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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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MITOCHOnDRIAL REDOX IMAGInG FOR CAnCER DIAGnOSTIC AnD THERAPEUTIC STUDIES

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Journal of Innovative Optical Health Sciences 2009年第4期2卷 325-341页

作者： LIn Z.LI HE n.xu MAHSA RAnJI SHOKO nIOKA BRITTOn CHAnCE Department of Radiology School of Medicine University of PennsylvaniaB6 Blockley Hall423 Guardian Drive PhiladelphiaPA 19104-6069USA The Institute for Translational Medicine and Therapeutics School of Medicine University of Pennsylvania PhiladelphiaPA 19104USA Biophotonics Laboratory Department of Electrical Engineering and Computer Science University of Wisconsin-Milwaukee MilwaukeeWI 53211USA Johnson Research Foundation Department of Biochemistry and Molecular Biophysics School of Medicine University of Pennsylvania 250 Anatomy Chemistry BuildingPhiladelphiaPA 19104USA

Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including *** redox scanning method developed at the Chance laboratory about 30 years ago has allowed 3D highresolution(∼50×50×10µm^(3))imaging of mitochondrial redox state in tissue on the basis of the fluorescence of nADH(reduced nicotinamide adenine dinucleotide)and Fp(oxidized flavoproteins including flavin adenine dinucleotide,i.e.,FAD).In this review,we illustrate its basic principles,recent technical developments,and biomedical applications to cancer diagnostic and therapeutic studies in small animal *** developed calibration procedures for the redox imaging using reference standards allow quantification of nominal nADH and Fp concentrations,and the concentration-based redox ratios,e.g.,Fp/(Fp+nADH)and nADH/(Fp+nADH)in *** calibration facilitates the comparison of redox imaging results acquired for different metabolic states at different times and/or with different instrumental settings.A redox imager using a CCD detector has been developed to acquire 3D images faster and with a higher in-plane resolution down to 10µ*** vivo imaging and in vivo imaging of tissue mitochondrial redox status have been demonstrated with the CCD *** of tissue redox imaging in small animal cancer models include metabolic imaging of glioma and myc-induced mouse mammary tumors,predicting the metastatic potentials of human melanoma and breast cancer mouse xenografts,differentiating precancerous and normal tissues,and monitoring the tumor treatment response to photodynamic *** future directions for the development of redox imaging are also discussed.

关键词： Redox ratio reduced nicotinamide adenine dinucleotide nADH flavoprotein flavin adenine dinucleotide FAD calibration

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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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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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REDOX IMAGInG OF THE p53-DEPEnDEnT MITOCHOnDRIAL REDOX STATE In COLOn CAnCER EX VIVO

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Journal of Innovative Optical Health Sciences 2013年第3期6卷 1-10页

作者： HE n.xu MIn FEnG LILY MOOn nATHAn DOLLOFF WAFIKEL-DEIRY LIn Z.LI Department of Radiology University of Pennsylvania PhiladelphiaPAUSA Britton Chance Laboratory of Redox Imaging Johnson Research Foundation Department of Biochemistry and Biophysics Perelman School of Medicine University of Pennsylvania PhiladelphiaPAUSA Department of Medicine Penn State Hershey Medical Center and Penn State College of MedicineHersheyPAUSA Hematology/Oncology Penn State Hershey Medical Center HersheyPAUSA Abramson Cancer Center University of Pennsylvania PhiladelphiaPAUSA Institute of Translational Medicine and Therapeutics University of Pennsylvania PhiladelphiaPAUSA

The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously *** has how p53 regulates mitochondial respi ration been measured at(deep)tissue level,presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration *** prior work demonstrated that the mito-chondrial redox state and its intnatumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models,with the more metastatic tumons exhi-bit ing localized negions of more oxidized redox *** the Chance redox scanner with an in-plane spatial resolution of 200 pm,we imaged the mitochondrial redox state of the wild-type p53 colon tumors(HCT116 p53 ut)and the p5-deleted colon tumors(HCT116 p53-/-)by cllcting the fuorescence si gnals of nicotinamide adenine dimucleotide(nA DH)and oxidized flavoproteins [Fp,including favin adenine dinucleotide(FAD)]from the mouse xenogmafts snap frozen at low *** results show that:(1)both tumor lines have significant degree of intratumor heterogeneity of the redox state,typically exhibiting a distinct bi modal distribution that either correlates with the spatial core-rim pattern or the“hot/oold”oxida tion-roduction patches;.(2)the p531-group is significantly more beterogencous in the mitochondrial redox state and has a more oxidized turmor core compared to the p53 wt group when the tunor sizes of the two groups are matched;(3)the tumor size dependence of the redox indices(such as Fp and Fp redox ratio)is significant in the p531-group with the larger ones being more oxidized and more hetero-geneous in their redox state,particularly more oxidized in the tumor central regions;(4)the H&E staining images of tumor soctions grossly correlate with the redox *** present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattem of the mitochon-drial redox state in colon cancer and

关键词： nADH favoprotein intratumor heterogeneity HCT116 p53 null necrotic

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This research was supported by ***6 Integrated Project“Molecular Imaging”LSHG-CT-2003-503259 and ***7 Collaborative Project“FMT-XCT”.*** support from the Marie Curie Program EST-MolecImag Early Stage Training MEST-CT-2004-007643.

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Journal of Innovative Optical Health Sciences 2009年第4期2卷 365-374页

作者： MAHSA RAnJI SHOKO nIOKA HE n.xu BAOHUA WU LIn Z.LI DWIGHT L.JAGGARD BRITTOn CHAnCE Biophotonics Laboratory Department of Electrical Engineering and Computer Science University of Wisconsin-Milwaukee MilwaukeeWI 53211USA Department of Electrical and Systems Engineering University of Pennsylvania PhiladelphiaPA 19104USA Department of Biochemistry and Biophysics University of Pennsylvania PhiladelphiaPA 19104USA Department of Radiology University of Pennsylvania PhiladelphiaPA 19104USA

We have imaged mitochondrial oxidation-reduction states by taking a ratio of mitochondrial fluorophores:nADH(reduced nicotinamide adenine dinucleotide)to Fp(oxidized flavoprotein).Although nADH has been investigated for tissue metabolic state in cancer and in oxygen deprived tissues,it alone is not an adequate measure of mitochondrial metabolic state since the nADH signal is altered by dependence on the number of mitochondria and by blood *** redox ratio,nADH/(Fp+nADH),gives a more accurate measure of steady-state tissue metabolism since it is less dependent on mitochondrial number and it compensates effectively for hemodynamic *** ratio provides important diagnostic information in living *** this study,the emitted fluorescence of mouse colon in situ is passed through an emission filter wheel and imaged on a CCD *** ratio images of the healthy and hypoxic mouse intestines clearly showed significant ***,the corrected redox ratio indicated an increase from an average value of 0.51±0.10 in the healthy state to 0.92±0.03 in dead tissue due to severe ischemia(n=5).We show that the CCD imaging system is capable of displaying the metabolic differences in normal and ischemic tissues as well as quantifying the redox ratio in vivo as a marker of these changes.

关键词： Optical diagnosis nADH flavoprotein in vivo ischemia fluorescence.

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IMAGInG REDOX STATE HETEROGEnEITY WITHIn InDIVIDUAL EMBRYOnIC STEM CELL COLOnIES

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Journal of Innovative Optical Health Sciences 2011年第3期4卷 279-288页

作者： HE n.xu RUSSELL C.ADDIS DAVIDA F.GOInGS SHOKO nIOKA BRITTOn CHAnCE JOHn D.GEARHART LIn Z.LI Molecular Imaging Laboratory Department of Radiology University of PennsylvaniaSchool of Medicine PhiladelphiaPA 19104USA Institute for Regenerative Medicine and Department of Cell and Developmental Biology University of Pennsylvania School of Medicine PhiladelphiaPA 19104USA Britton Chance Laboratory of Redox Imaging Johnson Research Foundation Department of Biochemistry and Biophysics University of Pennsylvania School of Medicine PhiladelphiaPA 19104USA Institute of Translational Medicine and Therapeutics University of Pennsylvania PhiladelphiaPA 19104USA

Redox state mediates embryonic stem cell(ESC)differentiation and thus offers an important complementary approach to understanding the pluripotency of stem *** redox ratio(nADH/(Fp t nADH)),where nADH is the reduced form of nicotinamide adenine dinucleotide and Fp is the oxidizedflavoproteins,has been established as a sensitive indicator of mitochondrial redox *** this paper,we report our redox imaging data on the mitochondrial redox state of mouse ESC(mESC)colonies and the implications *** low-temperature nADH/Fp redox scanner was employed to image mESC colonies grown on a feeder layer of gamma-irradiated mouse embryonicfibroblasts(MEFs)on glass cover *** result showed significant heterogeneity in the mitochondrial redox state within individual mESC colonies(size:~200-440μm),exhibiting a core with a more reduced state than the *** more reduced state positively correlates with the expression pattern of Oct4,a well-established marker of *** observation is thefirst to show the heterogeneity in the mitochondrial redox state within a mESC colony,suggesting that mitochondrial redox state should be further investigated as a potential new biomarker for the stemness of embryonic stem cells.

关键词： Redox imaging pluripotency nADH flavoproteins redox ratio

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Corrosion and cavitation erosion resistance enhancement of cast ni–Al bronze by laser surface melting

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Journal of Iron and Steel Research International 2022年第2期29卷 359-369页

作者： Q.n.Song Y.Tong H.L.Li H.n.Zhang n.xu G.Y.Zhang Y.F.Bao W.Liu Z.G.Liu Y.X.Qiao Engineering Research Center of Dredging Technology of Ministry of Education Hohai UniversityChangzhou213022JiangsuChina College of Mechanical and Electrical Engineering Hohai UniversityChangzhou213022JiangsuChina College of Materials Science and Engineering Jiangsu University of Science and TechnologyZhenjiang212003JiangsuChina

Laser surface melting (LSM) was applied on a cast ni–Al bronze (nAB), which was a crucial material for marine ship propellers. A 720 μm-thick LSM layer with fine equiaxed and dendritic microstructures was obtained. After immersion for 30 days, the corrosion rate of cast nAB was reduced by 25% after LSM. Preferential corrosion occurred and deep corrosion pits appeared at α + κIII microstructure for the cast nAB. LSM nAB underwent general corrosion, and a much more protective film formed on the surface because of the homogenized microstructure. The mass loss of the cast nAB was approximately 2.1 times larger than that of LSM nAB after cavitation erosion (CE) in 3.5 wt.% naCl solution for 5 h. For the two materials, the mechanical impact effect was dominantly responsible for CE damage. Therefore, the improved hardness and homogenized microstructure contributed to the improved CE resistance of LSM nAB. CE destructed the film, shifted the open circuit potential toward a more negative value, and raised the current density by an order of magnitude. Corrosion at the cast eutectoid microstructure and the dendrites of LSM nAB facilitates the degradation under the cavitation attack. CE-corrosion synergy was largely caused by corrosion-enhanced-CE.

关键词： Laser surface melting ni-Al bronze Microstructure Corrosion Cavitation erosion Synergy

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RHIC能区Au+Au碰撞中集合径向流的研究(英文)

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高能物理与核物理 2002年第4期26卷 305-308页

作者：张景波霍雷张卫宁刘亦铭 n.xu 哈尔滨工业大学理论物理教研室哈尔滨150001 nuclear Science Division LBNL

利用相对论量子分子动力学模型RQMD ,对RHIC能区s =2 0 0AGeVAu +Au碰撞的集体膨胀效应进行了研究 ,对散射粒子的横质量谱进行了分析 .研究表明 ,在RHIC能区的重离子反应中存在有强的集合径向流 .对单粒子谱的拟合结果给出Au +Au的源冻... 详细信息

利用相对论量子分子动力学模型RQMD ,对RHIC能区s =2 0 0AGeVAu +Au碰撞的集体膨胀效应进行了研究 ,对散射粒子的横质量谱进行了分析 .研究表明 ,在RHIC能区的重离子反应中存在有强的集合径向流 .对单粒子谱的拟合结果给出Au +Au的源冻结温度为 1 60MeV ,平均径向流速度为 0 .6c.

关键词：重离子碰撞集合径向流横质量谱相对论量子分子动力学模型 RHIC能区散射粒子集体膨胀效应

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RHIC能区Au+Au非对心碰撞中的事件形状(英文)

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高能物理与核物理 2002年第8期26卷 851-854页

作者：张景波 J.Yang 霍雷张卫宁刘亦铭 n.xu 哈尔滨工业大学理论物理教研室哈尔滨150001 nuclear Science Division

利用相对论量子分子动力学模型RQMD ,结合 2π干涉学分析 ,对RHIC能区s=2 0 0AGeVAu +Au非对心碰撞的事件形状进行了研究 .研究表明 ,HBT参数可以反映事件在坐标空间的非对称性 ,而不能直接给出事件在动量空间的压力梯度 .另外 ,HBT参... 详细信息

利用相对论量子分子动力学模型RQMD ,结合 2π干涉学分析 ,对RHIC能区s=2 0 0AGeVAu +Au非对心碰撞的事件形状进行了研究 .研究表明 ,HBT参数可以反映事件在坐标空间的非对称性 ,而不能直接给出事件在动量空间的压力梯度 .另外 ,HBT参数对横动量的依赖关系对系统的空间 -动量关联较为敏感 .

关键词： RHIC能区非对心碰撞事件形状重离子碰撞 HBT关联事件非对称性相对论量子分子动力学模型金

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