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Quantitative redox imaging biomarkers for studying tissue metabolic state and its heterogeneity

Journal of Innovative Optical Health Sciences 2014年第2期7卷 109-128页

作者： He N.Xu Lin Z.Li Department of RadiologyBrtton Chance Laboratory of Redoa Imaging johnson Research foundation Departmentof Biochemistry and BiophysicsPerelman School of MedicineUniversity of Pennsyluania PhiladelphiaPAUSA

NAD+/NADH redox state has been implicated in many diseases such as cancer and diabetes aswell as in the regulation of embryonic development and aging,To fluorimetrically sssthemitochondrial redox state,*** and co-workers measured the fluorescence of NADH andoxidized flavoproteins(Fp)including favin-adenine-dinucleotide(FAD)and demonstrated theirratio(*** redox ratio)is a sensitive indicator of the mitochondrial redox states.,The Chanceredox sca mer was built to simult aneously measure NADH and Fp in tisue at submilimeter scalein 3D using the freeze-trap *** paper summarizes our recent research experience,development and new applications of the redox scanning technique in collaboration with *** beginning in *** initiated or actively involved in many of the projectsduring the last several years of his *** advanced the redox scanning technigue by measuringthe nominal concentrations(in reference to the frozen solution standards)of the endogenousfuorescent analy tes,i.e.,[NADH]and[rp]to quantify the redox ratios in various *** advancement has enabled us to identify an array of the redox indices as quantitativeimaging,biomarkers(including[NADH],[Fp],[Fp]/[NADH]+[Fp],[NADH]/[Fp],and theirstandard deviations)for studying some important biological questions on cancer and normaltsue *** found that the redox indices were asociated or changed with(NADH)tumorigenesis(cancer versus non-cancer of human breast tisue biopsies);(2)tumor metastaticpotential;(3)tumor glucose uptake;(4)tumor p53 stat us;(5)PI3K pathway activation in pre-malignant tissue;(6)therapeutic ffects on tumors;(7)embryonic stem cell diferentiation;(8)the heart under fasting,Together,our work demonstrated that the tisue redox indices obtainedfrom the redox scanning technique may provide usefil information about tisue met abolism and physiology status in normal and diseased *** Chance redox scanner and other redoximaging techniques may ha

关键词： Tumor progresion mitochondria met astasis met astatic potential pre-malignancy NADH Fp FAD redox ratio

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QUANTITATIVE REDOX SCANNING OF TISSUE SAMPLES USING A CALIBRATION PROCEDURE

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Journal of Innovative Optical Health Sciences 2009年第4期2卷 375-385页

作者： HE N.XU BAOHUA WU SHOKO NIOKA BRITTON CHANCE LIN Z.LI Molecular Imaging Laboratory Department of Radiology University of PennsylvaniaPhiladelphia PA 19104USA johnson Research foundation Department of Biochemistry and Biophysics University of Pennsylvania PA 19104USA

The fluorescence properties of reduced nicotinamide adenine dinucleotide(NADH)and oxidizedflavoproteins(Fp)including flavin adenine dinucleotide(FAD)in the respiratory chain are sensitive indicators of intracellular metabolic states and have been applied to the studies of mitochondrial function with energy-linked *** redox scanner,a three-dimensional(3D)low temperature imager previously developed by Chance et al.,measures the in vivo metabolicproperties of tissue samples by acquiring fluorescence images of NADH and *** redox ratios,***/(Fp+NADH)and NADH/(Fp+NADH),provided a sensitive index of the mitochondrialredox state and were determined based on relative signal intensity *** we report thefurther development of the redox scanning technique by using a calibration method to quantifythe nominal concentration of the fluorophores in *** redox scanner exhibited very goodlinear response in the range of NADH concentration between 165–1318µM and Fp between90–720µM using snap-frozen solution *** samples such as human tumor mousexenografts and various mouse organs were redox-scanned together with adjacent NADH and Fpstandards of known concentration at liquid nitrogen *** nominal NADH and Fpconcentrations as well as the redox ratios in the tissue samples were quantified by normalizing the tissue NADH and Fp fluorescence signal to that of the snap-frozen solution *** calibration procedure allows comparing redox images obtained at different time,independent of instrument *** quantitative multi-slice redox images revealed heterogeneity inmitochondrial redox state in the tissues.

关键词： NADH flavoprotein redox ratio mitochondria tissue heterogeneity

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WORKING WITH AND LEARNING FROM BRIT

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Journal of Innovative Optical Health Sciences 2011年第4期4卷 479-482页

作者： LIN Z.LI Molecular Imaging Lab Department of Radiology Britton Chance Lab of Redox Imaging Eldridge Reeves Johnson Research Foundation Department of Biochemistry and Biophysics Perelman School of MedicineUniversity of Pennsylvania PhiladelphiaPA 19014USA

I had been closely working with *** Chance from 2005-2010 on imaging mitochondrial redox state in cancer and stem cells.I had also learned much from him in daily work and personal *** I would like to share some of my memories and experiences including(1)Great science is not necessarily done with top-grade expensive instruments;(2)Brit was genuinely interested in and dedicated to science;(3)Brit's attention to detail and timely action;(4)Brit's open-mindedness;and(5)Brit being modest,appreciative,and caring for others.

关键词： Britton Chance mitochondria redox state cancer stem cell

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Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson's disease

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Asian Journal of Pharmaceutical Sciences 2018年第6期13卷 507-517页

作者： Nrupa Borkar Huiling Mu René Holm Department of Pharmacy Faculty of Health and Medical Sciences University of Copenhagen Drug Product Development Janssen Research and Development Johnson & Johnson

Parkinson's disease(PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients,apomorphine is normally administered subcutaneously with frequent injections because of the compound's extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient *** present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD,such as sublingual delivery and transdermal delivery.

关键词： Apomorphine Drug delivery Parkinson’s disease Alternative apomorphine therapy Non-invasive delivery Excipients

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Electron transfer reactions of piperidine aminoxyl radicals

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Chinese Science Bulletin 2010年第25期55卷 2760-2783页

作者： ZHANG Fa LIU YouCheng johnson & johnson Consumer and Personal Products Worldwide Skillman New Jersey 08558 USA Department of Chemistry University of Science and Technology of China Hefei 230026 China

This review article summarizes the electron transfer reactions of piperidine aminoxyl radicals. Electrochemical studies revealed the single electron transfer nature of piperidine aminoxyl radicals. In solution, piperidine aminoxyl radicals serve as single electron transfer oxidation reagent to react with various biologically interesting molecules such as glutathione, cysteine, ascorbic acid, and amines. The reaction product distribution, reaction kinetics, intermediates, and the reaction features in biological mimic environments including micelles and cyclodextrins were investigated. Oxoammonium salts, the one-electron transfer oxidation products of piperidine aminoxyl radicals, are agents of organic synthesis to selectively generate ketones or di-ketones from alcohols or ketones bearing α-methylene group under mild conditions. The new reactions of oxoammonium salts with aromatic amines, phenols, heterocycles including phenothiazines, papaverine, and bilirubin are also illustrated.

关键词：电子转移反应自由基哌啶单电子转移生物反应反应动力学杂环化合物甲基酮

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3D imaging of the mitochondrial redox state of rathearts under normal and fasting conditions

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Journal of Innovative Optical Health Sciences 2014年第2期7卷 60-69页

作者： He N.Xu Rong Zhou Lily Moon Min Feng Lin Z.Li Department of Radiology Universityof PennsyluaniaPhilade lphia PA 19104USA Briton Chance Laboratory of Redor Imaging johnson Research foundation Department of Biochemistry and Biophysics University of Pennsyluania Philade lphiaPA 19104USA Institute of Translational Medicine and Therapeutics Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104USA

The heart requires continuous ATP availability that is generated in the *** using the cell culture and perfiused organ models have been carried out to investigate thebiochemistry in the mitochondria in response to a change in substrate supply,mitochondrialbioenergetics of heart under normal feed or fasting conditions has not been studied at the tissuelevel with a sub-millimeter spatial resolution either in vivo or er *** of many food-derived metabolites to generate ATP in the mitochondria is realized through the NADH/NAD+couple acting as a central electron *** employed the Chance redox scanner thelow-temperat ure fluorescence scanner to image the three-dimensional(3D)spatial distribution of themitochondrial redox states in heart tissues of rats under normai feeding or an overnight star-vation for 14.5 *** consecutive sections of each heart were imaged to map three redoxindices,i.e,NADH,oxidized favoproteins Fp,including flavin adenine dinucleotide(FAD)andthe redox ratio NADH/*** imaging results revealed the micro-heterogeneity and the spatial distribution of these redox *** quantitative analysis showed that in the fasted hearts thestandard deviation of both NADH and Fp,ie.,SD NADH and SDFp,significantly decreasedwith a p value of 0.032 and 0.045,respectively,indicating that the hearts become relatively morehomogeneous after *** fasted hearts contained 28.6%less NADH(p=0.038).No *** change in Fp was foumnd(p=0.4).The NADH/Fp ratio decreased with a marginalP value(0.076).The decreased NADH im the fasted hearts is consistent with the cardiac celsreliance of fatty acids consumption for energy metabolism when glucose becomes *** o bservation of N ADH decrease induced by dietary restriction in the heart at tissuelevel has not been reported to our best *** Chance redox scanner demonstrated thefeasibility of 3D imaging of the mitochondrial redox st ate in the heart and

关键词： Mitochondion metabolism bioenergetics cardiomyocyte NADH flavoproteins Fp FAD caloric restriction food deprivation.

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Are fat NKT cells born that way?

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Cellular & Molecular Immunology 2017年第8期14卷 658-661页

作者： Joshua A Vieth Derek B Sant'Angel Child Health Institute of New Jersey Rutgers Robert Wood Johnson Medical SchoolNew BrunswickNJ 08901USA Graduate School of Biomedical Sciences Rutgers Robert Wood Johnson Medical SchoolNew BrunswickNJ 08901USA Department of Pediatrics Rutgers Robert Wood Johnson Medical SchoolNew BrunswickNJ 08901USA

The role of natural killer T(NKT)cells in adipose tissue is a topic of much interest,as reports have suggested a correlation between depletion of the adipose-resident NKT(arNKT)cell population and chronic obesity.1 Fu... 详细信息

关键词： NKT killer obesity

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Fundamental aspects of solid dispersion technology for poorly soluble drugs

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Acta Pharmaceutica Sinica B 2014年第1期4卷 18-25页

作者： Yanbin Huang Wei-Guo Dai Key Laboratory of Advanced Materials(MOE) Department of Chemical EngineeringTsinghua UniversityBeijing 100084China Janssen Research and Development Johnson&Johnson CompanyRandor 19087PAUSA

The solid dispersion has become an established solubilization technology for poorly water soluble *** a solid dispersion is basically a drug-polymer two-component system,the drug-polymer interaction is the determining factor in its design and *** this review,we summarize our current understanding of solid dispersions both in the solid state and in dissolution,emphasizing the fundamental aspects of this important technology.

关键词： Solid dispersion Poorly soluble drug Phase separation Drug-polymer interaction

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INTRODUCTION SPECIAL ISSUE IN MEMORY OF PROFESSOR BRITTON CHANCE

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Journal of Innovative Optical Health Sciences 2011年第3期4卷 I0001-I0003页

作者： Lin Z.Li Shoko Nioka Molecular Imaging Lab Department of Radiology Britton Chance Lab of Redox Imaging johnson foundation Department of Biochemistry and Biophysics University of Pennsylvania

Britton Chance:One of the Most Outstanding Scientists in the World On June 3rd and 4th,2011,over 300 scientists and professionals from all over the world gathered at the Translational Research Center of the University of Pennsylvania to attend a memorial symposium on\Britton Chance:His Life,Times and Legacy"and a\Molecular Spectroscopy/Imaging Workshop:from bench top to bedside"dedicated to Britton Chance as well.

关键词： Times Chance symposium

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Ion channels in neurodevelopment:lessons from the Integrin-KCNB1 channel complex

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Neural Regeneration Research 2023年第11期18卷 2365-2369页

作者： Alessandro Bortolami Federico Sesti Department of Neuroscience and Cell Biology Robert Wood Johnson Medical SchoolRutgers UniversityWest PiscatawayNJUSA

Ion channels modulate cellular excitability by regulating ionic fluxes across biological *** mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals *** are trigge red by an imbalance between excitatory and inhibitory ***,pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function va riants,all able to trigger ***,certain alleles are associated with brain malformations even in the absence of a clear electrical *** body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally *** focusing on ion channels in prenatal cortical development have shed light on this apparent *** picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes,including neuronal migration,neurite outgrowth,and synapse ***,pathogenic channel mutants can not only cause epileptic disorders by alte ring excitability,but further,by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.

关键词： developmental and epileptic encephalopathies epilepsy K+channel KCNB1 Kv2.1 neurodevelopment potassium channel

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