterpenoids in its secondary metabolism. Here, we identified three regions containing tandemly duplicated diterpene synthase genes on chromosomes (Chr) 17 and 21 of T. wilfordii and obtained 11 diterpene synthases with different functions. We further revealed that these diterpene synthases underwent duplication and rearrangement at approximately 2.3–23.7 million years ago (MYA) by whole-genome triplication (WGT), transposon mediation, and tandem duplication, followed by functional divergence. We first demonstrated that four key amino acids in the sequences of TwCPS3, TwCPS5, and TwCPS6 were altered during evolution, leading to their functional divergence and the formation of diterpene secondary metabolites. Then, we demonstrated that the functional divergence of three TwKSLs was driven by mutations in two key amino acids. Finally, we discovered the mechanisms of evolution and pseudogenization of miltiradiene synthases in T. wilfordii and elucidated that the new function in TwMS1/2 from the terpene synthase (TPS)-b subfamily was caused by progressive changes in multiple amino acids after the WGT event. Our results provide key evidence for the formation of diverse diterpenoids during the evolution of secondary metabolites in T. wilfordii.

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

Fangfang Lai, Ming Ji, Lei Huang, Yunchen Wang, Nina Xue, Tingting Du, Kai Dong, Xiaoqing Yao, Jing Jin, Zhiqiang Feng, Xiaoguang Chen

, doi: 10.1016/j.apsb.2022.02.031

[摘要](85) [PDF 0KB](0)

摘要:
PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

Recent development on COX-2 inhibitors as promising anti-inflammatory agents: The past 10 years

Zhiran Ju, Menglan Li, Junde Xu, Daniel C. Howell, Zhiyun Li, Fen-Er Chen

, doi: 10.1016/j.apsb.2022.01.002

[摘要](50) [PDF 0KB](0)

摘要:
Cyclooxygenases play a vital role in inflammation and are responsible for the production of prostaglandins. Two cyclooxygenases are described, the constitutive cyclooxygenase-1 and the inducible cyclooxygenase-2, for which the target inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins are a class of lipid compounds that mediate acute and chronic inflammation. NSAIDs are the most frequent choices for treatment of inflammation. Nevertheless, currently used anti-inflammatory drugs have become associated with a variety of adverse effects which lead to diminished output even market withdrawal. Recently, more studies have been carried out on searching novel selective COX-2 inhibitors with safety profiles. In this review, we highlight the various structural classes of organic and natural scaffolds with efficient COX-2 inhibitory activity reported during 2011–2021. It will be valuable for pharmaceutical scientists to read up on the current chemicals to pave the way for subsequent research.

Development and clinical advancement of small molecules for ex vivo expansion of hematopoietic stem cell

Jiaxing Li, Xiao Wang, Jiayu Ding, Yasheng Zhu, Wenjian Min, Wenbing Kuang, Kai Yuan, Chengliang Sun, Peng Yang

, doi: 10.1016/j.apsb.2021.12.006

[摘要](62) [PDF 0KB](0)

摘要:
Hematopoietic stem cell (HSC) transplantation is the only curative therapy for many diseases. HSCs from umbilical cord blood (UCB) source have many advantages over from bone marrow. However, limited HSC dose in a single CB unit restrict its widespread use. Over the past two decades, ex vivo HSC expansion with small molecules has been an effective approach for obtaining adequate HSCs. Till now, several small-molecule compounds have entered the phase I/II trials, showing safe and favorable pharmacological profiles. As HSC expansion has become a hot topic over recent years, many newly identified small molecules along with novel biological mechanisms for HSC expansion would help solve this challenging issue. Here, we will give an overview of HSC biology, discovery and medicinal chemistry development of small molecules, natural products targeting for HSC expansion, and their recent clinical progresses, as well as potential protein targets for HSC expansion.

Nuciferine protects against high-fat diet-induced hepatic steatosis and insulin resistance via activating TFEB-mediated autophagy–lysosomal pathway

Xiliang Du, Chiara Di Malta, Zhiyuan Fang, Taiyu Shen, Xiaodi Niu, Meng Chen, Bo Jin, Hao Yu, Lin Lei, Wenwen Gao, Yuxiang Song, Zhe Wang, Chuang Xu, Zhijun Cao, Guowen Liu, Xinwei Li

, doi: 10.1016/j.apsb.2021.12.012

[摘要](58) [PDF 0KB](0)

摘要:
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy–lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1–TFEB–ALP axis could represent a novel pharmacological strategy to combat NAFLD.

Cytochrome P450s in algae: Bioactive natural product biosynthesis and light-driven bioproduction

Shanmin Zheng, Jiawei Guo, Fangyuan Cheng, Zhengquan Gao, Lei Du, Chunxiao Meng, Shengying Li, Xingwang Zhang

, doi: 10.1016/j.apsb.2022.01.013

[摘要](63) [PDF 0KB](0)

摘要:
Algae are a large group of photosynthetic organisms responsible for approximately half of the earth's total photosynthesis. In addition to their fundamental ecological roles as oxygen producers and as the food base for almost all aquatic life, algae are also a rich source of bioactive natural products, including several clinical drugs. Cytochrome P450 enzymes (P450s) are a superfamily of biocatalysts that are extensively involved in natural product biosynthesis by mediating various types of reactions. In the post-genome era, a growing number of P450 genes have been discovered from algae, indicating their important roles in algal life-cycle. However, the functional studies of algal P450s remain limited. Benefitting from the recent technical advances in algae cultivation and genetic manipulation, the researches on P450s in algal natural product biosynthesis have been approaching to a new stage. Moreover, some photoautotrophic algae have been developed into “photo-bioreactors” for heterologous P450s to produce high-value added pharmaceuticals and chemicals in a carbon-neutral or carbon-negative manner. Here, we comprehensively review these advances of P450 studies in algae from 2000 to 2021.

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

Ying Wu, Congying Pu, Yixian Fu, Guoqiang Dong, Min Huang, Chunquan Sheng

, doi: 10.1016/j.apsb.2021.12.017

[摘要](77) [PDF 0KB](0)

摘要:
Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin–proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies.

Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy

Jiayi Ye, Bo Hou, Fangmin Chen, Shunan Zhang, Muya Xiong, Tianliang Li, Yechun Xu, Zhiai Xu, Haijun Yu

, doi: 10.1016/j.apsb.2021.09.021

[摘要](73) [PDF 0KB](0)

摘要:
Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

Mitochondria targeting drugs for neurodegenerative diseases—Design, mechanism and application

Jiajia Xu, Wei Du, Yunhe Zhao, Kahleong Lim, Li Lu, Chengwu Zhang, Lin Li

, doi: 10.1016/j.apsb.2022.03.001

[摘要](64) [PDF 0KB](0)

摘要:
Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.

A hybrid bacterium with tumor-associated macrophage polarization for enhanced photothermal-immunotherapy

Jingya Zhao, Huabei Huang, Jinyan Zhao, Xiang Xiong, Sibo Zheng, Xiaoqing Wei, Shaobing Zhou

, doi: 10.1016/j.apsb.2021.10.019

[摘要](58) [PDF 0KB](0)

摘要:
Remodeling the tumor microenvironment through reprogramming tumor-associated macrophages (TAMs) and increasing the immunogenicity of tumors via immunogenic cell death (ICD) have been emerging as promising anticancer immunotherapy strategies. However, the heterogeneous distribution of TAMs in tumor tissues and the heterogeneity of the tumor cells make the immune activation challenging. To overcome these dilemmas, a hybrid bacterium with tumor targeting and penetration, TAM polarization, and photothermal conversion capabilities is developed for improving antitumor immunotherapy in vivo. The hybrid bacteria (B.b@QDs) are prepared by loading Ag₂S quantum dots (QDs) on the Bifidobacterium bifidum (B.b) through electrostatic interactions. The hybrid bacteria with hypoxia targeting ability can effectively accumulate and penetrate the tumor tissues, enabling the B.b to fully contact with the TAMs and mediate their polarization toward M1 phenotype to reverse the immunosuppressive tumor microenvironment. It also enables to overcome the intratumoral heterogeneity and obtain abundant tumor-associated antigens by coupling tumor penetration of the B.b with photothermal effect of the QDs, resulting in an enhanced immune effect. This strategy that combines B.b-triggered TAM polarization and QD-induced ICD achieved a remarkable inhibition of tumor growth in orthotopic breast cancer.

Tumor-targeted/reduction-triggered composite multifunctional nanoparticles for breast cancer chemo-photothermal combinational therapy

Yun Yang, Danrong Hu, Yi Lu, Bingyang Chu, Xinlong He, Yu Chen, Yao Xiao, Chengli Yang, Kai Zhou, Liping Yuan, Zhiyong Qian

, doi: 10.1016/j.apsb.2021.08.021

[摘要](52) [PDF 0KB](0)

摘要:
Breast cancer has become the most commonly diagnosed cancer type in the world. A combination of chemotherapy and photothermal therapy (PTT) has emerged as a promising strategy for breast cancer therapy. However, the intricacy of precise delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Therefore, to ensure that the therapeutic agents are synchronously delivered to the tumor site for their synergistic effect, a multifunctional nanoparticle system (PCRHNs) is developed, which is grafted onto the prussian blue nanoparticles (PB NPs) by reduction-responsive camptothecin (CPT) prodrug copolymer, and then modified with tumor-targeting peptide cyclo(Asp-d-Phe-Lys-Arg-Gly) (cRGD) and hyaluronic acid (HA). PCRHNs exhibited nano-sized structure with good monodispersity, high load efficiency of CPT, triggered CPT release in response to reduction environment, and excellent photothermal conversion under laser irradiation. Furthermore, PCRHNs can act as a photoacoustic imaging contrast agent-guided PTT. In vivo studies indicate that PCRHNs exhibited excellent biocompatibility, prolonged blood circulation, enhanced tumor accumulation, allow tumor-specific chemo-photothermal therapy to achieve synergistic antitumor effects with reduced systemic toxicity. Moreover, hyperthermia-induced upregulation of heat shock protein 70 in the tumor cells could be inhibited by CPT. Collectively, PCRHNs may be a promising therapeutic way for breast cancer therapy.

Enzyme-instructed and mitochondria-targeting peptide self-assembly to efficiently induce immunogenic cell death

Debin Zheng, Jingfei Liu, Limin Xie, Yuhan Wang, Yinghao Ding, Rong Peng, Min Cui, Ling Wang, Yongjie Zhang, Chunqiu Zhang, Zhimou Yang

, doi: 10.1016/j.apsb.2021.07.005

[摘要](122) [PDF 0KB](0)

摘要:
Immunogenic cell death (ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system. However, effective type II ICD inducers without biotoxicity are still very limited. Herein, a tentative drug- or photosensitizer-free strategy was developed by employing enzymatic self-assembly of the peptide F-pY-T to induce mitochondrial oxidative stress in cancer cells. Upon dephosphorylation catalyzed by alkaline phosphatase overexpressed on cancer cells, the peptide F-pY-T self-assembled to form nanoparticles, which were subsequently internalized. These affected the morphology of mitochondria and induced serious reactive oxygen species production, causing the ICD characterized by the release of danger-associated molecular patterns (DAMPs). DAMPs enhanced specific immune responses by promoting the maturation of DCs and the intratumoral infiltration of tumor-specific T cells to eradicate tumor cells. The dramatic immunotherapeutic capacity could be enhanced further by combination therapy of F-pY-T and anti-PD-L1 agents without visible biotoxicity in the main organs. Thus, our results revealed an alternative strategy to induce efficient ICD by physically promoting mitochondrial oxidative stress.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Yurong Lai, Xiaoyan Chu, Li Di, Wei Gao, Yingying Guo, Xingrong Liu, Chuang Lu, Jialin Mao, Hong Shen, Huaping Tang, Cindy Q. Xia, Lei Zhang, Xinxin Ding

, doi: 10.1016/j.apsb.2022.03.009

[摘要](83) [PDF 0KB](0)

摘要:
Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

A mitochondria-targeting lipid–small molecule hybrid nanoparticle for imaging and therapy in an orthotopic glioma model

Menghuan Tang, Kai Lin, Mythili Ramachandran, Longmeng Li, Hongye Zou, Huzhi Zheng, Zhao Ma, Yuanpei Li

, doi: 10.1016/j.apsb.2022.04.005

[摘要](82) [PDF 0KB](0)

摘要:
Hybrid lipid-nanoparticle complexes have shown attractive characteristics as drug carriers due to their integrated advantages from liposomes and nanoparticles. Here we developed a kind of lipid-small molecule hybrid nanoparticles (LPHNPs) for imaging and treatment in an orthotopic glioma model. LPHNPs were prepared by engineering the co-assembly of lipids and an amphiphilic pheophorbide a-quinolinium conjugate (PQC), a mitochondria-targeting small molecule. Compared with the pure nanofiber self-assembled by PQC, LPHNPs not only preserve the comparable antiproliferative potency, but also possess a spherical nanostructure that allows the PQC molecules to be administrated through intravenous injection. Also, this co-assembly remarkably improved the drug-loading capacity and formulation stability against the physical encapsulation using conventional liposomes. By integrating the advantages from liposome and PQC molecule, LPHNPs have minimal system toxicity, enhanced potency of photodynamic therapy (PDT) and visualization capacities of drug biodistribution and tumor imaging. The hybrid nanoparticle demonstrates excellent curative effects to significantly prolong the survival of mice with the orthotopic glioma. The unique co-assembly of lipid and small molecule provides new potential for constructing new liposome-derived nanoformulations and improving cancer treatment.

Liposome-based multifunctional nanoplatform as effective therapeutics for the treatment of retinoblastoma

Ying Liu, Yu Han, Shizhu Chen, Jingjie Liu, Dajiang Wang, Yifei Huang

, doi: 10.1016/j.apsb.2021.10.009

[摘要](43) [PDF 0KB](0)

摘要:
Photothermal therapy has the characteristics of minimal invasiveness, controllability, high efficiency, and strong specificity, which can effectively make up for the toxic side effects and tumor resistance caused by traditional drug treatment. However, due to the limited tissue penetration of infrared light, it is difficult to promote and apply in clinical practice. The eye is the only transparent tissue in human, and infrared light can easily penetrate the eye tissue, so it is expected that photothermal therapy can be used to treat fundus diseases. Here in, a new nano-platform assembled by liposome and indocyanine green (ICG) was used to treat retinoblastoma. ICG was assembled in liposomes to overcome some problems of ICG itself. For example, ICG is easily quenched, self-aggregating and instability. Moreover, liposomes can prevent free ICG from being cleared through the systemic circulation. The construction of the nano-platform not only ensured the stability of ICG in vivo, but also realized imaging-guide photothermal therapy, which created a new strategy for the treatment of retinoblastoma.

Chemotherapeutic nanomaterials in tumor boundary delineation: Prospects for effective tumor treatment

Ozioma Udochukwu Akakuru, Zhoujing Zhang, M. Zubair Iqbal, Chengjie Zhu, Yewei Zhang, Aiguo Wu

, doi: 10.1016/j.apsb.2022.02.016

[摘要](59) [PDF 0KB](0)

摘要:
Accurately delineating tumor boundaries is key to predicting survival rates of cancer patients and assessing response of tumor microenvironment to various therapeutic techniques such as chemotherapy and radiotherapy. This review discusses various strategies that have been deployed to accurately delineate tumor boundaries with particular emphasis on the potential of chemotherapeutic nanomaterials in tumor boundary delineation. It also compiles the types of tumors that have been successfully delineated by currently available strategies. Finally, the challenges that still abound in accurate tumor boundary delineation are presented alongside possible perspective strategies to either ameliorate or solve the problems. It is expected that the information communicated herein will form the first compendious baseline information on tumor boundary delineation with chemotherapeutic nanomaterials and provide useful insights into future possible paths to advancing current available tumor boundary delineation approaches to achieve efficacious tumor therapy.

Editor Profiles: Guest Editors of Special Column on A New Era of Nanobiomaterial-based Drug Delivery

, doi: 10.1016/j.apsb.2022.05.013

[摘要](139) [PDF 0KB](0)

摘要:

Tailoring combinatorial lipid nanoparticles for intracellular delivery of nucleic acids, proteins, and drugs

Yamin Li, Zhongfeng Ye, Hanyi Yang, Qiaobing Xu

, doi: 10.1016/j.apsb.2022.04.013

[摘要](54) [PDF 0KB](0)

摘要:
Lipid nanoparticle (LNP)-based drug delivery systems have become the most clinically advanced non-viral delivery technology. LNPs can encapsulate and deliver a wide variety of bioactive agents, including the small molecule drugs, proteins and peptides, and nucleic acids. However, as the physicochemical properties of small- and macromolecular cargos can vary drastically, every LNP carrier system needs to be carefully tailored in order to deliver the cargo molecules in a safe and efficient manner. Our group applied the combinatorial library synthesis approach and in vitro and in vivo screening strategy for the development of LNP delivery systems for drug delivery. In this Review, we highlight our recent progress in the design, synthesis, characterization, evaluation, and optimization of combinatorial LNPs with novel structures and properties for the delivery of small- and macromolecular therapeutics both in vitro and in vivo. These delivery systems have enormous potentials for cancer therapy, antimicrobial applications, gene silencing, genome editing, and more. We also discuss the key challenges to the mechanistic study and clinical translation of new LNP-enabled therapeutics.

A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation, apoptosis and M2 macrophages polarization

Tingting Yang, Yuzhu Hu, Junming Miao, Jing Chen, Jiagang Liu, Yongzhong Cheng, Xiang Gao

, doi: 10.1016/j.apsb.2022.02.009

[摘要](56) [PDF 0KB](0)

摘要:
Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood-brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d,l-lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d,l-lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

滇中盆地南缘富锂黏土岩地球化学特征及沉积环境初探

贾永斌, 于文修, 温汉捷, 罗重光, 杨光树, 杨洋, 崔燚

, doi: 10.14027/j.issn.1000-0550.2021.076

[摘要](108) [HTML全文](152) [PDF 0KB](0)

摘要:

沉积岩中的微量元素对沉积环境变化有较高的敏感度,是研究古沉积环境的有效手段。滇中盆地倒石头组是一套富锂的黏土岩地层,其古环境的研究对恢复该时期盆地沉积格局和锂元素富集具有重要意义。基于滇中盆地倒石头组两个典型钻孔样品详细的地球化学研究,探讨了倒石头组富锂黏土岩形成时的沉积环境及其对锂元素富集的影响。研究结果表明：所有样品Sr、Ga元素含量及Sr/Ba值指示研究区古水体介质为淡水陆相沉积环境；其δU值介于0.51~1.63,U/Th值介于0.11~1.49,V/（V+Ni）值介于0.48~0.86,V/Cr值介于0.45~1.24,同时在U_（EF）-Mo_（EF）协变模式图中,样品数据均未落在缺氧和硫化区域,表明研究区富锂黏土岩的沉积环境为氧化—弱还原环境；且样品Sr/Cu比值介于0.69~4.87,CIA值介于86.3~99.66,XRD全岩黏土矿物分析显示高岭石为主要的黏土矿物,表明富锂黏土岩在形成过程中处于温暖潮湿的沉积环境并伴随较为强烈的化学风化作用。

一株后生元菌株的抑菌特性研究及其细菌素基因簇的挖掘

张晓妍, 沙沈菲, 郭丽丹, 贾爽, 周婉婷, 陈雨滢, 汪立平

, doi: 10.13386/j.issn1002-0306.2022030280

[摘要](66) [HTML全文](69) [PDF 20152KB](0)

摘要:

本文旨在筛选一株可拮抗中国大鲵源嗜水气单胞菌的后生元菌株，并对其进行抑菌特性的研究和细菌素基因簇的挖掘。以中国大鲵病原性嗜水气单胞菌（Aeromonas hydrophila, Ah2）为指示菌，筛选一株产细菌素乳酸菌株并评估其药敏特性；采用有机溶剂萃取法初步纯化菌株产细菌素；通过pH、温度和消化酶耐受性、贮藏稳定性、抑菌谱及最小抑菌（MIC）和杀菌浓度（MBC）共六类指标评价细菌素的抑菌特性；溶血反应与细胞毒性实验测试细菌素对Ah2的抑菌效果，经扫描电子显微镜初步探究细菌素的抑菌机制；经由紫外全波长扫描定性细菌素以及Tricine-SDS-PAGE电泳测定细菌素的分子量范围；最后根据菌株的全基因组序列挖掘其潜在的细菌素基因簇（RiPPs）。结果显示，从青岛市售腐乳中筛出一株产细菌素植物乳植物杆菌M4L1（Lactiplantibacillus plantarum M4L1）。初步纯化M4L1产细菌素并命名为LP01。细菌素LP01具备良好的消化酶耐受性，且在pH2~10、−20~121 ℃和9个月贮藏期内均表现出稳定的抑菌活性，并对单增李斯特菌、弗氏柠檬酸杆菌等14株革兰氏阳性和阴性菌均有不同程度的抑制作用；另外，LP01对Ah2的MIC和MBC分别为12.94和25.88 μg/mL。经MBC浓度的LP01处理后的Ah2，溶血活性和细胞毒性均得到明显缓解；SEM观察其通过破坏Ah2的细胞壁具有抑制或杀伤作用。LP01在波长200~220 nm处的肽类特征吸收峰显著，电泳后条带显示其分子量在3.3~4.0 kDa，LP01为小分子肽类细菌素。此外，基因注释到M4L1有2个细菌素基因簇（RiPPs），对应产物分别为Plantaricin K和Plantaricin E，均属于植物乳杆菌II类细菌素。菌株M4L1不仅含有多种抗菌物质相关基因簇，而且其细菌素LP01具备了优良的抑菌性能，能有效抑制多种水产病原菌、食物腐败菌及食源性致病菌等。产细菌素植物乳植物杆菌M4L1作为一株潜在的后生元菌株具有较好的应用前景。

, doi: 10.3934/math.2023393

[摘要](46) [HTML全文](23) [PDF 0KB](0)

摘要:

, doi: 10.3934/math.2023411

[摘要](89) [HTML全文](51) [PDF 0KB](0)

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浅析现代法治体系下神圣与世俗之间的张力—以威斯康星州诉约德案为例

宋忠华

, doi: rhnk.1013934/.2021127

[摘要](74) [PDF 6788KB](8)

摘要:
随着现代法治体系的建立和不断完善，以及社会各项制度的成熟，以政教分离作为基本立原则的美国，在处理宗教信仰自由权问题上不断彰显了司法的能动性，最典型案件就是威斯康星州诉约德案。这场案件表面上是阿米什人的宗教信仰自由的权利和政府实施强制义务教育的权力之争、传统宗教教育和现代国民义务教育之争，实际上这场案件背后代表了民族传统文化与现代主流文明之间产生了巨大的张力、宗教信仰的神圣性与现代文明的世俗性之间也产生了巨大张力。本文将以威斯康星州诉约德案为例，从现代法律与宗教信仰自由之间的冲突为视角，探讨现代法治体系下的神圣与世俗之间的张力，以及在此基础上延伸出来的民族传统文化与现代主流文明之间的张力。

创意与技术的博弈：计算时代下本土 4A 广告公司的转型策略研究

莫牧

[摘要](143) [PDF 0KB](0)

摘要:
【目的】深入分析本土 4A 广告公司的计算化转型策略，以期进一步掌握广告业发展动态，为本土 4A 广告公司转型之路提供借鉴。【方法】通过案例分析法，对蓝色光标、省广集团等本土 4A 广告公司的经营范围、管理结构、技术应用、媒介投放、数据来源等进行研究总结。【结果】各本土 4A 广告公司应通过信息来源多元化、经营范围多样化、管理结构扁平化、内容形式细分化、媒介选择移动化等多方面进行计算化转型策略的尝试。【结论】向计算化转型将成为本土 4A 广告公司未来长期的发展趋势，也逐渐走向全面化、深层次、融合化。在此过程中如何处理创意与技术的关系将仍是本土 4A 广告公司需要解决的主要问题。

[摘要](11) [PDF 475KB](0)

摘要:

, doi: 10.3934/puqr.2023007

[摘要](38) [HTML全文](49) [PDF 0KB](0)

摘要:

2018－2020年上海市B/Victoria系流感病毒的流行特征及基因特性分析000

赵雪, 滕峥, 袁芳, 姜晨彦, 袁政安

[摘要](23) [HTML全文](31) [PDF 3072KB](0)

摘要:
目的

分析2018 — 2020年上海市分离的B/Victoria系流感毒株与疫苗株的匹配性及基因变异情况。

方法

利用血凝抑制实验，对142株B/Victoria系流感毒株进行了抗原性分析，并选取了63株开展了血凝素（HA）及神经氨酸酶（NA）基因序列分析。

结果

2018 — 2020年上海市流行的B/Victoria系流感毒株主要属于V1A.3分支，少数属于V1A.1分支及未缺失的V1A分支；抗原性分析显示，26.76%的流行株是疫苗株B/Colorado/06/2017鸡胚株的低反应株，与疫苗株相比，V1A.3分支流行株在HA蛋白的120环、150环、160环及190螺旋等关键的抗原决定簇及受体结合关键部位发生了5个氨基酸位点改变。

结论

2018 — 2020监测年度B/Victoria系流行株与世界卫生组织推荐的疫苗株组分B/Colorado/06/2017匹配性不佳，仍需密切监测流行株的谱系及变异情况，为疫苗株的筛选提供可靠的数据。

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