Acute lung injury(ALI)is a serious clinical condition with a high mortality rate.Oxidative stress and inflammatory responses play pivotal roles in the pathogenesis of ALI.ONOO^(−)is a key mediator that exacerbates oxi...Acute lung injury(ALI)is a serious clinical condition with a high mortality rate.Oxidative stress and inflammatory responses play pivotal roles in the pathogenesis of ALI.ONOO^(−)is a key mediator that exacerbates oxidative damage and microvascular permeability in ALI.Accurate detection of ONOO^(−)would facilitate early diagnosis and intervention in ALI.Near-infrared fluorescence(NIRF)probes offer new solutions due to their sensitivity,depth of tissue penetration,and imaging capabilities.However,the developed ONOO^(−)fluorescent probes face problems such as interference from other reactive oxygen species and easy intracellular diffusion.To address these issues,we introduced an innovative self-immobilizing NIRF probe,DCI2F-OTf,which was capable of monitoring ONOO^(−)in vitro and in vivo.Importantly,leveraging the high reactivity of the methylene quinone(QM)intermediate,DCI2F-OTf was able to covalently label proteins in the presence of ONOO^(−),enabling in situ imaging.In mice models of ALI,DCI2F-OTf enabled real-time imaging of ONOO^(−)levels and found that ONOO^(−)was tightly correlated with the progression of ALI.Our findings demonstrated that DCI2F-OTf was a promising chemical tool for the detection of ONOO^(−),which could help to gain insight into the pathogenesis of ALI and monitor treatment efficacy.展开更多
Epilepsy,as a chronic neurological disease of the brain,is closely related to oxidative stress,and the peroxynitrite(ONOO-)significantly rise up in this event.Therefore,ONOO-is considered as a potential biomarker for ...Epilepsy,as a chronic neurological disease of the brain,is closely related to oxidative stress,and the peroxynitrite(ONOO-)significantly rise up in this event.Therefore,ONOO-is considered as a potential biomarker for early prediction of epilepsy.However,some potential diagnostic reagents for epilepsy are hindered by the blood-brain barrier(BBB).Meanwhile,“drug repurposing”is attracting a growing interest.Edaravone(EDA),as a first-line drug in the clinical treatment of cerebral ischemia,plays antioxidant roles in scavenging free radicals,promising potential antiepileptic activity.Thus,it is imperative to develop fluorescent probes for monitoring ONOO-fluctuations in the epileptic brain.Hence,we proposed a novel fluorescent probe with the thiocarbonate as the promising recognition unit for ONOO-and dicyanoisophorone derivative as the fluorophore.Moreover,by the“three-in-one”strategy,the introduction of trifluoromethyl into DCI-ONOO-3 can extend the emission wavelength of the fluorophore,shorten the response and increase lipophilicity.Consequently,DCI-ONOO-3 was used for monitoring ONOO-fluxes in brain of epileptic mice and evaluating the antiepileptic efficacy of EDA.It opens up a new way for the design of BBB permeable fluorescent probes,and provides a convincing new method for the diagnosis and treatment of epilepsy.展开更多
AIM:To directly quantify peroxynitrite(ONOO-)using a highly sensitive fluorescence resonance energy transfer probe RN-NA,investigate the association between ONOOand primary open angle glaucoma(POAG),and clarify whethe...AIM:To directly quantify peroxynitrite(ONOO-)using a highly sensitive fluorescence resonance energy transfer probe RN-NA,investigate the association between ONOOand primary open angle glaucoma(POAG),and clarify whether RN-NA could be used as a potential tool for POAG diagnosis.METHODS:Plasma and aqueous humor(AH)samples were collected from POAG patients(n=100,age:59.70±6.87y)and age-related cataract(ARC)patients(n=100,age:61.15±4.60y)admitted to our hospital.Next,RN-NA was used to detect ONOO-in plasma and AH samples,and the relationship between ONOO-level and POAG was analyzed using binary logistic regression.Besides,Pearson correlation analysis was applied to characterize the correlation of the levels of ONOO-with the patients’age,intraocular pressure(IOP),and mean deviation of visual field testing.The ONOO-scavenger MnTMPyP was employed to treat the 3-morpholinosyndnomine(SIN-1)-induced ocular hypertension in mice(n=7,6-8wk).Finally,the IOP and ONOO-in both eyes were measured 30min after the last drug treatment.RESULTS:ONOO-levels of AH and plasma were significantly higher in the POAG group than in the ARC group(P<0.01).Additionally,ONOO-levels were closely correlated with POAG in a binary logistic regression analysis[odds ratio(OR)=1.008,95%confidence interval(CI):1.002-1.013,P<0.01 for AH;OR=1.004,95%CI:1.002-1.006,P<0.001 for plasma].Pearson correlation analysis showed that ONOO-levels in AH or plasma were positively associated with visual field defects(R=0.51,P<0.01 for AH;R=0.45,P<0.001 for plasma),and ONOO-levels in plasma and AH were correlated in the POAG group(R=0.69,P<0.001).However,administering MnTMPyP to mouse eyes reversed the elevated IOP caused by SIN-1(P<0.05).CONCLUSION:ONOO-levels in AH and plasma,detected by RN-NA,are significantly related to POAG and positively correlated with visual field defects in POAG patients.Hence,ONOO-is a potential biomarker of POAG,especially advanced POAG.Besides,anti-nitration compounds may be novel ocular hypotensive agents based on the animal study.展开更多
The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive ...The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive nitrogen species depends on their concentration and location of formation.Nitric oxide(NO)has anti-inflammatory and anticoagulant properties and a vasodilation effect,but NO can be deactivated by reacting with O_(2)^(-).This reaction between NO and O2-produces the potent oxidant ONOO−.Therefore,ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.展开更多
In vitro antioxidant activities of resveratrol and piceid against peroxynitrite（ONOO-） were examined by the inhibition of 3-nitrotyrosine formation.Trolox was used as a positive control.Resveratrol and piceid exhibi...In vitro antioxidant activities of resveratrol and piceid against peroxynitrite（ONOO-） were examined by the inhibition of 3-nitrotyrosine formation.Trolox was used as a positive control.Resveratrol and piceid exhibited high ONOO--scavenging activities in a concentration dependent manner.The antioxidant activities（the concentration of test compound required to yield a 50% inhibition of tyrosine nitration,IC 50） of resveratrol and piceid against ONOO-were（48.34±0.97） and（74.69±1.49） μmol/L,respectively.Compared with that of trolox[（105.40±1.16） μmol/L],their scavenging activities were 2.2-and 1.5-fold higher for resveratrol and piceid.Formation of nitroresveratrol as shown by UV-Vis spectroscopy and liquid chromatography-tandom mass spectrometry（LC-MS/MS） analysis indicates that resveratrol could directly scavenge ONOO-via nitration reaction.Our results demonstrate that foods and medicinal herbs with resveratrol and piceid as stronger ONOO-scavengers are valuable ingredients and have healthy application in preventing humans from peroxynitrite-mediated oxidative damage by scavenging peroxynitrite efficiently.展开更多
AIM: Peroxynitrite (ONOO-) is a powerful oxidant shown to damage membranes. In the present study, the effect of taurine on changes of liver plasma membrane Na+, K+-ATPase induced by ONOO- was investigated. METHODS: Li...AIM: Peroxynitrite (ONOO-) is a powerful oxidant shown to damage membranes. In the present study, the effect of taurine on changes of liver plasma membrane Na+, K+-ATPase induced by ONOO- was investigated. METHODS: Liver plasma membrane was exposed toONOO-with or without taurine. Na+, K+-ATPase activity and lipid peroxidation as thiobarbituric acid reactive substances (TBARS) levels were measured.RESULTS: Different concentrations of ONOO- (100, 200,500, and 1 000 μmol/L) were found to decrease liver plasma membrane Na+, K+-ATPase activity significantly. The depletion of enzyme activity was not concentration dependent. Effects of different concentrations of taurine on liver plasma membrane Na+, K+-ATPase activity were also measured. Taurine did not cause any increase in enzyme activity. When plasma membranes were treated with 200 μmol/L ONOO- with different concentrations of taurine, a restoring effect of taurine on enzyme activity was observed. TBARS levels were also measured and taurine was found to decrease the elevated values. CONCLUSION: Taurine is observed to act as an antioxidant of ONOO-to decrease lipid peroxidation and thus affect liver plasma membrane Na+, K+-ATPase by restoring its activity.展开更多
Objective: To characterize the types, contents, and peroxynitrite-scavenging activities of flavonoids in the leaf of Carica papaya(C. papaya).Methods: Chromatographic and spectroscopic techniques along with high perfo...Objective: To characterize the types, contents, and peroxynitrite-scavenging activities of flavonoids in the leaf of Carica papaya(C. papaya).Methods: Chromatographic and spectroscopic techniques along with high performance liquid chromatography quantitative analysis and peroxynitrite-scavenging assay were performed to isolate and quantify flavonoid compounds in the flavonoid-rich fraction(Bu OH fraction) derived from Me OH extract of C. papaya leaves and evaluate their peroxynitrite-scavenging activities.Results: Seven flavonoids were isolated from the leaves of C. papaya, including quercetin 3-(2~G-rhamnosylrutinoside), kaempferol 3-(2~G-rhamnosylrutinoside), quercetin 3-rutinoside, myricetin 3-rhamnoside, kaempferol 3-rutinoside, quercetin, and kaempferol. All of the substances exhibited potent activities on peroxynitrite scavenging(IC50 4.15 mmol/L), which were stronger than the positive control, L-penicillamine(6.90 mmol/L). The content of kaempferol 3-(2~G-rhamnosylrutinoside) was significantly higher than other identified compounds(123.18 mg/g Bu OH fraction and 7.23 mg/g Me OH extract).Conclusions: The results of the present study demonstrate the potent antioxidant flavonoids of C. papaya leaf, with kaempferol 3-(2~G-rhamnosylrutinoside) as the major one.展开更多
Phototherapies including photodynamic therapy(PDT)and photothermal therapy(PTT)are the most promising and non-invasive cancer treatments.However,the efficacy of mono-therapy of PDT or PTT is often limited by the photo...Phototherapies including photodynamic therapy(PDT)and photothermal therapy(PTT)are the most promising and non-invasive cancer treatments.However,the efficacy of mono-therapy of PDT or PTT is often limited by the phototherapeutic defects such as low light penetration depth of photosensitizers and insufficiency of photothermal agents.Peroxynitrite(ONOO−)has been proved to be an efficient oxidizing and nitrating agent that involves in various physiological and pathological processes.Therefore,ONOO−produced in tumor site could be an effective treatment in cancer therapy.Herein,a novel cyanine dye-based(Cy7)polymer nanoplatform is developed for enhanced phototherapy by in situ producing ONOO−.The Cy7 units in the nanoparticles can not only be served as the photosensitizer to produce reactive oxygen species(ROS)including singlet oxygen and superoxide anion for PDT,but also be used as a heat source for PTT and the release of NO gas from N-nitrosated napthalimide(NORM)at the same time.Since NO can react quickly with superoxide anion to generate ONOO−,the enhanced phototherapy could be achieved by in situ ONOO−produced by PCy7-NO upon exposure to the near infrared(NIR)light.Therefore,the NIR-triggered Cy7-based nanoplatform for ONOO−-enhanced phototherapy may provide a new perspective in cancer therapy.展开更多
Peroxynitrite(ONOO^(-))contributes to oxidative stress and neurodegeneration in Parkinson's disease(PD).Developing a peroxynitrite probe would enable in situ visualization of the overwhelming ONOO^(-)flux and unde...Peroxynitrite(ONOO^(-))contributes to oxidative stress and neurodegeneration in Parkinson's disease(PD).Developing a peroxynitrite probe would enable in situ visualization of the overwhelming ONOO^(-)flux and understanding of the ONOO^(-)stress-induced neuropathology of PD.Herein,a novelα-ketoamide-based fluorogenic probe(DFlu)was designed for ONOO^(-)monitoring in multiple PD models.The results demonstrated that DFlu exhibits a fluorescence turn-on response to ONOO^(-)with high specificity and sensitivity.The efficacy of DFlu for intracellular ONOO^(-)imaging was demonstrated systematically.The results showed that DFlu can successfully visualize endogenous and exogenous ONOO^(-)in cells derived from chemical and biochemical routes.More importantly,the two-photon excitation ability of DFlu has been well demonstrated by monitoring exogenous/endogenous ONOO^(-)production and scavenging in live zebraflsh PD models.This work provides a reliable and promisingα-ketoamide-based optical tool for identifying variations of ONOO^(-)in PD models.展开更多
Py^(+)razinamide (PZA), isoniazid (INH) and rifampicin (RFP) are all commonly used anti-tuberculosis drugs in clinical practice, and long-term medication may cause severe liver damage and toxicity. The level of peroxy...Py^(+)razinamide (PZA), isoniazid (INH) and rifampicin (RFP) are all commonly used anti-tuberculosis drugs in clinical practice, and long-term medication may cause severe liver damage and toxicity. The level of peroxynitrite (ONOO^(-)) generated in liver has long been regarded as a biomarker for the prediction and measurement of drug-induced liver injury (DILI). In this article, we constructed a BODIPY-based fluorescent probe (BDP-Py^(+)) that enabled quickly and sensitively detect and image ONOO^(-) in vivo. Utilizing this probe, we demonstrated the change of ONOO^(-) content in cells and mice model of DILI induced by acetaminophen (APAP), and for the first time revealed the mechanism of liver injury induced by antituberculosis drug PZA. Moreover, BDP-Py^(+) could be applied to screen out and evaluate the hepatotoxicity of different anti-tuberculosis drugs. Comparing with the existing serum enzymes detection and H&E staining, the probe could achieve early diagnosis of DILI before solid lesions in liver via monitoring the up-regulation of ONOO^(-) levels. Collectively, this work will promote the understanding of the pathogenesis of anti-tuberculosis drug induced liver injury (ATB-DILI), and provide a powerful tool for the early diagnosis and treatment of DILI.展开更多
Peroxynitrite （ONOO-） is a powerful oxidant and nitrosative agent and has in vivo existence. The half life of ONOO- at physiological pH is less than 1 s. It can react with nucleic acids, proteins, lipoproteins, sacc...Peroxynitrite （ONOO-） is a powerful oxidant and nitrosative agent and has in vivo existence. The half life of ONOO- at physiological pH is less than 1 s. It can react with nucleic acids, proteins, lipoproteins, saccharides, cardi- olipin, etc., and can modify their native structures. Action of ONOO-, synthesized in the authors＇ laboratory by a rapid quenched flow process, on structural changes of commercially available RNA was studied by ultraviolet （UV）, fluo- rescence, and agarose gel electrophoresis. Compared to native RNA, the ONOO--modified RNA showed hyper- chromicity at 260 nm. Furthermore, the ethidium bromide （EtBr） assisted emission intensities of ONOO--modified RNA samples were found to be lower than the emission intensity of native RNA-EtBr complex. Agarose gel electrophoresis of ONOO--modifled RNA showed a gradual decrease in band intensities compared to native RNA, an observation clearly due to the poor intercalation of EtBr with ONOO--modified RNA. Native and ONOO--modified RNA samples were used as an antigen to detect autoantibodies in sera of patients with clinically defined breast cancer. Both direct binding and inhibition enzyme-linked immunosorbent assay （ELISA） confirmed the prevalence of native and 0.8 mmol/L ONOO--modified RNA specific autoantibodies in breast cancer patients. Moreover, the progressive retarda- tion in the mobility of immune complexes formed with native or 0.8 mmol/L ONOO--modified RNA and affinity purified immunoglobulin G （IgG） from sera of breast cancer patients supports the findings of the direct binding and inhibition ELISAs. The peroxynitrite treatment to RNA at a higher concentration appears to have damaged or destroyed the typical epitopes on RNA and thus there was a sharp decrease in autoantibodies binding to 1.4 mmol/L ONOO--modified RNA. It may be interpreted that cellular nitrosative stress can modify and confer immunogenicity on RNA molecules. Higher concentrations of nitrogen reactive species can be detrimental to RNA. However, the emergence of native as well as 0.8 mmol/L ONOO--modified RNA as a novel antigen/substrate for autoantibodies in breast cancer patients indicates that, in future, these molecules might find a place on the panel of antigens for early diagnosis of breast cancer.展开更多
Objective: To prove probable relations between serum E3 SUMO-protein ligase NSE2(NSMCE2) concentration, peroxynitrite related to oxidative stress in nephrolithiasis patients.Methods: A total of 60 patients with nephro...Objective: To prove probable relations between serum E3 SUMO-protein ligase NSE2(NSMCE2) concentration, peroxynitrite related to oxidative stress in nephrolithiasis patients.Methods: A total of 60 patients with nephrolithiasis and 50 healthy volunteers were involved in this study. Colorimetric method was used to detect blood urea, creatinine, uric acid, protein, albumin, total antioxidant status, total oxidant status, peroxynitrite, nitric oxide and oxidative stress index. Glutathione, NSMCE2 and superoxide dismutase were measured by ELISA.Results: A significant increase in level of peroxynitrite, total oxidant status, NSMCE2 and oxidative stress index in patients was observed, while total antioxidant status and glutathione were significantly decreased.Conclusions: The study concluded that serum NSMCE2 significantly correlated with peroxynitrite and oxidative stress in patients with nephrolithiasis.展开更多
Fluorescent dyes with fluorescence emission above 700 nm are favorable for bio-imaging due to the higher tissue transparency and lower background fluorescence. In this study, we present a mesobenzimidazole-pyronin pla...Fluorescent dyes with fluorescence emission above 700 nm are favorable for bio-imaging due to the higher tissue transparency and lower background fluorescence. In this study, we present a mesobenzimidazole-pyronin platform(Si BMs) with fluorescence emission maxima above 700 nm, which possess good cell permeability, photostability, and lysosomal localization. The great photophysical properties of the Si BMs encouraged us to further exploit their application toward bio-imaging. We synthesized the reduced ‘dihydro’ derivative HSi BM3 for sensing ONOO^(-), with high selectivity and sensitivity and a fast fluorescence “off-on” response(within 2 s). Then, we confirmed the potential of HSi BM3 for visualizing exogenous and endogenous ONOO-in cells and mice. More importantly, HSi BM3 was successfully employed for visualizing acute-liver-injury-induced peroxynitrite.展开更多
The conversion of peroxynitrite （ONOO-） to nitrate （NO3-） mediated by peroxynitrous acid （ONOOH） has been investigated at the CCSD/6-311G（d）//B3LYP/6-31 1＋G（d,p） level. Two kinds of pathways for the title r...The conversion of peroxynitrite （ONOO-） to nitrate （NO3-） mediated by peroxynitrous acid （ONOOH） has been investigated at the CCSD/6-311G（d）//B3LYP/6-31 1＋G（d,p） level. Two kinds of pathways for the title reaction were found. The results show that the energy barrier of isomerization through pathway 1 is around 25 kcal/mol in the gas phase. This value is significantly lower than that of isomerization without any catalysts. Thus, it indicates that ONOOH definitely makes the conversion from ONOO- to NO3- feasible. Although pathway 2 does not decrease the energy barrier of this isomerization, peroxynitric acid （O2NOOH） was obtained; moreover, this is a new pathway for this formation. In view of the results that peroxynitrate anion can decompose into nitrite and dioxygen, we conclude that our results are consistent with the experimental observation that nitrate, nitrite, and dioxygen are the main final products of the decay of peroxynitrite around pH 7.展开更多
The peroxynitrite/porphyrin biomimetic system was established to investigate the effects of peroxynitrite on benzo[a]pyrene （B[a]P） metabolism. Three model systems consisting of different iron porphyrins were compar...The peroxynitrite/porphyrin biomimetic system was established to investigate the effects of peroxynitrite on benzo[a]pyrene （B[a]P） metabolism. Three model systems consisting of different iron porphyrins were compared, and the results showed that the peroxynitdte/T（p-Cl）PPFeCl system was the highest catalytic efficiency in the metabolism of B [a]P. We analyzed the B [a]P metabolites produced from this system by RP-HPLC method and firstly identified the formation of nitrobenzo[a]pyrenes which are the special metabolites of B [a]P induced by peroxynitrite.展开更多
Perivascular adipose tissue (PVAT) surrounds the exterior of blood vessels and releases numerous substances such as adiponectin which positively modulate blood vessel tone. In some cardiovascular diseases such as diab...Perivascular adipose tissue (PVAT) surrounds the exterior of blood vessels and releases numerous substances such as adiponectin which positively modulate blood vessel tone. In some cardiovascular diseases such as diabetes and high blood pressure, the function of PVAT changes and we speculate that oxidant stress may play a role in this change. PVAT has the ability to generate both superoxide and nitric oxide and these can combine rapidly under physiological conditions to form peroxynitrite (ONOO-). In disease states, the production of ONOO- may be increased and so its effect on the function of PVAT is of great interest. Consequently, we studied the effects of acute addition of the oxidant species ONOO- on vascular tone and production of adiponectin by mouse thoracic aortic PVAT. Murine PVAT was immunostained for nitrotyrosine, indicating that ONOO- is formed in the PVAT. Exogenous ONOO- significantly increased the anticontractile effect of PVAT via increased adiponectin content but had no effect on eNOS expression or phosphorylation. These results suggest that generation of ONOO- within PVAT may be an important regulatory mechanism which influences the activity of PVAT. The effect of chronic exposure to raised levels of ONOO- on PVAT function remains to be determined.展开更多
The cytoprotective messenger nitric oxide (NO) and cytotoxic peroxynitrite (ONOO-) are the main components of oxidative stress and can be generated by endothelial cells. A tandem of electrochemical nanosensors (diamet...The cytoprotective messenger nitric oxide (NO) and cytotoxic peroxynitrite (ONOO-) are the main components of oxidative stress and can be generated by endothelial cells. A tandem of electrochemical nanosensors (diameter 200-300 nm) were used to measure, in situ, the balance between NO and ONOO-produced by human umbilical vein endothelial cells (HUVEC’s). The amperometric nanosensors were placed 5 ± 2 μm from the surface of the endothelial cells and the concentration of NO and ONOO- was measured at 630 mV and -300 mV (vs Ag/AgCl) respectively. Normal, functional, endothelial cells produced maximal 450 ± 25 nmol.L-1 of NO and 180 ± 15 nmol.L-1 of ONOO- in about 3 s, after stimulation with calcium ionophore. The in situ measurements of NO and ONOO- were validated using nitric oxide synthase inhibitor L-NMMA, ONOO- scavenger Mn(III) porphyrin, and superoxide dismutase (PEG-SOD). The ratio of NO concentration to ONOO- concentration ([NO]/[ONOO-]) was introduced for quantification of both, the redox balance and the level of the nitroxidative stress in the endothelium. [NO]/[ONOO-] was 2.7 ± 0.1 in a functional endothelium. The model of the dysfunctional endothelium was made by the treatment of HUVEC’s with angiotensin II for 20 min. Dysfunctional HUVEC’s produced only 115 ± 15 nmol.L-1 of NO, but generated a significantly higher concentration of ONOO- of 490 ± 30 nmol.L-1. The [NO]/[ONOO-] ratio decreased to 0.23 ± 0.14 in the dysfunctional endothelium. Electrochemical nanosensors can be effectively used for in situ monitoring of changing levels of nitroxidative/ oxidative stress, and may be useful in early medical diagnosis of the cardiovascular system.展开更多
Drug-induced hepatotoxicity is a long-standing concern of modern medicine.The production of peroxynitrite(ONOO^(-))is proposed as an early sign of the progression of drug-induced hepatotoxicity.However,conventional bl...Drug-induced hepatotoxicity is a long-standing concern of modern medicine.The production of peroxynitrite(ONOO^(-))is proposed as an early sign of the progression of drug-induced hepatotoxicity.However,conventional blood tests fail to offer a real-time unambiguous visualization of such hepatotoxicity in vivo.ONOO^(-)probes that are currently reported are mainly located in the visible or the first near-infrared(NIR-I)window,which have limited in vivo biosensing application due to the autofluorescence and photon scattering.Here,we report an ONOO^(-)responsive cyanine dye,IR-1061 J-aggregate(J_(IR-1061)),which exhibits a red shift over 500 nm,with an absorption peak at 1580 nm in the NIR-IIb region.By conjugating J_(IR-1061) with rare earth nanoparticles(RENPs)that have NIR-IIb emission at 1550 nm,a dual-mode imaging probe RENPs-J_(IR-1061) is developed.RENPs-J_(IR-1061) shows a fast and sensitive response to ONOO^(-),with activatable NIR-IIb fluorescence and a change in the photoacoustic signals,which is successfully applied for real-time monitoring of hepatotoxicity in vivo.展开更多
Screening anti-Parkinson’s disease(PD)drugs at in vivo brain level is imperative for managing PD yet currently remains unaccomplished.Peroxynitrite(ONOO^(−))has been implicated in PD progression.Thus,developing in vi...Screening anti-Parkinson’s disease(PD)drugs at in vivo brain level is imperative for managing PD yet currently remains unaccomplished.Peroxynitrite(ONOO^(−))has been implicated in PD progression.Thus,developing in vivo ONOO^(−)-based imaging tools for anti-PD drug screening holds promise for early prognosis and treatment of PD.Consequently,a near-infrared(NIR)fluorescence probe,BOB-Cl-PN,with high specificity,good sensitivity(LOD=24 nM),and rapid response(<60 s),was devised to investigate ONOO−and PD relationships.Utilizing NIR fluorescence imaging,BOB-Cl-PN effectively monitored ONOO^(−)fluctuations in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine(MPTP)-induced PD cell models,establishing a cellular high throughput screening(cHTS)system for anti-PD drugs.In live animal imaging,BOB-Cl-PN’s ability to penetrate the blood−brain barrier enabled ONOOC^(-)flux imaging of PD mouse brains.Moreover,BOB-Cl-PN served as an imaging contrast for in vivo screening of potential traditional Chinese medicines for PD therapy,identifying fisetin as having the best therapeutic index among 10 Chinese medicines.This study constructs a sensitive,efficient imaging contrast for monitoring ONOO^(−)dynamics in PD brains and provides a valuable platform for cellular and in vivo screening of anti-PD drugs.展开更多
基金supported by the National Natural Science Foundation of China(Nos.22264013,21961010)Hainan Province Science and Technology Special Fund(Nos.ZDYF2021SHFZ219,ZDYF2022SHFZ037)+4 种基金Special Funds of S&T Cooperation and Exchange Projects of Shanxi Province(No.202204041101040)Natural Science Research Talent Project of Hainan Medical University(No.JBGS202101)Postgraduate Innovative Research Project of Hainan(No.Qhys2021-384)Hainan Province Clinical Medical Center(2021)Project for Functional Materials and Molecular Imaging Science Innovation Group of Hainan Medical University.
文摘Acute lung injury(ALI)is a serious clinical condition with a high mortality rate.Oxidative stress and inflammatory responses play pivotal roles in the pathogenesis of ALI.ONOO^(−)is a key mediator that exacerbates oxidative damage and microvascular permeability in ALI.Accurate detection of ONOO^(−)would facilitate early diagnosis and intervention in ALI.Near-infrared fluorescence(NIRF)probes offer new solutions due to their sensitivity,depth of tissue penetration,and imaging capabilities.However,the developed ONOO^(−)fluorescent probes face problems such as interference from other reactive oxygen species and easy intracellular diffusion.To address these issues,we introduced an innovative self-immobilizing NIRF probe,DCI2F-OTf,which was capable of monitoring ONOO^(−)in vitro and in vivo.Importantly,leveraging the high reactivity of the methylene quinone(QM)intermediate,DCI2F-OTf was able to covalently label proteins in the presence of ONOO^(−),enabling in situ imaging.In mice models of ALI,DCI2F-OTf enabled real-time imaging of ONOO^(−)levels and found that ONOO^(−)was tightly correlated with the progression of ALI.Our findings demonstrated that DCI2F-OTf was a promising chemical tool for the detection of ONOO^(−),which could help to gain insight into the pathogenesis of ALI and monitor treatment efficacy.
基金supported by the National Natural Science Foundation of China(Nos.22177025,21807021,22325703,22177026)Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province(No.B2021201038)+2 种基金the Interdisciplinary Research Program of Natural Science of Hebei University(No.DXK202113)the Central Government Guided Local Science,Technology Development Fund(Hebei Province,No.216Z2603G)National High-End Foreign Expert Recruitment Plan(No.G2022003007L)。
文摘Epilepsy,as a chronic neurological disease of the brain,is closely related to oxidative stress,and the peroxynitrite(ONOO-)significantly rise up in this event.Therefore,ONOO-is considered as a potential biomarker for early prediction of epilepsy.However,some potential diagnostic reagents for epilepsy are hindered by the blood-brain barrier(BBB).Meanwhile,“drug repurposing”is attracting a growing interest.Edaravone(EDA),as a first-line drug in the clinical treatment of cerebral ischemia,plays antioxidant roles in scavenging free radicals,promising potential antiepileptic activity.Thus,it is imperative to develop fluorescent probes for monitoring ONOO-fluctuations in the epileptic brain.Hence,we proposed a novel fluorescent probe with the thiocarbonate as the promising recognition unit for ONOO-and dicyanoisophorone derivative as the fluorophore.Moreover,by the“three-in-one”strategy,the introduction of trifluoromethyl into DCI-ONOO-3 can extend the emission wavelength of the fluorophore,shorten the response and increase lipophilicity.Consequently,DCI-ONOO-3 was used for monitoring ONOO-fluxes in brain of epileptic mice and evaluating the antiepileptic efficacy of EDA.It opens up a new way for the design of BBB permeable fluorescent probes,and provides a convincing new method for the diagnosis and treatment of epilepsy.
基金Supported by the National Natural Science Foundation of China(No.81870692,No.82070959,No.82271082)the Shanghai Committee of Science and Technology,China(No.20S31905800)Clinical Research Plan of SHDC(No.SHDC2020CR6029).
文摘AIM:To directly quantify peroxynitrite(ONOO-)using a highly sensitive fluorescence resonance energy transfer probe RN-NA,investigate the association between ONOOand primary open angle glaucoma(POAG),and clarify whether RN-NA could be used as a potential tool for POAG diagnosis.METHODS:Plasma and aqueous humor(AH)samples were collected from POAG patients(n=100,age:59.70±6.87y)and age-related cataract(ARC)patients(n=100,age:61.15±4.60y)admitted to our hospital.Next,RN-NA was used to detect ONOO-in plasma and AH samples,and the relationship between ONOO-level and POAG was analyzed using binary logistic regression.Besides,Pearson correlation analysis was applied to characterize the correlation of the levels of ONOO-with the patients’age,intraocular pressure(IOP),and mean deviation of visual field testing.The ONOO-scavenger MnTMPyP was employed to treat the 3-morpholinosyndnomine(SIN-1)-induced ocular hypertension in mice(n=7,6-8wk).Finally,the IOP and ONOO-in both eyes were measured 30min after the last drug treatment.RESULTS:ONOO-levels of AH and plasma were significantly higher in the POAG group than in the ARC group(P<0.01).Additionally,ONOO-levels were closely correlated with POAG in a binary logistic regression analysis[odds ratio(OR)=1.008,95%confidence interval(CI):1.002-1.013,P<0.01 for AH;OR=1.004,95%CI:1.002-1.006,P<0.001 for plasma].Pearson correlation analysis showed that ONOO-levels in AH or plasma were positively associated with visual field defects(R=0.51,P<0.01 for AH;R=0.45,P<0.001 for plasma),and ONOO-levels in plasma and AH were correlated in the POAG group(R=0.69,P<0.001).However,administering MnTMPyP to mouse eyes reversed the elevated IOP caused by SIN-1(P<0.05).CONCLUSION:ONOO-levels in AH and plasma,detected by RN-NA,are significantly related to POAG and positively correlated with visual field defects in POAG patients.Hence,ONOO-is a potential biomarker of POAG,especially advanced POAG.Besides,anti-nitration compounds may be novel ocular hypotensive agents based on the animal study.
文摘The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive nitrogen species depends on their concentration and location of formation.Nitric oxide(NO)has anti-inflammatory and anticoagulant properties and a vasodilation effect,but NO can be deactivated by reacting with O_(2)^(-).This reaction between NO and O2-produces the potent oxidant ONOO−.Therefore,ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.
基金Supported by the National Basic Research Program of China(Nos.2012CB721105,2011CBA00802,2007CB714301)the National Natural Science Foundation of China(No.30873400)the Specialized Research Fund for the Doctoral Program of Higher Education of China(No.20090032110015)
文摘In vitro antioxidant activities of resveratrol and piceid against peroxynitrite（ONOO-） were examined by the inhibition of 3-nitrotyrosine formation.Trolox was used as a positive control.Resveratrol and piceid exhibited high ONOO--scavenging activities in a concentration dependent manner.The antioxidant activities（the concentration of test compound required to yield a 50% inhibition of tyrosine nitration,IC 50） of resveratrol and piceid against ONOO-were（48.34±0.97） and（74.69±1.49） μmol/L,respectively.Compared with that of trolox[（105.40±1.16） μmol/L],their scavenging activities were 2.2-and 1.5-fold higher for resveratrol and piceid.Formation of nitroresveratrol as shown by UV-Vis spectroscopy and liquid chromatography-tandom mass spectrometry（LC-MS/MS） analysis indicates that resveratrol could directly scavenge ONOO-via nitration reaction.Our results demonstrate that foods and medicinal herbs with resveratrol and piceid as stronger ONOO-scavengers are valuable ingredients and have healthy application in preventing humans from peroxynitrite-mediated oxidative damage by scavenging peroxynitrite efficiently.
基金Supported by the Istanbul University Research Foundation,No.BYP-247/20082003
文摘AIM: Peroxynitrite (ONOO-) is a powerful oxidant shown to damage membranes. In the present study, the effect of taurine on changes of liver plasma membrane Na+, K+-ATPase induced by ONOO- was investigated. METHODS: Liver plasma membrane was exposed toONOO-with or without taurine. Na+, K+-ATPase activity and lipid peroxidation as thiobarbituric acid reactive substances (TBARS) levels were measured.RESULTS: Different concentrations of ONOO- (100, 200,500, and 1 000 μmol/L) were found to decrease liver plasma membrane Na+, K+-ATPase activity significantly. The depletion of enzyme activity was not concentration dependent. Effects of different concentrations of taurine on liver plasma membrane Na+, K+-ATPase activity were also measured. Taurine did not cause any increase in enzyme activity. When plasma membranes were treated with 200 μmol/L ONOO- with different concentrations of taurine, a restoring effect of taurine on enzyme activity was observed. TBARS levels were also measured and taurine was found to decrease the elevated values. CONCLUSION: Taurine is observed to act as an antioxidant of ONOO-to decrease lipid peroxidation and thus affect liver plasma membrane Na+, K+-ATPase by restoring its activity.
基金Supported by the National Competitive Research Grant funded by the Ministry of Research,Technology and Higher Education,Republic of Indonesia(Grant No.056/UN8.2/PL/2015)
文摘Objective: To characterize the types, contents, and peroxynitrite-scavenging activities of flavonoids in the leaf of Carica papaya(C. papaya).Methods: Chromatographic and spectroscopic techniques along with high performance liquid chromatography quantitative analysis and peroxynitrite-scavenging assay were performed to isolate and quantify flavonoid compounds in the flavonoid-rich fraction(Bu OH fraction) derived from Me OH extract of C. papaya leaves and evaluate their peroxynitrite-scavenging activities.Results: Seven flavonoids were isolated from the leaves of C. papaya, including quercetin 3-(2~G-rhamnosylrutinoside), kaempferol 3-(2~G-rhamnosylrutinoside), quercetin 3-rutinoside, myricetin 3-rhamnoside, kaempferol 3-rutinoside, quercetin, and kaempferol. All of the substances exhibited potent activities on peroxynitrite scavenging(IC50 4.15 mmol/L), which were stronger than the positive control, L-penicillamine(6.90 mmol/L). The content of kaempferol 3-(2~G-rhamnosylrutinoside) was significantly higher than other identified compounds(123.18 mg/g Bu OH fraction and 7.23 mg/g Me OH extract).Conclusions: The results of the present study demonstrate the potent antioxidant flavonoids of C. papaya leaf, with kaempferol 3-(2~G-rhamnosylrutinoside) as the major one.
基金by the National Natural Science Foundation of China(No.21875063)the Science and Technology Commission of Shanghai Municipality for the Shanghai International Cooperation Program(No.19440710600).
文摘Phototherapies including photodynamic therapy(PDT)and photothermal therapy(PTT)are the most promising and non-invasive cancer treatments.However,the efficacy of mono-therapy of PDT or PTT is often limited by the phototherapeutic defects such as low light penetration depth of photosensitizers and insufficiency of photothermal agents.Peroxynitrite(ONOO−)has been proved to be an efficient oxidizing and nitrating agent that involves in various physiological and pathological processes.Therefore,ONOO−produced in tumor site could be an effective treatment in cancer therapy.Herein,a novel cyanine dye-based(Cy7)polymer nanoplatform is developed for enhanced phototherapy by in situ producing ONOO−.The Cy7 units in the nanoparticles can not only be served as the photosensitizer to produce reactive oxygen species(ROS)including singlet oxygen and superoxide anion for PDT,but also be used as a heat source for PTT and the release of NO gas from N-nitrosated napthalimide(NORM)at the same time.Since NO can react quickly with superoxide anion to generate ONOO−,the enhanced phototherapy could be achieved by in situ ONOO−produced by PCy7-NO upon exposure to the near infrared(NIR)light.Therefore,the NIR-triggered Cy7-based nanoplatform for ONOO−-enhanced phototherapy may provide a new perspective in cancer therapy.
基金supported by the National Natural Science Foundation of China(22077101)the Open Project Program of Wuhan National Laboratory for Optoelectronics(No.2020WNLOKF023)+4 种基金Natural Science Foundation of Shaanxi Province(2022JM-130)the Joint Research Funds of Department of Science&Technology of Shaanxi Province and Northwestern Polytechnical University(2020GXLH-Z-008,2020GXLH-Z-021,2020GXLH-Z-023)the China Postdoctoral Science Foundation(2022M711595,2022M722595)Postdoctoral Research Funding Schemes of Jiangsu Province(2021K036A)The Natural Science Foundation of Ningbo(202003N4049,202003N4065).
文摘Peroxynitrite(ONOO^(-))contributes to oxidative stress and neurodegeneration in Parkinson's disease(PD).Developing a peroxynitrite probe would enable in situ visualization of the overwhelming ONOO^(-)flux and understanding of the ONOO^(-)stress-induced neuropathology of PD.Herein,a novelα-ketoamide-based fluorogenic probe(DFlu)was designed for ONOO^(-)monitoring in multiple PD models.The results demonstrated that DFlu exhibits a fluorescence turn-on response to ONOO^(-)with high specificity and sensitivity.The efficacy of DFlu for intracellular ONOO^(-)imaging was demonstrated systematically.The results showed that DFlu can successfully visualize endogenous and exogenous ONOO^(-)in cells derived from chemical and biochemical routes.More importantly,the two-photon excitation ability of DFlu has been well demonstrated by monitoring exogenous/endogenous ONOO^(-)production and scavenging in live zebraflsh PD models.This work provides a reliable and promisingα-ketoamide-based optical tool for identifying variations of ONOO^(-)in PD models.
基金financially supported by the National Natural Science Foundation of China (Nos. 82030107 and 21702046)the China Postdoctoral Science Foundation (No. 2018M632757)+1 种基金the Key Scientific and Technological Project of Henan Province (Nos.212102311064 and 212102310870)the Innovation Scientists and Technicians Troop Construction Projects of Henan Province(No. 20IRTSTHN020)。
文摘Py^(+)razinamide (PZA), isoniazid (INH) and rifampicin (RFP) are all commonly used anti-tuberculosis drugs in clinical practice, and long-term medication may cause severe liver damage and toxicity. The level of peroxynitrite (ONOO^(-)) generated in liver has long been regarded as a biomarker for the prediction and measurement of drug-induced liver injury (DILI). In this article, we constructed a BODIPY-based fluorescent probe (BDP-Py^(+)) that enabled quickly and sensitively detect and image ONOO^(-) in vivo. Utilizing this probe, we demonstrated the change of ONOO^(-) content in cells and mice model of DILI induced by acetaminophen (APAP), and for the first time revealed the mechanism of liver injury induced by antituberculosis drug PZA. Moreover, BDP-Py^(+) could be applied to screen out and evaluate the hepatotoxicity of different anti-tuberculosis drugs. Comparing with the existing serum enzymes detection and H&E staining, the probe could achieve early diagnosis of DILI before solid lesions in liver via monitoring the up-regulation of ONOO^(-) levels. Collectively, this work will promote the understanding of the pathogenesis of anti-tuberculosis drug induced liver injury (ATB-DILI), and provide a powerful tool for the early diagnosis and treatment of DILI.
文摘Peroxynitrite （ONOO-） is a powerful oxidant and nitrosative agent and has in vivo existence. The half life of ONOO- at physiological pH is less than 1 s. It can react with nucleic acids, proteins, lipoproteins, saccharides, cardi- olipin, etc., and can modify their native structures. Action of ONOO-, synthesized in the authors＇ laboratory by a rapid quenched flow process, on structural changes of commercially available RNA was studied by ultraviolet （UV）, fluo- rescence, and agarose gel electrophoresis. Compared to native RNA, the ONOO--modified RNA showed hyper- chromicity at 260 nm. Furthermore, the ethidium bromide （EtBr） assisted emission intensities of ONOO--modified RNA samples were found to be lower than the emission intensity of native RNA-EtBr complex. Agarose gel electrophoresis of ONOO--modifled RNA showed a gradual decrease in band intensities compared to native RNA, an observation clearly due to the poor intercalation of EtBr with ONOO--modified RNA. Native and ONOO--modified RNA samples were used as an antigen to detect autoantibodies in sera of patients with clinically defined breast cancer. Both direct binding and inhibition enzyme-linked immunosorbent assay （ELISA） confirmed the prevalence of native and 0.8 mmol/L ONOO--modified RNA specific autoantibodies in breast cancer patients. Moreover, the progressive retarda- tion in the mobility of immune complexes formed with native or 0.8 mmol/L ONOO--modified RNA and affinity purified immunoglobulin G （IgG） from sera of breast cancer patients supports the findings of the direct binding and inhibition ELISAs. The peroxynitrite treatment to RNA at a higher concentration appears to have damaged or destroyed the typical epitopes on RNA and thus there was a sharp decrease in autoantibodies binding to 1.4 mmol/L ONOO--modified RNA. It may be interpreted that cellular nitrosative stress can modify and confer immunogenicity on RNA molecules. Higher concentrations of nitrogen reactive species can be detrimental to RNA. However, the emergence of native as well as 0.8 mmol/L ONOO--modified RNA as a novel antigen/substrate for autoantibodies in breast cancer patients indicates that, in future, these molecules might find a place on the panel of antigens for early diagnosis of breast cancer.
基金Supported by International Islamic University of Malaysia under the research management center Grant Scheme Project No.ⅡUM/504/5/29/1
文摘Objective: To prove probable relations between serum E3 SUMO-protein ligase NSE2(NSMCE2) concentration, peroxynitrite related to oxidative stress in nephrolithiasis patients.Methods: A total of 60 patients with nephrolithiasis and 50 healthy volunteers were involved in this study. Colorimetric method was used to detect blood urea, creatinine, uric acid, protein, albumin, total antioxidant status, total oxidant status, peroxynitrite, nitric oxide and oxidative stress index. Glutathione, NSMCE2 and superoxide dismutase were measured by ELISA.Results: A significant increase in level of peroxynitrite, total oxidant status, NSMCE2 and oxidative stress index in patients was observed, while total antioxidant status and glutathione were significantly decreased.Conclusions: The study concluded that serum NSMCE2 significantly correlated with peroxynitrite and oxidative stress in patients with nephrolithiasis.
基金Scientific and Technological Innovation Program of Colleges and Universities in Shanxi Province (Nos.2021L529, 2021L530)。
文摘Fluorescent dyes with fluorescence emission above 700 nm are favorable for bio-imaging due to the higher tissue transparency and lower background fluorescence. In this study, we present a mesobenzimidazole-pyronin platform(Si BMs) with fluorescence emission maxima above 700 nm, which possess good cell permeability, photostability, and lysosomal localization. The great photophysical properties of the Si BMs encouraged us to further exploit their application toward bio-imaging. We synthesized the reduced ‘dihydro’ derivative HSi BM3 for sensing ONOO^(-), with high selectivity and sensitivity and a fast fluorescence “off-on” response(within 2 s). Then, we confirmed the potential of HSi BM3 for visualizing exogenous and endogenous ONOO-in cells and mice. More importantly, HSi BM3 was successfully employed for visualizing acute-liver-injury-induced peroxynitrite.
基金supported by the National Natural Science Foundation of China (No. 20672011)
文摘The conversion of peroxynitrite （ONOO-） to nitrate （NO3-） mediated by peroxynitrous acid （ONOOH） has been investigated at the CCSD/6-311G（d）//B3LYP/6-31 1＋G（d,p） level. Two kinds of pathways for the title reaction were found. The results show that the energy barrier of isomerization through pathway 1 is around 25 kcal/mol in the gas phase. This value is significantly lower than that of isomerization without any catalysts. Thus, it indicates that ONOOH definitely makes the conversion from ONOO- to NO3- feasible. Although pathway 2 does not decrease the energy barrier of this isomerization, peroxynitric acid （O2NOOH） was obtained; moreover, this is a new pathway for this formation. In view of the results that peroxynitrate anion can decompose into nitrite and dioxygen, we conclude that our results are consistent with the experimental observation that nitrate, nitrite, and dioxygen are the main final products of the decay of peroxynitrite around pH 7.
基金Project supported by the Beijing Natural Science Foundation (No. 2052004)the Beijing Nova Programme (No. 2003B05) the National Natural Science Foundation of China (No. 20605002).
文摘The peroxynitrite/porphyrin biomimetic system was established to investigate the effects of peroxynitrite on benzo[a]pyrene （B[a]P） metabolism. Three model systems consisting of different iron porphyrins were compared, and the results showed that the peroxynitdte/T（p-Cl）PPFeCl system was the highest catalytic efficiency in the metabolism of B [a]P. We analyzed the B [a]P metabolites produced from this system by RP-HPLC method and firstly identified the formation of nitrobenzo[a]pyrenes which are the special metabolites of B [a]P induced by peroxynitrite.
文摘Perivascular adipose tissue (PVAT) surrounds the exterior of blood vessels and releases numerous substances such as adiponectin which positively modulate blood vessel tone. In some cardiovascular diseases such as diabetes and high blood pressure, the function of PVAT changes and we speculate that oxidant stress may play a role in this change. PVAT has the ability to generate both superoxide and nitric oxide and these can combine rapidly under physiological conditions to form peroxynitrite (ONOO-). In disease states, the production of ONOO- may be increased and so its effect on the function of PVAT is of great interest. Consequently, we studied the effects of acute addition of the oxidant species ONOO- on vascular tone and production of adiponectin by mouse thoracic aortic PVAT. Murine PVAT was immunostained for nitrotyrosine, indicating that ONOO- is formed in the PVAT. Exogenous ONOO- significantly increased the anticontractile effect of PVAT via increased adiponectin content but had no effect on eNOS expression or phosphorylation. These results suggest that generation of ONOO- within PVAT may be an important regulatory mechanism which influences the activity of PVAT. The effect of chronic exposure to raised levels of ONOO- on PVAT function remains to be determined.
文摘The cytoprotective messenger nitric oxide (NO) and cytotoxic peroxynitrite (ONOO-) are the main components of oxidative stress and can be generated by endothelial cells. A tandem of electrochemical nanosensors (diameter 200-300 nm) were used to measure, in situ, the balance between NO and ONOO-produced by human umbilical vein endothelial cells (HUVEC’s). The amperometric nanosensors were placed 5 ± 2 μm from the surface of the endothelial cells and the concentration of NO and ONOO- was measured at 630 mV and -300 mV (vs Ag/AgCl) respectively. Normal, functional, endothelial cells produced maximal 450 ± 25 nmol.L-1 of NO and 180 ± 15 nmol.L-1 of ONOO- in about 3 s, after stimulation with calcium ionophore. The in situ measurements of NO and ONOO- were validated using nitric oxide synthase inhibitor L-NMMA, ONOO- scavenger Mn(III) porphyrin, and superoxide dismutase (PEG-SOD). The ratio of NO concentration to ONOO- concentration ([NO]/[ONOO-]) was introduced for quantification of both, the redox balance and the level of the nitroxidative stress in the endothelium. [NO]/[ONOO-] was 2.7 ± 0.1 in a functional endothelium. The model of the dysfunctional endothelium was made by the treatment of HUVEC’s with angiotensin II for 20 min. Dysfunctional HUVEC’s produced only 115 ± 15 nmol.L-1 of NO, but generated a significantly higher concentration of ONOO- of 490 ± 30 nmol.L-1. The [NO]/[ONOO-] ratio decreased to 0.23 ± 0.14 in the dysfunctional endothelium. Electrochemical nanosensors can be effectively used for in situ monitoring of changing levels of nitroxidative/ oxidative stress, and may be useful in early medical diagnosis of the cardiovascular system.
基金the National Natural Science Foundation of China,grant number 22374073.
文摘Drug-induced hepatotoxicity is a long-standing concern of modern medicine.The production of peroxynitrite(ONOO^(-))is proposed as an early sign of the progression of drug-induced hepatotoxicity.However,conventional blood tests fail to offer a real-time unambiguous visualization of such hepatotoxicity in vivo.ONOO^(-)probes that are currently reported are mainly located in the visible or the first near-infrared(NIR-I)window,which have limited in vivo biosensing application due to the autofluorescence and photon scattering.Here,we report an ONOO^(-)responsive cyanine dye,IR-1061 J-aggregate(J_(IR-1061)),which exhibits a red shift over 500 nm,with an absorption peak at 1580 nm in the NIR-IIb region.By conjugating J_(IR-1061) with rare earth nanoparticles(RENPs)that have NIR-IIb emission at 1550 nm,a dual-mode imaging probe RENPs-J_(IR-1061) is developed.RENPs-J_(IR-1061) shows a fast and sensitive response to ONOO^(-),with activatable NIR-IIb fluorescence and a change in the photoacoustic signals,which is successfully applied for real-time monitoring of hepatotoxicity in vivo.
基金supported by the National Natural Science Foundation of China(No.22174034).
文摘Screening anti-Parkinson’s disease(PD)drugs at in vivo brain level is imperative for managing PD yet currently remains unaccomplished.Peroxynitrite(ONOO^(−))has been implicated in PD progression.Thus,developing in vivo ONOO^(−)-based imaging tools for anti-PD drug screening holds promise for early prognosis and treatment of PD.Consequently,a near-infrared(NIR)fluorescence probe,BOB-Cl-PN,with high specificity,good sensitivity(LOD=24 nM),and rapid response(<60 s),was devised to investigate ONOO−and PD relationships.Utilizing NIR fluorescence imaging,BOB-Cl-PN effectively monitored ONOO^(−)fluctuations in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine(MPTP)-induced PD cell models,establishing a cellular high throughput screening(cHTS)system for anti-PD drugs.In live animal imaging,BOB-Cl-PN’s ability to penetrate the blood−brain barrier enabled ONOOC^(-)flux imaging of PD mouse brains.Moreover,BOB-Cl-PN served as an imaging contrast for in vivo screening of potential traditional Chinese medicines for PD therapy,identifying fisetin as having the best therapeutic index among 10 Chinese medicines.This study constructs a sensitive,efficient imaging contrast for monitoring ONOO^(−)dynamics in PD brains and provides a valuable platform for cellular and in vivo screening of anti-PD drugs.
