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Hemorrhagic transformation in patients with large-artery atherosclerotic stroke is associated with the gut microbiota and lipopolysaccharide

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Neural Regeneration research 2024年第7期19卷 1532-1540页

作者： Qin Huang Minping Wei Xianjing Feng Yunfang Luo Yunhai Liu Jian Xia Department of Neurology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Department of Neurology Peking University People’s HospitalBeijingChina Clinical research center for Cerebrovascular Disease of Hunan Province Central South UniversityChangshaHunan ProvinceChina National Clinical research center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

Hemorrhagic transformation is a major complication of large-artery atheroscle rotic stroke(a major ischemic stro ke subtype)that wo rsens outcomes and increases *** of the gut microbiota is an important feature of stroke,and some specific bacteria and bacterial metabolites may contribute to hemorrhagic transformation *** aimed to investigate the relationship between the gut microbiota and hemorrhagic transformation in largearte ry atheroscle rotic stro *** observational retrospective study was *** May 2020 to September 2021,blood and fecal samples were obtained upon admission from 32 patients with first-ever acute ischemic stroke and not undergoing intravenous thrombolysis or endovascular thrombectomy,as well as 16 healthy *** with stro ke who developed hemorrhagic transfo rmation(n=15)were compared to those who did not develop hemorrhagic transformation(n=17)and with healthy *** gut microbiota was assessed through 16S ribosomal ribonucleic acid *** also examined key components of the lipopolysaccharide pathway:lipopolysaccharide,lipopolysaccharide-binding protein,and soluble *** observed that bacterial diversity was decreased in both the hemorrhagic transformation and non-hemorrhagic transfo rmation group compared with the healthy *** patients with ischemic stro ke who developed hemorrhagic transfo rmation exhibited altered gut micro biota composition,in particular an increase in the relative abundance and dive rsity of members belonging to the Enterobacteriaceae *** lipopolysaccharide and lipopolysaccharide-binding protein levels were higher in the hemorrhagic transformation group compared with the non-hemorrhagic transfo rmation ***,lipopolysaccharide-binding protein,and soluble CD14 concentrations were associated with increased abundance of Enterobacte ***,the role of the gut microbiota in hemorrhagic transformation was evaluated using

关键词： gut microbiota hemorrhagic transformation inflammation lipopolysaccharide stroke

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Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152):a novel triple angiokinase inhibitor for cancer therapy

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1453-1475页

作者： Yuqin Yao Zhuowei Liu Manyu Zhao Zhengxia Chen Peng Li Yang Zhang Yuxi Wang Chengjian Zhao Chaofeng Long Xiaoxin Chen Jinliang Yang State Key Laboratory of Biotherapy and cancer center West China HospitalWest China School of Public Health and West China Fourth HospitalSichuan UniversityChengdu 610041China Guangdong Zhongsheng Pharmaceutical Co. Ltd.Dongguan 523325China West China School of Public Health and West China Fourth Hospital Healthy Food Evaluation Research CenterSichuan UniversityChengdu 610041China Guangdong Raynovent Biotech Co. Ltd.Dongguan 523325China WuXi AppTec Ltd.Shanghai 200131 China

Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and *** conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.

关键词： inhibited clinical synthesis

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Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2550-2567页

作者： Lihuan Shang Xue Jiang Ting Yang Hongbo Xu Qi Xie Mei Hu Conglian Yang Li Kong Zhiping Zhang Tongji School of Pharmacy Huazhong University of Science and TechnologyWuhan 430030China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China National Engineering research center for Nanomedicine Huazhong University of Science and TechnologyWuhan 430030China Hubei Engineering research Centre for Novel Drug Delivery System Huazhong University of Science and TechnologyWuhan 430030China

In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel(NG@M) to co-deliver chemotherapeutic paclitaxel(PTX) and immunotherapeutic agent interleukin-2(IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate(39 days).

关键词： Chemo-immunotherapy Nanogel pH-responsive cancer cell membrane Biomimetic

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Stem cells and the pursuit of youth,a tale of limitless possibilities and commercial fraud

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World Journal of Biological Chemistry 2021年第4期12卷 52-56页

作者： Batla S Al-Sowayan Alaa T Al-Shareeda Department of Cell Therapy and cancer research King Abdullah International Medical Research CenterKing Saud Bin Abdulaziz University for Health SciencesMinistry of National Guard Health AffairsRiyadh 11632Saudi Arabia Department of Cell Therapy and cancer research and Departmebt of the Saudi Biobank King Abdullah International Medical Research CenterKing Saud Bin Abdulaziz University for Health SciencesMinistry of National Guard Health AffairsRiyadh 11481Saudi Arabia

This article examines the hype generated around the term“stem cell”,and the capitalization of the stem cell craze by the cosmetic *** started by introducing product lines containing active ingredients derived from plant stem ***,evolved to using own cells for skin regeneration and hair loss treatment,and allogenic cells for the manufacturing of stem cell-derived *** article also discusses the missing links for safe and reliable stem cell applications in cosmetics,and why local regulatory bodies,members of the industry and consumers must all work together to stop the illegitimate use of the“stem cell”good name in unsafe or fraudulent commercial practices.

关键词： Stem cell Stem cell-derived products Cosmetics Regulations

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Nanotechnology based CRISPR/Cas9 system delivery for genome editing:Progress and prospect

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Nano research 2019年第10期12卷 2437-2450页

作者： Huan Deng Wei Huang Zhiping Zhang Tongji School of Pharmacy Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China National Engineering research center for Nanomedicine Huazhong University of Science and TechnologyWuhan 430030China Hubei Engineering research center for Novel Drug Delivery System Huazhong University of Science and TechnologyWuhan 430030China

The genome editing tool,clustered regularly interspaced short palindromic repeats(CRISPR)/Cas9 system,has achieved successful therapeutic efficacy via precise modification of the genome and exceeded previous genome engineering methods owing to its versatility and *** expansion in biomedical research has benefited from this newly emerged technique,such as genetic diseases treatment,cancer characterization,and plant ***,the key challenge is efficient delivery of CRISPR components in vivo and nanotechnology plays an in dispensable role in non viral gene *** this review,we will first briefly describe the mechanism and delivery strategies of CRISPR/Cas9 ***,the past and current researches of nan oparticles based CRISPR/Cas9 system delivery for genome editi ng will be *** ally,we will discuss the challe nges and prospects of CRISPR/Cas9 system combi ned with nano tech no logy for clinical translation in the future.

关键词： clustered regularly in terspaced short palindromic repeats(CRISPR)/Cas9 genome editi ng nan oparticle polymer liposome

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A pilot study of the association between genetic polymorphisms involved in estrogen signaling and infant male genital phenotypes

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Asian Journal of Andrology 2012年第5期14卷 766-772页

作者： Sheela Sathyanarayana Shanna H Swan Federico M Farin Hui-Wen Wilkerson Michael Bamshad Richard Grady Chuan Zhou Stephen M Schwartzy Department of Pediatrics University of WashingtonSeattleWA 98195USA center for Child Health Behaviorand DevelopmentSeattle Children's Research InstituteSeattleWA 98105USA Department of Preventive Medicine Mount Sinai School of MedicineNew YorkNY 10029USA Department of Environmental and Occupational Health Sciences University of WashingtonSeattleWA 98195USA Department of Genome Sciences University of WashingtonSeattleWA 98195USA Division of Pediatric Urology Seattle Children's HospitalSeattleWA 98105USA Department of Epidemiology University of WashingtonSeattleWA 98195USA Epidemiology Program Fred Hutchinson Cancer Research CenterSeattleWA 98109USA

Single nucleotide polymorphisms （SNPs） in genes that influence development of the male reproductive tract have been associated with male genitourinary abnormalities. However, no studies have tested the relationship between SNPs and intermediate phenotypes such as anogenital distance （AGD）, anoscrotal distance （ASD） and penile width （PW）. We tested whether 24 common SNPs in eight genes that influence male genital development were associated with intermediate phenotypes in 106 healthy male infants from the Study for Future Families. We used DNA from buccal smears and linear regression models to assess the relationship between anogenital measurements and SNP genotypes with adjustment for covariates. We found that the rs2077647 G allele, located in the coding region of estrogen receptor alpha （ESR1）, was associated with a shorter AGD （P=0.02; -7.3 mm, 95% confidence interval （CI）： -11.6 to -3.1）, and the rs10475 T allele, located in the 3＇ untranslated region of activating transcription factor 3 （ATF3）, was associated with a shorter ASD （-4.3 mm, 95% Ch -7.2 to -1.4）, although this result was not significant （P=0.07） after controlling for multiple comparisons. We observed no association between PW and the SNPs tested. Minor alleles for two SNPs in genes that regulate estrogen signaling during male genital development were associated with AGD and ASD, although the significance of the association was marginal. Our findings suggest that AGD and ASD are influenced by heritable factors in genes known to be associated with frank male genital abnormalities such as hvpospadias and crvotorchidism.

关键词： gene hypospadias male phenotype polymorphism reproductive

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Discovery and development of brain-penetrant ^(18)F-labeled radioligands for neuroimaging of the sigma-2 receptors

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1406-1415页

作者： Ying Zhang Tao Wang Xiaojun Zhang Winnie Deuther-Conrad Hualong Fu Mengchao Cui Jinming Zhang Peter Brust Yiyun Huang Hongmei Jia Key Laboratory of Radiopharmaceuticals(Beijing Normal University) Ministry of EducationCollege of ChemistryBeijing Normal UniversityBeijing 100B75China Nuclear Medicine Department Chinese PLA General HospitalBeijing 100853China Helmholtz-Zentrum Dresden-Rossendorf Institute of Radiopharmaceutical Cancer ResearchDepartment of NeuroradiopharmaceuticalsLeipzig 04318Germany PET center Department of Radiology and Biomedical ImagingYale University School of MedicineCT 06520-8048USA The Lübeck Institute of Experimental Dermatology University Medical Center Schleswig-HolsteinLubeck 23538Germany

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2(σ_(2))receptor *** ligands with high σ_(2) receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities,and evaluated in *** biodistribution studies in male ICR mice,radioligand[18F]9,or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole,was found to display high brain uptake and high brain-to-blood *** of animals with the selective σ_(2) receptor ligand CM398 led to significant reductions in both brain uptake(29%-54%)and brain-to-blood ratio(60%-88%)of the radioligand in a dose-dependent manner,indicating high and saturable specific binding of[18F]9 to σ_(2) receptors in the ***,ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of[18F]9 in the brain that is consistent with the distribution pattern of σ_(2) *** positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for[18F]9 in the rat brain,along with appropriate tissue *** together,results from our current study indicated the novel radioligand[18F]9 as the first highly specific and promising imaging agent for σ_(2) receptors in the brain.

关键词： Indole-based derivatives σ2 receptor Fluorine-18 Positron emission tomography Neuroimaging

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Novel computational biology methods and their applications to drug discovery

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Frontiers in Biology 2011年第4期6卷 289-299页

作者： Sharangdhar S.PHATAK Hoang T.TRAN Shuxing ZHANG School of Biomedical Informatics The University of Texas Health Science Center7000 Fannin StreetHoustonTX 77030USA The Integrated Molecular Discovery Laboratory Department of Experimental TherapeuticsThe University of Texas M.D.Anderson Cancer Center1515 Holcombe BlvdHoustonTX 77030USA

Computational biology methods are now firmly entrenched in the drug discovery *** methods focus on modeling and simulations of biological systems to complement and direct conventional experimental *** important branches of computational biology include protein homology modeling and the computational biophysics method of molecular *** modeling methods attempt to accurately predict three-dimensional(3D)structures of uncrystallized proteins for subsequent structure-based drug design *** dynamics methods aim to elucidate the molecular motions of the static representations of crystallized protein *** this review we highlight recent novel methodologies in the field of homology modeling and molecular *** drug discovery applications using these methods conclude the review.

关键词： computational biology drug discovery homology modeling molecular dynamics structure-based drug design

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Exercise and cancer Prevention: Current Evidence and Future Directions

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Journal of Science in Sport and Exercise 2020年第3期2卷 190-200页

作者： Lee W.Jones Department of Medicine Memorial Sloan Kettering Cancer Center1275 York AvenueNew YorkNY 10065USA Weill Cornell Medical College New YorkNYUSA

Establishment of the strong putative relationship between exercise and risk of virtually all non-communicable diseases prompted several research groups over the past two decades to investigate a question of significant public health concern:whether exercise lowers the risk of certain forms of *** this Opinion review I first overview studies of exercise in cancer prevention summarizing evidence from observational studies and available clinical *** the final section,I consider the next steps in the continued development of exercise as a cancer prevention strategy.

关键词： cancer Exercise Oncology Physical activity Primary prevention

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Anti-C4d chimeric antigen receptor regulatory T cells suppressed allograft rejection in ABO-incompatible heart transplantation

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Genes & Diseases 2022年第1期9卷 1-4页

作者： Sun-Kyung Lee Jerome Han Honglin Piao Nara Shin Joon Young Jang Ji-Jing Yan Hyori Kim Junho Chung Jaeseok Yang Biomedical research Institute Seoul National University HospitalSeoul 03080Republic of Korea Department of Medicine Graduate SchoolSeoul National University College of MedicineSeoul 03080Republic of Korea Department of Biochemistry and Molecular Biology Seoul National University College of MedicineSeoul 03080Republic of Korea Department of Biomedical Science Seoul National University College of MedicineSeoul 03080Republic of Korea cancer research Institute Seoul National University College of MedicineSeoul 03080Republic of Korea Division of Nephrology Department of Internal MedicineYonsei University College of MedicineSeoul 03722Republic of Korea Convergence Medicine research center Asan Medical CenterSeoul 05505Republic of Korea

ABO blood group-incompatible(ABOi)transplantation has been developed to overcome the serious problem of donor organ ***,antibody-mediated rejection(ABMR)remains as the main limitation to successful ABOi *** of desensitization treatment improved the outcomes of ABOi transplantation by suppressing ABMR;however,this strong,nonspecific immunosuppression also increases infectious ***,chimeric antigen receptor regulatory T cells(CAR Tregs)were developed to improve the antigen specificity,viability,and suppressive activity of Tregs.C4d deposition is a marker of ABMR and is also found in most ABOi allograft *** on these findings,we developed anti-C4d CAR Tregs to suppress ABMR in ABOi allografts.

关键词： C4d ABO allograft

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