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Selenium and the Thioredoxin and Glutaredoxin Systems

Biomedical and Environmental Sciences 1997年第2期10卷 271-279页

作者： MIKAEL BJORNSTEDT SUSHIL KUMAR LINDA BJ■RKHEM GIANNIS SPYROU AND ARNE HOLMGREN(The medical Nobel Institute for Biochemistry, department of medical Biochemistry and biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden department of Bioscience, medical Nobel Institute for Biochemistry Department of Medical Biochemistry and Biophysics Karolinska Institute Stockholm Sweden.

Thioredoxin (Trx) is a small ubiquitous dithiol protein which together with the FADcontaining enzyme thioredoxin reductase (TR) and NADPH (the Trx system) is a hydrogen donor for ribonucleotide reductase essential for DNA synthesis and a general protein disulfide reductase involved in redox regulation. Selenite, selenodiglutathione (GS-Se-SG) and selenocystine are efficiently reduced by thioredoxins and also directly by NADPH and mammalian TR but not by the E. coli enzyme. Incubation of selenite or GS-Se-SG with the Trx system or with mammalian TR results in a rapid formation of selenide, which by redox cycling with oxygen may cause a large non-stoichiometric oxidation of NADPH. Selenocystine is efficiently reduced into two molecules of the selenol amino acid selenocysteine by mammalian TR with a Km-value (6μmol·L-1 ) and a high turnover number (kcat, 3200 min-1) almost identical to the natural substrate Trx-S2. TR also directly reduces lipid hydroperoxides and this peroxidase reaction is strongly stimulated by the presence of catalytic amounts of free selenocysteine. Glutaredoxin (Grx) which catalyzes GSH dependent disulfide reduction also via a redox-active disulfide and Trx are both efficient electron donors to the hut-nan plasrna glutathione peroxidase providing a mechanism by which human plasma glutathione peroxidase may reduce hydroperoxides in an environment almost free from glutathione. Selenate is reduced by Grx and Trx in the presence of GSH. The DNA-binding of the transcription factor AP-1 is strongly inhibited by GS-Se-SG and selenite. Furtherrnore, selenide formed by TR-mediated reduction of selenite and GS-Se-SG inhibits lipoxygenase and changes the electron spin resonance spectrum of the active site iron. Mammalian TR with two subunits of 57 kDa has recently been cloned and shown to be homologous to glutathione reductase. The rat enzyme contains a selenocysteine residue in a unique Cterminal position and a conserved SEClS sequence directing insertion of the selenocysteine. The discovery of selenocy

关键词： NADPH Selenium and the Thioredoxin and Glutaredoxin Systems GSH USA ADF

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Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors

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The Innovation 2024年第3期5卷 129-137页

作者： Balázs Gyorffy department of biophysics Medical SchoolUniversity of Pecs7624 PecsHungary department of Bioinformatics Semmelweis University1094 BudapestHungary Cancer Biomarker Research Group Institute of Molecular Life SciencesHUN-REN Research Centre for Natural Sciences1117 BudapestHungary

Identifying genes with prognostic significance that can act as biomarkers in solid tumors can help stratify patients and uncover novel therapy targets.Here,our goal was to expand our previous ranking analysis of survival-associated genes in various solid tumors to include colon cancer specimens with available transcriptomic and clinical data.A Gene Expression Omnibus search was performed to identify available datasets with clinical data and raw gene expression measurements.A combined database was set up and integrated into our Kaplan-Meier plotter,making it possible to identify genes with expression changes linked to altered survival.As a demonstration of the utility of the platform,the most powerful genes linked to overall survival in colon cancer were identified using uni-and multivariate Cox regression analysis.The combined colon cancer database includes 2,137 tumor samples from 17 independent cohorts.The most significant genes associated with relapse-free survival with a false discovery rate below 1%in colon cancer carcinoma were RBPMS(hazard rate[HR]=2.52),TIMP1(HR=2.44),and COL4A2(HR=2.36).The three strongest genes associated with shorter survival in stage II colon cancer include CSF1R(HR=2.86),FLNA(HR=2.88),and TPBG(HR=2.65).In summary,a new integrated database for colon cancer is presented.A colon cancer analysis subsystem was integrated into our Kaplan-Meier plotter that can be used to mine the entire database(https://***).The portal has the potential to be employed for the identification and prioritization of promising biomarkers and therapeutic target candidates in multiple solid tumors including,among others,breast,lung,ovarian,gastric,pancreatic,and colon cancers.

关键词： colon tumors analysis

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Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1344-1360页

作者： Chun-Yuan Yang Li-Mei Guo Yang Li Guang-Xi Wang Xiao-Wei Tang Qiu-Lu Zhang Ling-Fu Zhang Jian-Yuan Luo department of Pathology Institute of Systems BiomedicineSchool of Basic Medical Sciences Peking UniversityPeking University Third HospitalPeking University Health Science CenterBeijing 100191China department of General Surgery Peking University Third HospitalBeijing 100191China department of medical Genetics Department of Biochemistry and BiophysicsSchool of Basic Medical Sciences Peking UniversityPeking University Health Science CenterBeijing 100191China

BACKGROUND Cholangiocarcinoma(CCA)is a highly malignant cancer,characterized by frequent mucin overexpression.MUC1 has been identified as a critical oncogene in the progression of CCA.However,the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete.AIM To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients.METHODS Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins,complemented by bioinformatic analyses.Subse-quent validations were conducted through spatial transcriptomics and immuno-histochemistry.The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm,which was further confirmed by independent cohorts and diverse data types.RESULTS CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness.MUC5AC-high cells were found to promote CCA progression through WNT signaling.MUC5B-high cells exhibited robust cellular oxidation activities,leading to resistance against antitumoral treatments.MUC13-high cells were observed to secret chemokines,recruiting and transforming macrophages into the M2-polarized state,thereby suppressing antitumor immunity.MUC16-high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils.Utilizing the expression levels of these mucins,a risk factor evaluation formula for CCA was developed and validated across multiple cohorts.CCA samples with higher risk factors exhibited stronger metastatic potential,chemotherapy resistance,and poorer prognosis.CONCLUSION Our study elucidates the functional mechanisms through which mucins contribute to CCA development,and provides tools for risk stratification in CCA.

关键词： Mucin Cholangiocarcinoma Single-cell RNA sequencing Spatial transcriptomics Prognosis

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High-yield and rapid isolation of extracellular vesicles by flocculation via orbital acoustic trapping:FLOAT

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Microsystems & Nanoengineering 2024年第1期10卷 313-323页

作者： Joseph Rufo Peiran Zhang Zeyu Wang Yuyang Gu Kaichun Yang Joseph Rich Chuyi Chen Ruoyu Zhong Ke Jin Ye He Jianping Xia Ke Li Jiarong Wu Yingshi Ouyang Yoel Sadovsky Luke P.Lee Tony Jun Huang department of Mechanical Engineering and Materials Science Duke UniversityDurhamNCUSA department of Biomedical Engineering Duke UniversityDurhamNCUSA department of Obstetrics Gynecologyand Reproductive SciencesMagee-Womens Research InstituteUniversity of PittsburghPittsburghPAUSA department of Microbiology and Molecular Genetics School of MedicineUniversity of PittsburghPittsburghPAUSA Renal Division and Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolBostonMAUSA department of Bioengineering Department of Electrical Engineering and Computer ScienceUniversity of CaliforniaBerkeleyBerkeleyCAUSA department of biophysics Institute of Quantum BiophysicsSungkyunkwan UniversitySuwonKorea

Extracellular vesicles(EVs)have been identified as promising biomarkers for the noninvasive diagnosis of various diseases.However,challenges in separating EVs from soluble proteins have resulted in variable EV recovery rates and low purities.Here,we report a high-yield(>90%)and rapid(<10 min)EV isolation method called FLocculation via Orbital Acoustic Trapping(FLOAT).The FLOAT approach utilizes an acoustofluidic droplet centrifuge to rotate and controllably heat liquid droplets.By adding a thermoresponsive polymer flocculant,nanoparticles as small as 20 nm can be rapidly and selectively concentrated at the center of the droplet.We demonstrate the ability of FLOAT to separate urinary EVs from the highly abundant Tamm-Horsfall protein,addressing a significant obstacle in the development of EV-based liquid biopsies.Due to its high-yield nature,FLOAT reduces biofluid starting volume requirements by a factor of 100(from 20 mL to 200µL),demonstrating its promising potential in point-of-care diagnostics.

关键词： trapping utilize separating

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New clinical trial design in precision medicine:discovery,development and direction

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1293-1321页

作者： Xiao-Peng Duan Bao-Dong Qin Xiao-Dong Jiao Ke Liu Zhan Wang Yuan-Sheng Zang department of medical Oncology Changzheng HospitalNaval Medical UniversityShanghaiChina

In the era of precision medicine,it has been increasingly recognized that individuals with a certain disease are complex and different from each other.Due to the underestimation of the significant heterogeneity across participants in traditional"one-sizefits-all"trials,patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket,umbrella,and platform trial designs under the master protocol framework.In recent years,the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities.Despite the rapid increase in the number of basket,umbrella,and platform trials,the current clinical and research understanding of these new trial designs,as compared with traditional trial designs,remains limited.The majority of the research focuses on methodologies,and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs.Therefore,we provide this comprehensive review of the discovery and development of basket,umbrella,and platform trials and their underlying logic from the perspective of precision medicine.Meanwhile,we discuss future directions on the potential development of these new clinical design in view of the"Precision Pro","Dynamic Precision",and"Intelligent Precision".This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic,which be essential to accelerate the progression of precision medicine.

关键词： clinical approval successive

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Progress in the generation of spinal cord organoids over the past decade and future perspectives

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Neural Regeneration Research 2024年第5期19卷 1013-1019页

作者： Gang Zhou Siyuan Pang Yongning Li Jun Gao department of Neurosurgery Peking Union Medical College HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina department of International medical Service Peking Union Medical College HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina

Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo.As emerging bioengineering methods have led to the optimization of cell culture protocols,spinal cord organoids technology has made remarkable advancements in the past decade.Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes.Moreover,fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment.These qualities make spinal cord organoids valuable tools for disease modeling,drug screening,and tissue regeneration.By utilizing this emergent technology,researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases.However,at present,spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine.Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.

关键词： development organoid-on-a-chip pluripotent stem cells progress spinal cord diseases spinal cord organoids vascularization

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Efficient adsorption separation of methane from C_(2)-C_(3) hydrocarbons in a Co(Ⅱ)-nodes metal-organic framework

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Chinese Journal of Chemical Engineering 2024年第5期69卷 192-198页

作者： Jie Zhang Xingzhe Guo Bing Lin Guangzu Xiong Hanshuang Wang Min Zhang Liwen Fan Bingwen Li Shuisheng Chen department of Chemistry and Chemical Engineering Taiyuan Institute of TechnologyTaiyuan 030008China Engineering Research Center of Oligosaccharides Fuyang Normal UniversityFuyang 236041China Shandong Key Laboratory of biophysics Institute of BiophysicsDezhou UniversityDezhou 253023China

Methane(CH_(4))as a substitute for other mineral fuels plays a crucial role in reducing energy consumption and preventing environmental pollution.The present study employs a solvothermal method to fabricate a porous framework Co-metal-organic framework(Co-MOF)containing two distinct secondary building units(SBUs):an anionic[Co_(2)(μ_(2)-OH)(COO)_(4)(H_(2)O)]and a neutral[CoN_(2)(COO)_(2)].Notably,within the anionic SBUs,the coordinated water molecules induce the generation of divergent unsaturated Co(Ⅱ)centers in the unidirectional porous channels,thereby creating open metal sites.The adsorption performance of Co-MOF towards pure component gases was systematically investigated.The results demonstrated that Co-MOF exhibits superior adsorption capacity for C_(2)-C_(3) hydrocarbons compared to CH_(4),which offers the potential for efficient adsorption and separation of CH_(4) from C_(2)-C_(3) hydrocarbons.The gas selectivity separation ratios of Co-MOF for C_(2)H_(6)/CH_(4) and C_(3)H_8/CH_(4) were calculated using the ideal adsorbed solution theory method at 273/298 K and 0.1 MPa.The results revealed that Co-MOF achieved remarkable equilibrium separation selectivity for CH_(4) and C_(2)-C_(3) hydrocarbon gases among non-modified MOFs,signifying the potential of the synthesized Co-MOF for efficient recovery and purification of CH_(4) from C_(2)-C_(3) hydrocarbons.Breakthrough experiments further demonstrate the ability of Co-MOF to purify methane from C_(2)-C_(3) hydrocarbons in practical gas separation scenarios.Additionally,molecular simulation calculations further substantiate the propensity of anionic SBUs to interact with C_(2)-C_(3) hydrocarbon compounds.This study provides a novel paradigm for the development of porous MOF materials in the application of gas mixture separation.

关键词： Co-MOF Separation hydrocarbons Dynamic breakthrough curves Molecular simulations adsorbent Monte Carlo simulation

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Leveraging diverse cell-death patterns to predict the clinical outcome of immune checkpoint therapy in lung adenocarcinoma:Based on muti-omics analysis and vitro assay

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Oncology Research 2024年第2期32卷 393-407页

作者： HONGYUAN LIANG YANQIU LI YONGGANG QU LINGYUN ZHANG department of Radiology Shengjing Hospital of China Medical UniversityShenyangChina department of Nephrology The First Affiliated Hospital of China Medical UniversityShenyangChina department of Clinical Medicine China Medical UniversityShenyangChina department of medical Oncology The First Hospital of China Medical UniversityShenyangChina

Advanced LUAD shows limited response to treatment including immune therapy.With the development of sequencing omics,it is urgent to combine high-throughput multi-omics data to identify new immune checkpoint therapeutic response markers.Using GSE72094(n=386)and GSE31210(n=226)gene expression profile data in the GEO database,we identified genes associated with lung adenocarcinoma(LUAD)death using tools such as“edgeR”and“maftools”and visualized the characteristics of these genes using the“circlize”R package.We constructed a prognostic model based on death-related genes and optimized the model using LASSO-Cox regression methods.By calculating the cell death index(CDI)of each individual,we divided LUAD patients into high and low CDI groups and examined the relationship between CDI and overall survival time by principal component analysis(PCA)and Kaplan-Meier analysis.We also used the“ConsensusClusterPlus”tool for unsupervised clustering of LUAD subtypes based on model genes.In addition,we collected data on the expression of immunomodulatory genes and model genes for each cohort and performed tumor microenvironment analyses.We also used the TIDE algorithm to predict immunotherapy responses in the CDI cohort.Finally,we studied the effect of PRKCD on the proliferation and migration of LUAD cells through cell culture experiments.The study utilized the TCGA-LUAD cohort(n=493)and identified 2,901 genes that are differentially expressed in patients with LUAD.Through KEGG and GO enrichment analysis,these genes were found to be involved in a wide range of biological pathways.The study also used univariate Cox regression models and LASSO regression analyses to identify 17 candidate genes that were best associated with mortality prognostic risk scores.By comparing the overall survival(OS)outcomes of patients with different CDI values,it was found that increased CDI levels were significantly associated with lower OS rates.In addition,the study used unsupervised cluster analysis to divide 115 LUAD patients into two distinct cluste

关键词： Lung adenocarcinoma Programmed cell death Iron-death Drug sensitivity Cancer therapy

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Effect of cytochrome P4502C19(CYP2C19)gene polymorphism and clopidogrel reactivity on long term prognosis of patients with coronary heart disease after PCI

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Journal of Geriatric Cardiology 2024年第1期21卷 90-103页

作者： Cheng-Yan HU Yan-Ling WANG Zhen-Xing FAN Xi-Peng SUN Shuai WANG Zhi LIU department of Geriatrics Fu Xing HospitalCapital Medical UniversityBeijingChina department of Cardiology Xuanwu Hospital Capital Medical UniversityBeijingChina Emergency department of Xuanwu Hospital Capital Medical UniversityBeijingChina

Objective To investigate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity and its association with longterm clinical outcome in patients with coronary heart disease(CHD)undergoing percutaneous coronary intervention(PCI).Methods In total,675 patients were enrolled.Based on the platelet inhibition rate,patients were categorized into two groups:clopidogrel low responsiveness(CLR)and normal clopidogrel responsiveness(NCR).The CLR group was divided into ticagrelor and clopidogrel group based on the antiplatelet drugs used in the follow-up treatment.Patients were classified into three groups(normal metabolizer,intermediate metabolizer,and poor metabolizer)based on the CYP2C19 genotype.We aimed to evaluate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity.The cumulative rates of 12-month all-cause deaths,major adverse cardiovascular events(MACCEs),and bleeding events were calculated.Results CLR was observed in 44.4%of the overall population.Significant differences were observed in the platelet inhibition rate of clopidogrel among the three metabolic genotypes(P0.05).Conclusions Low response to clopidogrel in CHD patients is correlated with CYP2C19 gene polymorphism.CYP2C19 genotyping combined with platelet reactivity is an independent predictor of 12-months MACCEs in patients with clopidogrel treatment after PCI,which is better than either test alone.

关键词： CYP2C19 drugs PCI

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Single-cell RNA sequencing to understand host-virus interactions

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Virologica Sinica 2024年第1期39卷 1-8页

作者： Jia-Tong Chang Li-Bo Liu Pei-Gang Wang Jing An department of Microbiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China

Single-cell RNA sequencing(scRNA-seq)has allowed for the profiling of host and virus transcripts and host-virus interactions at single-cell resolution.This review summarizes the existing scRNA-seq technologies together with their strengths and weaknesses.The applications of scRNA-seq in various virological studies are discussed in depth,which broaden the understanding of the immune atlas,host-virus interactions,and immune repertoire.scRNA-seq can be widely used for virology in the near future to better understand the pathogenic mechanisms and discover more effective therapeutic strategies.

关键词： Single-cell RNA sequencing(scRNA-seq) Host-virus interaction COVID-19 Flavivirus

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