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Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

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Current Medical Science 2024年第2期44卷 298-308页

作者： Zhen LU Qian LAI Zhi-feng LI meng-ya ZHONG Yue-long jiang Li-ying FENG Jie ZHA Jing-wei YAO Yin LI Xian-ming DENG Bing XU Department of Hematology The First Affiliated Hospital of Xiamen University and Institute of HematologySchool of MedicineXiamen UniversityXiamen361005China Key Laboratory of Xiamen for diagnosis and Treatment of Hematological Malignancy Xiamen361005China Department of Oncology The First Affiliated Hospital of Jinan UniversityJinan UniversityGuangzhou510630China State Key Laboratory of Cellular Stress Biology Innovation Center for Cell Signaling NetworkSchool of Life SciencesXiamen UniversityXiamen361003China

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient *** present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL ***:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were *** addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in ***:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor *** of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these ***:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

关键词： B-cell acute lymphoblastic leukemia dual-target inhibitor NF-kB c-Myc PI3K/AKT p53

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Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1

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Chinese Chemical Letters 2024年第5期35卷 201-206页

作者： Yulong Shi Fenbei Chen mengyuan Wu Xin Zhang Runze meng Kun Wang Yan Wang Yuheng Mei Qionglu Duan Yinghong Li Rongmei Gao Yuhuan Li Hongbin Deng Jiandong jiang Yanxiang Wang Danqing Song Beijing Key Laboratory of Antimicrobial Agents Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Pharmacy Affiliated Hospital of Jining Medical UniversityJining Medical UniversityJining 272000China

Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and *** them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of *** chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against ***,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane ***,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).

关键词： Aloperine SARS-CoV-2 TMPRSS2 SR-B1 Synthesis

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Study on the preservation effects of the amputated forelimb by machine perfusion at physiological temperature

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Chinese Journal of Traumatology 2024年第2期27卷 114-120页

作者： Sheng-Feng Chen Bo-Yao Yang Tie-Yuan Zhang Xiang-Yu Song Zhi-Bo Jia Lei-Jia Chen meng-Yi Cui Wen-Jing Xu jiang Peng Guizhou Medical University Guiyang550025China Medical School of PLA Beijing100048 China Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma and War Injuries PLADepartment of OrthopedicsThe Fourth Medical CenterChinese PLA General HospitalBeijing100048China Hebei North Universiy Zhangjiakou075000Hebei ProvinceChina

Purpose:Ischemia and hypoxia are the main factors limiting limb replantation and *** cold storage(SCS),a common preservation method for tissues and organs,can only prolong limb ischemia time to 4-6 *** normothermic machine perfusion(NMP)is a promising method for the preservation of tissues and organs,which can extend the preservation time in vitro by providing continuous oxygen and *** study aimed to evaluate the difference in the efficacy of the 2 limb preservation ***:The 6 forelimbs from beagle dogs were divided into 2 *** the SCS group(n=3),the limbs were preserved in a sterile refrigerator at 4°C for 24 h,and in the NMP group(n=3),the perfusate prepared with autologous blood was used for the oxygenated machine perfusion at physiological temperature for 24 h,and the solution was changed every 6 *** effects of limb storage were evaluated by weight gain,perfusate biochemical analysis,enzyme-linked immunosorbent assay,and histological *** statistical analyses and graphs were performed using GraphPad Prism 9.0 one-way or two-way analysis of *** p value of less than 0.05 was considered to indicate statistical ***:In the NMP group,the weight gained percentage was 11.72%±4.06%;the hypoxia-inducible factor-1αcontents showed no significant changes;the shape of muscle fibers was normal;the gap between muscle fibers slightly increased,showing the intercellular distance of(30.19±2.83)μm;and the vascularα-smooth muscle actin(α-SMA)contents were lower than those in the normal blood *** creatine kinase level in the perfusate of the NMP group increased from the beginning of perfusion,decreased after each perfusate change,and remained stable at the end of perfusion showing a peak level of 4097.6 U/*** lactate dehydrogenase level of the NMP group increased near the end of perfusion and reached the peak level of 374.4 U/*** the SCS group,the percentage of weight gain was 0.18%±0.10%,a

关键词： Traumatic amputation Machine perfusion Static cold storage Limb replantation

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Enhancing hyperspectral power transmission line defect and hazard identification with an improved YOLO-based model

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Optoelectronics Letters 2024年第11期 681-688页

作者： WANG meng SUN Long jiang Jiong YANG Jinsong ZHANG Xingru Ningbo Power Transmission and Transformation Construction Co. Ltd.Yongyao Technology Branch State Grid Ningbo Power Supply Company

To address the challenges of inefficient manual inspections and time-consuming video monitoring for power transmission lines, this paper presents an innovative solution. It combines deep learning algorithms with visib...

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Glycnsisitin A:A promising bicyclic peptide against heart failure that facilitates TFRCmediated uptake of iron in cardiomyocytes

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3125-3139页

作者： Jichao Zhou Yuanyuan Liu Xiaoli Wei meng Yuan Xu Zhang Lingfeng Qin Bing Cui Pingping Li Jing Zhang Ziming Feng Jianshuang jiang Xiang Yuan Ruibing Xu Zhimeng Zhang Peicheng Zhang Xiaowei Zhang Yanan Yang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Zhigancao decoction is a traditional prescription for treating irregular pulse and palpitations in *** the monarch drug of Zhigancao decoction,the bioactive molecules of licorice against heart diseases remain *** established the HRESIMS-guided method leading to the isolation of three novel bicyclic peptides,glycnsisitins A-C(1-3),with distinctive C-C and C-O-C side-chain-toside-chain linkages from the roots of Glycyrrhiza uralensis(Licorice).Glycnsisitin A demonstrated stronger cardioprotective activity than glycnsisitins B and C in an in vitro model of doxorubicin(DOX)-induced cardiomyocyte *** A treatment not only reduced the mortality of heart failure(HF)mice in a dose-dependent manner but also significantly attenuated DOX-induced cardiac dysfunction and myocardial *** set enrichment analysis(GSEA)of the differentially expressed genes indicated that the cardioprotective effect of glycnsisitin A was mainly attributed to its ability to maintain iron homeostasis in the ***,glycnsisitin A interacted with transferrin and facilitated its binding to the transferrin receptor(TFRC),which caused increased uptake of iron in *** findings highlight the key role of bicyclic peptides as bioactive molecules of Zhigancao decoction for the treatment of HF,and glycnsisitin A constitutes a promising therapeutic agent for the treatment of HF.

关键词： Glycyrrhiza uralensis Bicyclic peptides Myocardial energy metabolism Iron homeostasis TFRC

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Development of an Agrobacterium-mediated CRISPR/Cas9 gene editing system in jute(Corchorus capsularis)

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The Crop Journal 2024年第4期12卷 1266-1270页

作者： Shaolian jiang Qin Li Xiangxue meng mengxin Huang Jiayu Yao Chuanyu Wang Pingping Fang Aifen Tao Jiantang Xu Jianmin Qi Shuangxia Jin Liwu Zhang Key Laboratory of Ministry of Education for Genetic Breeding and Multiple Utilization of Crops Fujian Agriculture and Forestry UniversityFuzhou 350002FujianChina Experiment Station of Ministry of Agriculture and Rural Affairs for Jute and Kenaf in Southeast China/Fujian Public Platform for Germplasm Resources of Bast Fiber Crops/Fujian Provincial Key Laboratory of Crop Breeding by Design/Key Laboratory of Ministry of Agriculture and Rural Affairs for Biological Breeding of Fujian and Taiwan Crops Fujian Agriculture and Forestry UniversityFuzhou 350002FujianChina National Key Lab of Crop Genetic Improvement Huazhong Agricultural UniversityWuhan 430070HubeiChina

Jute(Corchorus capsularis L.)is the second most important natural plant fiber source after ***,developing an efficient gene editing system for jute remains a *** this study,the transgenic hairy root system mediated by Agrobacterium rhizogenes strain K599 was developed for Meifeng 4,an elite jute variety widely cultivated in *** transgenic hairy root system for jute was verified by subcellular localization and bimolecular fluorescence complementation(BiFC)*** CHLOROPLASTOS ALTERADOS 1(CcCLA1)gene,which is involved in the development of chloroplasts,was targeted for editing at two sites in Meifeng *** on this hairy root transformation,the gRNA scaffold was placed under the control of cotton ubiquitin GhU6.7 and-GhU6.9 promoters,respectively,to assess the efficiency of gene *** indicated the 50.0%(GhU6.7)and 38.5%(GhU6.9)editing events in the target 2 alleles(gRNA2),but no mutation was detected in the target 1 allele(gRNA1)in transgenic-positive hairy ***1 gene editing at gRNA2 under the control of GhU6.7 in Meifeng 4 was also carried out by Agrobacterium tumefaciens-mediated *** CcCLA1 mutants were albinic,with a gene editing efficiency of 5.3%.These findings confirm that the CRISPR/Cas9 system,incorporating promoter GhU6.7,can be used as a gene editing tool for jute.

关键词： Jute Agrobacterium-mediated transformation Genome editing Hairy root system

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Multimodality management for chronic subdural hematoma in China: protocol and characteristics of an ambidirectional, nationwide, multicenter registry study

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中华神经外科杂志(英文) 2024年第02期10卷 124-133页

作者： Liu Tao Zhao Zhihao Huang Jinhao Zhu Xide Chen Weiliang Lin Kun Yu Yunhu Li Zhanying Fan Yibing Liu Mingqi Nie meng Liu Xuanhui Gao Chuang Quan Wei Qian Yu Wu Chenrui Yuan jiangyuan Wu di Lv Chuanxiang Dong Shiying Mi Liang Tian Yu Tian Ye Zhang Jianning jiang Rongcai Department of Neurosurgery Tianjin Medical University General Hospital Tianjin China Ministry of Education Tianjin Neurological Institute Key Laboratory of Post Neuro-injury Neuro-repair and Regeneration in Central Nervous System Tianjin Medical University General Hospital Tianjin China Department of Neurosurgery Linyi People’s Hospital Shandong China Department of Neurosurgery Haining People’s Hospital Zhejiang China Department of Neurosurgery Fujian Provincial Hospital Fujian China Department of Clinical Research Center for Neurological disease the People’s Hospital of HongHuaGang District of ZunYi Guizhou China Department of Neurosurgery Kailuan General Hospital Hebei China Department of Neurosurgery Tianjin First Central Hospital Tianjin China Department of Neurosurgery The First Hospital of Jilin University Changchun China

Background Despite its prevalence, there is ongoing debate regarding the optimal management strategy for chronic subdural hematoma (CSDH), reflecting the variability in clinical presentation and treatment outcomes. This ambidirectional, nationwide, multicenter registry study aims to assess the efficacy and safety of multimodality treatment approaches for CSDH in the Chinese ***/design A multicenter cohort of CSDH patients from 59 participating hospitals in mainland China was enrolled in this study. The treatment modalities encompassed a range of options and baseline demographics, clinical characteristics, radiographic findings, and surgical techniques were documented. Clinical outcomes, including hematoma resolution, recurrence rates, neurological status, and complications, were assessed at regular intervals during treatment, 3 months, 6 months, 1 year, and 2 years *** Between March 2022 and August 2023, a comprehensive cohort comprising 2173 individuals who met the criterion was assembled across 59 participating clinical sites. Of those patients, 81.1% were male, exhibiting an average age of 70.12 ± 14.53 years. A historical record of trauma was documented in 48.0% of cases, while headache constituted the predominant clinical presentation in 58.1% of patients. The foremost surgical modality employed was the burr hole (61.3%), with conservative management accounting for 25.6% of cases. Notably, a favorable clinical prognosis was observed in 88.9% of CSDH patients at 3 months, and the recurrence rate was found to be 2.4%.Conclusion This registry study provides critical insights into the multimodality treatment of CSDH in China, offering a foundation for advancing clinical practices, optimizing patient management, and ultimately, improving the quality of life for individuals suffering from this challenging neurosurgical *** registration ChiCTR2200057179

关键词： Chronic subdural hematoma Multimodality therapy Outcome Recurrence

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Prophylactic effects of Edible Lilium-Egg yolk compound powder on depression-like behaviors in rats exposed to chronic unpredictable mild stress: A role of gut-brain axis

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Food Science and Human Wellness 2024年

作者： Yu Huang Yu-xin Luo Sai-nan Tian meng-zhou Xie Liang Li Ming-xing jiang Zhi-ying Yuan Hunan University of Chinese Medicine Key Laboratory of TCM Heart and Lung Syndrome differentiation & Medicated diet and dietotherapy， Hunan University of Chinese Medicine TCM and Ethnomedicine Innovation & Development International Laboratory， School of Pharmacy， Hunan University of Chinese Medicine

The incidence rate and harmfulness of depression are increasing yearly， and the research on the antidepressant effect of regulating the intestinal microecology balance has attracted widespread attention. The purpose of this research was to study the preventive effects and the regulatory mechanism of edible Lilium-egg yolk compound powder(Chinese abbreviation， BHT) on gut-brain crosstalk in depressive rats induced by chronic unpredictable mild stress(CUMS) through the "microbiota-gut-brain" axis. Results showed that infusion of BHT for 21 days ameliorated the morphology of the hippocampus and colon， increased the rate of sucrose preference， reduced the immobility time of forced swimming， increased the expression level of anti-inflammatory cytokine Interleukin-10 (IL-10) in serum， up-regulate the expression level of plasma neurotransmitter 5-hydroxy tryptamine (5-HT)， down-regulate the expression of inflammatory factors tumor necrosis factor-α (TNF-α)， interleukin-6 (IL-6)， and interleukin-1β (IL-1β) and neurotransmitter glutamic acid (Glu) in serum， and decrease the expression levels of lipopolysaccharide (LPS)， diamine oxidase (DAO) and lactate dehydrogenase (LD) in plasma. The underlying mechanism may be to reduce the activation of microglia (lower levels of CD11b， IBa1 protein and gene expression)， regulate hippocampal GR/BDNF/NPY signal pathway (higher levels of GR， BDNF， NPY protein and gene expression)， enhance intestinal mucosal barrier function (higher levels of ZO-1， Occludin protein and gene expression)， regulate the composition and structure of intestinal flora(Analysis results of LEfSe combined with random forest showed that Prevotella and Paraprevotella might be biomarkers of BHT intervention in depression)， and it is related to the improvement of glutathione metabolism， and other metabolic pathways. Pearson correlation analysis found that 5-HT is strongly positively correlated with Prevotella，and Glu has a strong negative correlation with ***

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SlBEL11 regulates flavonoid biosynthesis,thus fine-tuning auxin efflux to prevent premature fruit drop in tomato

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Journal of Integrative Plant Biology 2024年第4期66卷 749-770页

作者： Xiufen Dong Xianfeng Liu Lina Cheng Ruizhen Li Siqi Ge Sai Wang Yue Cai Yang Liu Sida meng Cai-Zhong jiang Chun-Lin Shi Tianlai Li Daqi Fu Mingfang Qi Tao Xu College of Horticulture Shenyang Agricultural UniversityShenyang 110866China Collaborative Innovation Center for Efficient and Green Production of Agriculture in Mountainous Areas of Zhejiang Province College of Horticulture ScienceZhejiang A&F UniversityHangzhou 311300China Key Laboratory for Quality and Safety Control of Subtropical Fruits and Vegetables Collaborative Innovation Center for Efficient and Green Production of Agriculture in Mountainous Areas of Zhejiang ProvinceMinistry of Agriculture and Rural AffairsCollege of Horticulture ScienceZhejiang A&F UniversityHangzhou 311300China Key Laboratory of Protected Horticulture of Ministry of Education Shenyang 110866China Crops Pathology and Genetic Research Unit United States Department of Agriculture Agricultural Research ServiceWashingtonDC 20250USA Department of Plant Sciences University of CaliforniaDavisCA 95616USA ANGENOVO Oslo 0753Norway Laboratory of Fruit Biology College of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijing 100083China

Auxin regulates flower and fruit abscission,but how developmental signals mediate auxin transport in abscission remains ***,we reveal the role of the transcription factor BEL1-LIKE HOMEODOMAIN11(SlBEL11)in regulating auxin transport during abscission in tomato(Solanum lycopersicum).SlBEL11 is highly expressed in the fruit abscission zone,and its expression increases during fruit *** of SlBEL11 expression by RNA interference(RNAi)caused premature fruit drop at the breaker(Br)and 3d post-breaker(Br+3)stages of fruit *** and metabolome analysis of SlBEL11-RNAi lines revealed impaired flavonoid biosynthesis and decreased levels of most flavonoids,especially quercetin,which functions as an auxin transport *** suggested that SlBEL11 prevents premature fruit abscission by modulating auxin efflux from fruits,which is crucial for the formation of an auxin response ***,quercetin treatment suppressed premature fruit drop in SlBEL11-RNAi *** affinity purification sequencing(DAP-seq)analysis indicated that SlBEL11 induced expression of the transcription factor gene SlMYB111 by directly binding to its *** immunoprecipitation-quantitative polymerase chain reaction and electrophoretic mobility shift assay showed that *** MYELOBLASTOSIS VIRAL ONCOGENE HOMOLOG111(SlMYB111)induces the expression of the core flavonoid biosynthesis genes SlCHS1,SlCHI,SlF3H,and SlFLS by directly binding to their *** findings suggest that the SlBEL11-SlMYB111 module modulates flavonoid biosynthesis to fine-tune auxin efflux from fruits and thus maintain an auxin response gradient in the pedicel,thereby preventing premature fruit drop.

关键词： abscission auxin flavonoid SlBEL11 tomato

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Molecular mechanisms of Buqing granule for the treatment of diabetic retinopathy:Network pharmacology analysis and experimental validation

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World Journal of diabetes 2024年第9期15卷 1942-1961页

作者： Yi-Fan Yang Ling Yuan Xiang-Yang Li Qian Liu Wen-Jie jiang Tai-Qiang Jiao Jia-Qing Li meng-Yi Ye Yang Niu Yi Nan Key Laboratory of Ningxia Minority Medicine Modernization Ministry of Education Ningxia Medical UniversityYinchuan 750004Ningxia Hui Autonomous RegionChina College of Pharmacy Ningxia Medical UniversityYinchuan 750004Ningxia Hui Autonomous RegionChina Traditional Chinese Medicine College Ningxia Medical UniversityYinchuan 750004Ningxia Hui Autonomous RegionChina School of Clinical Medicine Ningxia Medical UniversityYinchuan 750004Ningxia Hui Autonomous RegionChina

BACKGROUND diabetic retinopathy(DR)is a common microvascular complication of diabetes *** blindness rate is high;therefore,finding a reasonable and safe treatment plan to prevent and control DR is ***,there are abundant and diverse research results on the treatment of DR by Chinese medicine Traditional Chinese medicine compounds are potentially advantageous for DR prevention and treatment because of its safe and effective therapeutic *** To investigate the effects of Buqing granule(BQKL)on DR and its mechanism from a systemic perspective and at the molecular level by combining network pharmacology and in vivo *** This study collected information on the drug targets of BQKL and the therapeutic targets of DR for intersecting target gene analysis and protein-protein interactions(PPI),identified various biological pathways related to DR treatment by BQKL through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses,and preliminarily validated the screened core targets by molecular ***,we constructed a diabetic rat model with a high-fat and high-sugar diet and intraperitoneal streptozotocin injection,and administered the appropriate drugs for 12 weeks after the model was successfully *** mass and fasting blood glucose and lipid levels were measured,and pathological changes in retinal tissue were detected by hematoxylin and eosin *** was used to detect the oxidative stress index expression in serum and retinal tissue,and immunohistochemistry,real-time quantitative reverse transcription PCR,and western blotting were used to verify the changes in the expression of core *** Six potential therapeutic targets of BQKL for DR treatment,including Caspase-3,c-Jun,TP53,AKT1,MAPK1,and MAPK3,were screened using *** analysis indicated that the MAPK signaling pathway might be the core target pathway of BQKL in DR *** docking prediction indica

关键词： diabetic retinopathy Network pharmacology Animal models Oxidative stress Inflammatory

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