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Antibacterial and cytotoxic metabolites produced by Streptomyces tanashiensis BYF-112 isolated from Odontotermes formosanus

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Chinese Journal of Natural Medicines 2024年第9期22卷 822-830页

作者： WU Jun SONG Tao ZHANG Le HUANG Zhongdi HUANG Fang YIN Caiping ZHANG Shuxiang LIU Xinhua ZHANG Yinglao school of life science Anhui Agricultural UniversityHefei 230036China school of pharmacy Anhui Medical UniversityHefei 230036China

Chemical investigations of the termite-associated Streptomyces tanashiensis BYF-112 resulted in the discovery of four novel alkaloid derivatives: vegfrecines A and B(1 and 2), exfoliazone A(3), and venezueline H(7), in addition to nine known metabolites(4-6, 8-13). The structures of these compounds were elucidated through comprehensive spectroscopic analysis and comparison with existing literature data. Antibacterial assays revealed that viridomycin A(11) exhibited potent antibacterial activity against Staphylococcus aureus, with a zone of inhibition(ZOI) of 12.67 mm, in comparison to a ZOI of 17.67 mm for the positive control gentamicin sulfate. Viridomycin A(11) showed moderate activity against Micrococcus tetragenus and Pseudomonas syringae pv. actinidae, with ZOI values of 15.50 and 14.33 mm, respectively, which were inferior to those of gentamicin sulfate(34.67 and 24.00mm). Viridomycin F(12) also exhibited moderate antibacterial effects against S. aureus, M. tetragenus, and P. syringae pv. actinidae,with ZOI values of 8.33, 16.50, and 10.83 mm, respectively. Cytotoxicity assays demonstrated that viridobruunine A(5), exfoliazone(6), viridomycin A(11), and X-14881E(13) exhibited significant cytotoxicity against human malignant melanoma(A375), ovarian cancer(SKOV-3), and gastric cancer(MGC-803) cell lines, with IC_(50) values ranging from 4.61 to 19.28 μmol·L^(-1). Furthermore, bioinformatic analysis of the complete genome of S. tanashiensis suggested a putative biosynthetic gene cluster(BGC) responsible for the production of compounds 1-12. These findings indicate that the secondary metabolites of insect-associated S. tanashiensis BYF-112hold promise as potential sources of novel antibacterial and anticancer agents.

关键词： Odontotermes formosanus Streptomyces tanashiensis Alkaloid Cytotoxic activity Antibacterial activity Biosynthetic pathway

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STING signaling in islet macrophages impairs insulin secretion in obesity

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science China(life sciences) 2024年第2期67卷 345-359页

作者： Ze Hong Saihua Chen Jing Sun Dan Cheng Hanli Guo Jiahao Mei Xiang Zhang Munire Maimaiti Haiping Hao Peng Cao Haiyang Hu Chen Wang school of pharmacy Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory of Natural Medicines Department of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 211198China school of life sciences Westlake UniversityHangzhou 310012China

The innate immune regulator stimulator of interferon genes(STING)mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines,which promotes the progression of various inflammatory and autoimmune *** immune system plays a critical role in regulating obesity-induced islet dysfunction,whereas the potential effect of STING signaling is not fully ***,we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet(HFD)***^(-/-)alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of ***,palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in ***,STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment ofβcell insulin secretory *** inhibiting STING activation enhances insulin secretion to control ***,our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

关键词： STING obesity type 2 diabetes insulin macrophages islet

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Morphology and phylogenetic placement of Mallomonas vietnamica(Synurales,Chrysophyceae)from China

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Journal of Oceanology and Limnology 2024年第4期42卷 1325-1335页

作者： Junxue HAO Fangru NAN Junping LÜ Qi LIU Xudong LIU Shulian XIE Jia FENG school of life science Shanxi UniversityTaiyuan 030006China

The newly described chrysophyte,Mallomonas vietnamica,is reported for the first time in China from specimens collected in Guizhou Province,SW *** morphological characteristics were studied using light and scanning electron *** species was described based on morphological characteristics,including cell size,scale size,dome,V-rib,and ***,molecular sequencing of *** was conducted and a phylogenetic tree was constructed based on concatenated SSU,LSU,and rbc L *** phylogenetic tree led us to suggest raising a new section named Uncatusipedae for this *** study provides new molecular data from the genus Mallomonas and enriches our understanding of the species diversity and geographical distribution of the genus Mallomonas in China.

关键词： Chrysophyta Mallomonas vietnamica phylogenetic study taxonomy

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Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

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Asian Journal of Pharmaceutical sciences 2024年第2期19卷 170-187页

作者： Bao Li Haoran Niu Xiaoyun Zhao Xiaoyu Huang Yu Ding Ke Dang Tianzhi Yang Yongfeng Chen Jizhuang Ma Xiaohong Liu Keda Zhang Huichao Xie Pingtian Ding school of pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China school of life science and Biopharmaceutics Shenyang Pharmaceutical University Shenyang 110016 China Department of Basic Pharmaceutical sciences school of pharmacy Husson University Bangor ME 04401USA College of pharmacy Shenzhen Technology UniversityShenzhen 518118China

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

关键词： Anti-angiogenesis Tumor apoptosis Nanoparticles VEGF siRNA Hypoxia inducible factor(HIF)-1 protein Phenethyl isothi ocyanate(PEITC)

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Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma

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Journal of Pharmaceutical Analysis 2024年第2期14卷 211-224页

作者： Jingjing Wang Qi Su Kun Chen Qing Wu Jiayan Ren Wenjuan Tang Yu Hu Zeren Zhu Cheng Cheng Kaihui Tu Huaizhen He Yanmin Zhang school of pharmacy Health Science CenterXi'an Jiaotong UniversityXi'an710061China

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

关键词： Pyrimethamine BNIP3 SNARE Autophagosome-lysosome fusion Hepatocellular carcinoma Sorafenib

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Resolving the geometric structure of trastuzumab by mobility capillary electrophoresis and native mass spectrometry

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Chinese Chemical Letters 2024年第3期35卷 221-225页

作者： Wenjing Zhang Jie Hong Lei Yang Zuqiang Xu Yu Xiang Wei Xu school of life science Beijing Institute of TechnologyBeijing 100081China

Available online Immunoglobulins G(IgGs)are Y-shaped globular proteins,however,their high flexibility and heterogeneity pose great challenges to their structure and conformation *** structure of IgG closely correlates to its biofunctions,such as the antibody escape of human immunodeficiency virus(HIV)could attribute to the distance mismatch between the ends of two Fab arms(antigen-binding sites)and envelope glycoprotein spikes on virion ***,we report the first use of mobility capillary electrophoresis(MCE)and native mass spectrometry(nMS)to resolve the internal geometric structure and conformation of an IgG(trastuzumab)in solution *** proteolysis,the ellipsoid dimensions of IgG and its subunits were measured by MCE-nMS *** was then reconstructed,in which the sizes and relative positions of these three subunits in three-dimensional space were *** was found that the two Fab arms have an angle of~102.1°and a distance of~11.0 nm between the two antigen-binding sites under native condition,and the Fc arm was tilted~16.0°towards one of the Fab *** was not on the plane of Fab-Fab,but has an angle of no larger than 103.1°.Under acidic environment(pH 3.0),each subunit of the IgG would unfold into larger dimensions,and the angles between these subunits also *** great potential for tumor imaging and therapy,the structure of F(ab')_(2)fragments was also measured and validated by molecular dynamic *** was found that the electrostatic force among these three subunits and steric hindrance stemming from Fc help maintaining the angle between two Fab arms.

关键词： Native mass spectrometry Mobility capillary electrophoresis Trastuzumab Protein structure Geometric structure

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The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease

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Neural Regeneration Research 2024年第5期19卷 1150-1155页

作者： Shuanglong Yi Linfang Wang Margaret S.Ho Shiping Zhang school of life science and Technology ShanghaiTech UniversityShanghaiChina College of life sciences University of Chinese Academy of SciencesBeijingChina

Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy *** in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s ***,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the *** the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult *** from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in ***9 is persistently in contact with these *** glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate *** suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic ***,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial *** findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s *** results may provide new insights on the underlying mechanism of Parkinson’s disease.

关键词： Atg9 autophagy glia Parkinson’s disease

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Inhibition mechanisms of CRISPR-Cas9 by AcrⅡA25.1 and AcrⅡA32

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science China(life sciences) 2024年第9期67卷 1781-1791页

作者： Jianlin Zheng Yuwei Zhu Tengjin Huang Wenbo Gao Jiale He Zhiwei Huang HIT Center for life sciences School of Life Science and TechnologyHarbin Institute of TechnologyHarbin 150080China Westlake Center for Genome Editing Westlake Laboratory of Life Sciences and BiomedicineSchool of Life SciencesWestlake UniversityHangzhou 310024China

In the ongoing arms race between bacteria and bacteriophages,bacteriophages have evolved anti-CRISPR proteins to counteract bacterial CRISPR-Cas ***,AcrⅡA25.1 and AcrⅡA32 have been found to effectively inhibit the activity of Spy Cas9 both in bacterial and human ***,their molecular mechanisms remain ***,we report the cryo-electron microscopy structures of ternary complexes formed by AcrⅡA25.1 and AcrⅡA32 bound to Spy Cas9-sg *** structural analysis and biochemical experiments,we revealed that AcrⅡA25.1 and AcrⅡA32 recognize a novel,previously-unidentified anti-CRISPR binding site on Spy *** found that both AcrⅡA25.1 and AcrⅡA32 directly interact with the WED domain,where they spatially obstruct conformational changes of the WED and PI domains,thereby inhibiting Spy Cas9 from recognizing protospacer adjacent motif(PAM)and unwinding double-stranded *** addition,they may inhibit nuclease activity by blocking the dynamic conformational changes of the Spy Cas9 surveillance *** summary,our data elucidate the inhibition mechanisms of two new anti-CRISPR proteins,provide new strategies for the modulation of Spy Cas9 activity,and expand our understanding of the diversity of anti-CRISPR protein inhibition mechanisms.

关键词： anti-CRISPR cryo-EM Spy Cas9 AcrⅡA25.1 AcrⅡA32 inhibiton

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Involvement of the ABA-and H_(2)O_(2)-Mediated Ascorbate-Glutathione Cycle in the Drought Stress Responses of Wheat Roots

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Phyton-International Journal of Experimental Botany 2024年第2期93卷 329-342页

作者： Mengyuan Li Zhongye Gao Lina Jiang Leishan Chen Jianhui Ma College of life science Henan Normal UniversityXinxiang453007China school of life science and Basic Medicine Xinxiang UniversityXinxiang453003China

Abscisic acid(ABA),hydrogen peroxide(H_(2)O_(2)) and ascorbate(AsA)–glutathione(GSH)cycle are widely known for their participation in various ***,the relationship between ABA and H_(2)O_(2) levels and the AsA–GSH cycle under drought stress in wheat has not been *** this study,a hydroponic experiment was conducted in wheat seedlings subjected to 15%polyethylene glycol(PEG)6000–induced *** stress caused the rapid accumulation of endogenous ABA and H_(2)O_(2) and significantly decreased the number of root tips compared with the *** application of ABA significantly increased the number of root tips,whereas the application of H_(2)O_(2) markedly reduced the number of root tips,compared with that under 15%*** addition,drought stress markedly increased the DHA,GSH and GSSG levels,but decreased the AsA levels,AsA/DHA and GSH/GSSG ratios compared with those in the *** activities of the four enzymes in the AsA–GSH cycle were also markedly increased under drought stress,including glutathione reductase(GR),ascorbate peroxidase(APX),monodehydroascorbate reductase(MDHAR)and dehydroascorbate reductase(DHAR),compared with those in the ***,the application of an ABA inhibitor significantly inhibited GR,DHAR and APX activities,whereas the application of an H_(2)O_(2) inhibitor significantly inhibited DHAR and MDHAR ***,the application of ABA inhibitor significantly promoted the increases of H_(2)O_(2) and the application of H_(2)O_(2) inhibitor significantly blocked the increases of ABA,compared with those under 15% *** together,the results indicated that ABA and H_(2)O_(2) probably interact under drought stress in wheat;and both of them can mediate drought stress by modulating the enzymes in AsA–GSH cycle,where ABA acts as the main regulator of GR,DHAR,and APX activities,and H_(2)O_(2) acts as the main regulator of DHAR and MDHAR activities.

关键词： ABA H_(2)O_(2) AsA-GSH cycle drought stress wheat roots

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Screening of morphology-related genes based on predatorinduced transcriptome sequencing and the functional analysis of Dagcut gene in Daphnia galeata

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Current Zoology 2024年第4期70卷 440-452页

作者： Ya-Qin Cao Ya-Jie Zhao Hui-Ying Qi Jin-Fei Huang Fu-Cheng Zhu Wen-Ping Wang Dao-Gui Deng school of life science Huaibei Normal UniversityHuaibei 235000AnhuiChina

High fish predation pressure can trigger"induced defense"in Daphnia species,resulting in phenotypic plasticity in morphology,behavior,or life-history *** molecular mechanisms of defense morphogenesis(e.g.,the tail spine and helmet)in Daphnia remain *** the pres-ent study,the tail spine,helmet,and body of Daphnia galeata under fish and non-fish kairomones conditions were collected for transcriptome analysis.A total of 24 candidate genes related to the morphological defense of *** were identified,including 2 trypsin,one cuticle protein,1 C1qDC protein,and 2 ferritin *** function of the Dagcut gene(*** cuticle protein gene)in relation to tail spine morphology was assessed using RNA interference(RNAi).Compared with the EGFP(Enhanced green fluorescent protein)treatment,after RNAi,the expression levels of the Dagcut gene(*** cuticle protein gene)showed a significant ***,the tail spines of the offspring pro-duced by *** after RNAi of the Dagcut gene appeared curved during the *** whole-mount in situ hybridization,a clear signal site was detected on the tail spine of *** before RNAi which disappeared after *** results suggest that the Dagcut gene may play an important role in tail spine formation of ***,and will provide a theoretical basis for studying the molecular mechanisms of the morpho-logical plasticityin cladocera inthefuture.

关键词： Dagcut Daphnia galeata fish kairomones RNAi tail spine transcriptome sequencing.

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