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1.
Theranostics ; 10(7): 3064-3082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194855

RESUMO

A successful matching of a PEG group size with the EPR effect for an off-to-on responsive NIR-fluorophore conjugate has been accomplished which allows two distinct in vivo tumor imaging periods, the first being the switch on during the initial tumor uptake via enhanced permeability into the ROI (as background is suppressed) and a second, later, due to enhanced retention within the tumor. Methods: Software simulation (https://mihaitodor.github.io/particle_simulation/index.html), synthetic chemistry, with in vitro and in vivo imaging have been synergistically employed to identify an optimal PEG conjugate of a bio-responsive NIR-AZA fluorophore for in vivo tumor imaging. Results: A bio-responsive NIR-AZA fluorophore conjugated to a 10 kDa PEG group has shown excellent in vivo imaging performance with sustained high tumor to background ratios and peak tumor emission within 24 h. Analysis of fluorescence profiles over 7 days has provided evidence for the EPR effect playing a positive role. Conclusion: Preclinical results show that exploiting the EPR effect by utilizing an optimized PEG substituent on a bio-responsive fluorophore may offer a means for intraoperative tumor margin delineation. The off-to-on responsive nature of the fluorophore makes tumor imaging achievable without waiting for clearance from normal tissue.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32134683

RESUMO

Effects of training and sex on V̇O2 dynamics during exercise in type 2 diabetes mellitus (T2DM) are not well established. We tested the hypotheses that exercise training improves the time constant of the primary phase of V̇O2 (taupV̇O2) and with greater effect in males than females. Forty-one subjects with T2DM were assigned to two training groups (Tmale, Tfemale) and two control groups (Cmale, Cfemale), assessed before and after a 12-week intervention period. Twelve weeks of aerobic/resistance training was performed three times per week, 60-90 minutes per session. Assessments included ventilatory threshold (VT), V̇O2peak, taupV̇O2 (80 %VT) and dynamic responses of cardiac output, mean arterial pressure and systemic vascular conductance (80 %VT). Training significantly decreased taupV̇O2 in males by a mean of 20 % (Tmale = 42.7±6.2 to 34.3±7.2 s) and females by a mean of 16 % (Tfemale = 42.2±9.3 to 35.4±8.6 s); whereas taupV̇O2 was not affected in controls (Cmale = 41.6±9.8 to 42.9±7.6 s; Cfemale = 40.4±12.2 to 40.6±13.4 s). Training increased V̇O2peak in both sexes (12-13 %) but did not alter systemic cardiovascular dynamics in either sex. Training improved V̇O2 dynamics to a similar extent in males and females in the absence of changes in systemic cardiovascular dynamics. Novelty Bullets Similar training improvements in V̇O2 dynamics were observed in males and females with type 2 diabetes. In both sexes these improvements occurred without changes in systemic cardiovascular dynamics.

3.
Proc Natl Acad Sci U S A ; 117(12): 6349-6355, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32156732

RESUMO

A combined analytical, theoretical, and experimental study has shown that the vaping of vitamin E acetate has the potential to produce exceptionally toxic ketene gas, which may be a contributing factor to the upsurge in pulmonary injuries associated with using e-cigarette/vaping products. Additionally, the pyrolysis of vitamin E acetate also produces carcinogen alkenes and benzene for which the negative long-term medical effects are well recognized. As temperatures reached in vaping devices can be equivalent to a laboratory pyrolysis apparatus, the potential for unexpected chemistries to take place on individual components within a vape mixture is high. Educational programs to inform of the danger are now required, as public perception has grown that vaping is not harmful.

4.
BMJ Open ; 10(2): e034137, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32060156

RESUMO

INTRODUCTION: In the UK and Ireland, severe and complex obesity is managed in specialist weight management services (SWMS), which provide multicomponent lifestyle interventions to support weight loss, and use of medication if available. Liraglutide 3 mg (LIRA 3 mg) is an effective weight-loss medication, but weight loss in individual patients is variable, and its efficacy has not been assessed in SWMS. This study aims to investigate whether a targeted prescribing pathway for LIRA 3 mg with multiple prespecified stopping rules could help people with severe obesity and established complications achieve ≥15% weight loss in order to determine whether this could be considered a clinically effective and cost-effective strategy for managing severe and complex obesity in SWMS. METHODS AND ANALYSIS: In this 2-year, multicentre, open-label, real-world randomised controlled trial, 384 adults with severe and complex obesity (defined as body mass index ≥35 kg/m2 plus either prediabetes, type 2 diabetes, hypertension or sleep apnoea) will be randomised via a 2:1 ratio to receive either standard SWMS care (n=128) or standard SWMS care plus a targeted prescribing pathway for LIRA 3 mg with prespecified stopping rules at 16, 32 and 52 weeks (n=256).The primary outcome is to compare the proportion of participants achieving a weight loss of ≥15% at 52 weeks with a targeted prescribing pathway versus standard care. Secondary outcomes include a comparison of (1) the weight loss maintenance at 104 weeks and (2) the budget impact and cost effectiveness between the two groups in a real-world setting. ETHICS AND DISSEMINATION: The Health Research Authority and the Medicines and Healthcare products Regulatory Authority in UK, the Health Products Regulatory Authority in Ireland, the North West Deanery Research Ethics Committee (UK) and the St Vincent's University Hospital European Research Ethics Committee (Ireland) have approved the study. The findings of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-Identifier: NCT03036800.European Clinical Trials Database-Identifier: EudraCT Number 2017-002998-20.

5.
J Appl Physiol (1985) ; 128(1): 227, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31939722
6.
J Matern Fetal Neonatal Med ; 33(7): 1203-1210, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30261783

RESUMO

Background: To determine the association of maternal and fetal inflammatory factors with gender-specific infant adiposity, independent of leptin.Methods: Analysis of anthropometry from 265 mother-infant pairs at birth and 280 pairs at 6 months from the randomised control trial of low glycaemic index diet in pregnancy (ROLO) study (Randomised control trial of low glycaemic index diet) and their association with Maternal TNF-alpha, interleukin 6 and leptin as measured in early and late pregnancy and fetal levels in cord blood.Results: No associations were noted in the male cohort. On multiple regression amongst the female neonatal cohort late pregnancy IL-6 was inversely associated with sum of skinfolds (p ≤ .001); at 6 months infant sum of skinfolds were positively associated with early pregnancy IL-6 (p = .046) and central adiposity positively associated with early pregnancy TNF alpha (p = .018) independent of leptin.Conclusion: Although maternal inflammatory cytokines were not associated with neonatal adiposity independent of leptin (as this association is known), both IL-6 and TNF-α were associated with female infant anthropometry at 6 months of age independent of leptin. These results suggest inflammatory cytokines may exert an in-utero influence on later infant adiposity with a tendency to influence female adiposity more than male. Further research is required to ascertain whether these cytokines may be used as reliable early predictors of infant adiposity.

7.
Eur J Med Chem ; 187: 111959, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846830

RESUMO

Chlorophyll a exhibits excellent photosensitive activity in photosynthesis. The unstability limited its application as photoensitizer drug in photodynamic therapy. Here a series of novel chlorophyll a degradation products pyropheophorbide-a derivatives were synthesized and evaluated for lung cancer in PDT. These compounds have strong absorption in 660-670 nm with high molar extinction coefficient, and fluorescence emission in 660-675 nm upon excitation with 410-415 nm light. They all have much higher ROS yields than pyropheophorbide-a, and compound 10 was even higher than [3-(1-hexyloxyethyl)]-pyrophoeophorbide a (HPPH). Distinctive phototoxicity was observed in vitro and the inhibition effect was in light dose-dependent and drug dose-dependent style. They can effectively inhibit the growth of lung tumor in vivo. Among them, compound 8 and 11 have outstanding photodynamic anti-tumor effects without obvious skin photo-toxicity, so they can act as new drug candidates for photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Clorofila A/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Clorofila A/síntese química , Clorofila A/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Imagem Óptica , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Ir J Med Sci ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721041

RESUMO

BACKGROUND: Subjects with severe obesity (BMI > 40 kg/m2) have worse physical function and sleep less than lean people (BMI 18.5-25 kg/m2). METHODS: In 554 subjects with severe obesity, we compared physical function in those with normal sleep duration (NSD, 6-9 h/night), short sleep duration (SSD, ≤ 6 h/night) and long sleep duration (LSD, ≥ 9 h/night). RESULTS: The mean (±SD) age and BMI were 43.1 (± 11.1) years and 50.9 ± 8.6 kg/m2 respectively. One hundred ninety-six (35.4%) were male. More subjects in the NSD group (n = 256) were able to ascend and descend a step 50 times than in the SSD group (n = 247) or the LSD group (n = 51, 75.5% vs 62.8% vs 56.9%, p = 0.002). A similar observation was made for step speed (0.45 ± 0.11 vs 0.43 ± 0.10 vs 0.40 ± 0.11 steps/s respectively, p = 0.001). NSD participants were less likely to have fallen in the preceding year compared to LSD participants (21.1% vs 39.2%, p = 0.007) and also reported less low back pain compared to SSD participants (60.8% vs 75.9%, p = 0.004). CONCLUSIONS: In conclusion, abnormal sleep duration is associated with reduced physical function in non-elderly severely obese subjects. The effects of sleep hygiene interventions in this cohort warrant further assessment and may be beneficial to their physical function.

10.
Chem Sci ; 10(29): 6944-6956, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588261

RESUMO

The use of NIR-fluorescence imaging to demarcate tumour boundaries for real-time guidance of their surgical resection has a huge untapped potential. However, fluorescence imaging using molecular fluorophores, even with a targeting biomolecule attached, has a major shortcoming of signal interference from non-specific background fluorescence outside the region of interest. This poor selectivity necessitates prolonged time delays to allow clearance of background fluorophore and retention within the tumour prior to image acquisition. In this report, an innovative approach to overcome this issue is described in which cancer targeted off to on bio-responsive NIR-fluorophores are utilised to switch-on first within the tumour. Bio-responsive cRGD, iRGD and PEG conjugates have been synthesised using activated ester/amine or maleimide/thiol couplings to link targeting and fluorophore components. Their off to on emission responses were measured and compared with an always-on non-responsive control with each bio-responsive derivative showing large fluorescence enhancement values. Live cell imaging experiments using metastatic breast cancer cells confirmed in vitro bio-responsive capabilities. An in vivo assessment of MDA-MB 231 tumour imaging performance for bio-responsive and always-on fluorophores was conducted with monitoring of fluorescence distributions over 96 h. As anticipated, the always-on fluorophore gave an immediate, non-specific and very strong emission throughout whereas the bio-responsive derivatives initially displayed very low fluorescence. All three bio-responsive derivatives switched on within tumours at time points consistent with their conjugated targeting groups. cRGD and iRGD conjugates both had effective tumour turn-on in the first hour, though the cRGD derivative had superior specificity for tumour over the iRGD conjugate. The pegylated derivative had similar switch-on characteristics but over a much longer period, taking 9 h before a significant emission was observable from the tumour. Evidence for in vivo active tumour targeting was obtained for the best performing cRGD bio-responsive NIR-AZA derivative from competitive binding studies. Overall, this cRGD-conjugate has the potential to overcome the inherent drawback of targeted always-on fluorophores requiring prolonged clearance times and shows excellent potential for clinical translation for intraoperative use in fluorescence guided tumour resections.

11.
Nat Commun ; 10(1): 4003, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488830

RESUMO

Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis.


Assuntos
Citocinas/metabolismo , Microbioma Gastrointestinal/fisiologia , Interleucina-1/metabolismo , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Animais , Colo/imunologia , Colo/microbiologia , Colo/patologia , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal/imunologia , Expressão Gênica , Teste de Tolerância a Glucose , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucina-2/metabolismo , Obesidade/imunologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transcriptoma , Verrucomicrobia
12.
J Appl Physiol (1985) ; 127(4): 1140-1149, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414958

RESUMO

The pulmonary oxygen uptake (V̇o2) kinetics during the transition to moderate-intensity exercise is slowed in individuals with type 2 diabetes (T2D), at least in part because of limitations in O2 delivery. The present study tested the hypothesis that a prior heavy-intensity warm-up or "priming" exercise (PE) bout would accelerate V̇o2 kinetics in T2D, because of a better matching of O2 delivery to utilization. Twelve middle-aged individuals with T2D and 12 healthy controls (ND) completed moderate-intensity constant-load cycling bouts either without (Mod A) or with (Mod B) prior PE. The rates of muscle deoxygenation (i.e., deoxygenated hemoglobin and myoglobin concentration, [HHb+Mb]) and oxygenation (i.e., tissue oxygenation index) were continuously measured by near-infrared spectroscopy at the vastus lateralis muscle. The local matching of O2 delivery to O2 utilization was assessed by the Δ[HHb+Mb]-to-ΔV̇o2 ratio. Both groups demonstrated an accelerated V̇O2 kinetics response during Mod B compared with Mod A (T2D, 32 ± 9 vs. 42 ± 12 s; ND, 28 ± 9 vs. 34 ± 8 s; means ± SD) and an elevated muscle oxygenation throughout Mod B, whereas the [HHb+Mb] amplitude was greater during Mod B only in individuals with T2D. The [HHb+Mb] kinetics remained unchanged in both groups. In T2D, Mod B was associated with a decrease in the "overshoot" relative to steady state in the Δ[HHb+Mb]-to-ΔV̇o2 ratio (1.17 ± 0.17 vs. 1.05 ± 0.15), whereas no overshoot was observed in the control group before (1.04 ± 0.12) or after (1.01 ± 0.12) PE. Our findings support a favorable priming-induced acceleration of the V̇o2 kinetics response in middle-aged individuals with uncomplicated T2D attributed to an enhanced matching of microvascular O2 delivery to utilization.NEW & NOTEWORTHY Heavy-intensity "priming" exercise (PE) elicited faster pulmonary oxygen uptake (V̇o2) kinetics during moderate-intensity cycling exercise in middle-aged individuals with type 2 diabetes (T2D). This was accompanied by greater near-infrared spectroscopy-derived muscle deoxygenation (i.e., deoxygenated hemoglobin and myoglobin concentration, [HHb+Mb]) responses and a reduced Δ[HHb+Mb]-to-ΔV̇o2 ratio. This suggests that the PE-induced acceleration in oxidative metabolism in T2D is a result of greater O2 extraction and better matching between O2 delivery and utilization.

13.
Respir Physiol Neurobiol ; 269: 103258, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31349019

RESUMO

We tested the hypothesis that type 2 diabetes (T2D) alters the profile of muscle fractional oxygen (O2) extraction (near-infrared spectroscopy) during incremental cycle exercise. Seventeen middle-aged individuals with uncomplicated T2D and 17 controls performed an upright ramp test to exhaustion. The rate of muscle deoxygenation (i.e. deoxygenated haemoglobin and myoglobin concentration, Δ[HHb+Mb]) profiles of the vastus lateralis muscle were normalised to 100% of the response, plotted against % power output (PO) and fitted with a double linear regression model. Peak oxygen uptake was significantly (P < 0.05) reduced in individuals with T2D. The %Δ[HHb+Mb]/%PO slope of the first linear segment of the double linear regression function was significantly (P < 0.05) steeper in T2D than controls (1.59 (1.14) vs 1.23 (0.51)). Both groups displayed a near-plateau in Δ[HHb+Mb] at an exercise intensity (%PO) not different amongst them. Such findings suggest that a reduced O2 delivery to active muscles is an important underlying cause of exercise intolerance during a maximum graded test in middle-aged individuals with T2D.

14.
J Immunol ; 202(12): 3404-3411, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31076528

RESUMO

Obesity underpins the development of numerous chronic diseases, such as type II diabetes mellitus. It is well established that obesity negatively alters immune cell frequencies and functions. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells, which we have previously reported are dysregulated in obesity, with altered circulating and adipose tissue frequencies and a reduction in their IFN-γ production, which is a critical effector function of MAIT cells in host defense. Hence, there is increased urgency to characterize the key molecular mechanisms that drive MAIT cell effector functions and to identify those which are impaired in the obesity setting. In this study, we found that MAIT cells significantly upregulate their rates of glycolysis upon activation in an mTORC1-dependent manner, and this is essential for MAIT cell IFN-γ production. Furthermore, we show that mTORC1 activation is dependent on amino acid transport via SLC7A5. In obese patients, using RNA sequencing, Seahorse analysis, and a series of in vitro experiments, we demonstrate that MAIT cells isolated from obese adults display defective glycolytic metabolism, mTORC1 signaling, and SLC7A5 aa transport. Collectively, our data detail the intrinsic metabolic pathways controlling MAIT cell cytokine production and highlight mTORC1 as an important metabolic regulator that is impaired in obesity, leading to altered MAIT cell responses.

15.
Eur J Pain ; 23(8): 1403-1415, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30963658

RESUMO

BACKGROUND: Musculoskeletal (MSK) pain is common in obese populations. Multidisciplinary Tier 3 weight management services (WMS) are effective in reducing weight; however, MSK pain as an outcome is not routinely reported post-WMS interventions. METHODS: Following ethical approval this retrospective design study using anonymized data from a national WMS established changes in anthropometric and pain prevalence and intensity scores as well as establishing variables predictive of achieving clinically significant changes (CSC) in pain scores. RESULTS: Of the 806 patients registered to the WMS (January 2011-February 2015), 59% (n = 476; CI = 56-62) attended their reassessments at 6 months. The overall mean age was 45.1 ± 12 years and 62% (n = 294) were female. At baseline 70% (n = 281; CI = 65-75) reported low back pain (LBP) and 59% (n = 234; CI = 54-64) had knee pain. At reassessment 37.3% (n = 177) of patients lost ≥5% body weight, 58.7% (n = 279) were weight stable (5% weight loss or gain) and 4.0% (n = 19) gained ≥5% body weight. Low back and knee pain prevalence reduced significantly for those who lost ≥5% body weight. Variables predictive of a CSC in LBP numerical rating scale (NRS) score included a higher baseline NRS score, weighing more, and rating losing weight as being important (p < 0.05). Higher baseline NRS and being younger resulted in higher odds of a CSC in knee pain NRS (p < 0.05). CONCLUSIONS: Overall this WMS was effective for clinical weight loss. For those who lost most weight prevalence of knee and LBP reduced. Imbedding pain management strategies within WMS's may provide a more holistic approach to obesity management. SIGNIFICANCE: Weight loss can reduce musculoskeletal pain, particularly for those who lose more weight. Imbedding pain management strategies within these services may provide a more holistic approach to obesity management.

16.
Cancers (Basel) ; 11(4)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018563

RESUMO

Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity.

18.
Toxicol Pathol ; 47(4): 436-443, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30722763

RESUMO

Digital pathology is defined as the ability to examine digitized microscopic slides and to generate qualitative and quantitative data. The field of digital pathology is rapidly evolving and has the potential to revolutionize toxicologic pathology. Techniques such as automated 2-D image analysis, whole slide imaging, and telepathology are already considered "mature" technologies and have been used for decades in exploratory studies; however, many organizations are reluctant to use digital pathology in regulatory toxicology studies. Innovative technologies using digitized slides including high-content imaging modalities and artificial intelligence are still under development but are increasingly used in toxicologic pathology. While software validation requirements are already described, clear guidance for application of these rules to the digital pathology field are few and the acceptance of these technologies by regulatory authorities remains necessary for successful adoption of digital pathology into the mainstream of toxicologic pathology. This topic was discussed during a roundtable at the 2018 Annual Congress of the French Society of Toxicologic Pathology. This opinion article summarizes the discussion regarding the current questions and challenges on the integration of innovative digital pathology tools within a good laboratory practice framework and is meant to stimulate further discussion among the toxicologic pathology community. *This is an opinion article submitted to the Toxicologic Pathology Forum and does not constitute an official position of the Society of Toxicologic Pathology or the journal Toxicologic Pathology. The views expressed in this article are those of the authors and do not necessarily represent the policies, positions, or opinions of their respective agencies and organizations. The Toxicologic Forum is designed to stimulate broad discussion of topics relevant to regulatory issues in Toxicologic pathology. Readers of Toxicologic Pathology are encouraged to send their thoughts on these articles or ideas for new topics to toxicologicpathologyforum@toxpath.org .


Assuntos
Processamento de Imagem Assistida por Computador/normas , Telepatologia/tendências , Toxicologia/tendências , Humanos , Microscopia/métodos , Microscopia/normas , Guias de Prática Clínica como Assunto , Telepatologia/normas , Toxicologia/normas
19.
Eur J Med Chem ; 161: 343-353, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368132

RESUMO

Clinical imaging utilising near-infrared fluorescence is growing as an intraoperative aid for the decision-making processes during complex surgical procedures. Existing uses include perfusion assessment and lymph node identification with many new applications currently being proposed and developed. While imaging hardware and software have significantly progressed in recent times, suitable NIR-fluorophores remain a limiting factor. In this report, we describe the design, synthesis, photophysical characterization and in vivo imaging assessment of new PEGylated NIR-fluorophores based on the BF2-azadipyrromethene fluorophore class. The synthetic route includes PEGylation as the final step, thereby allowing routine access to derivatives substituted with different molecular weights of PEG. Absorption and emission wavelength maxima in PBS lie at 690 and 720 nm respectively with quantum yields over 12%. They show excellent photostability and no light induced singlet oxygen production. A time-course of NIR-fluorescence imaging, post i.v. administration, in BALB/c mice showed a rapid and preferential accumulation in the renal excretion pathway within 20 min, indicative of potential clinical usage for intraoperative identification of vial structures along this pathway. Assessment with clinical imaging equipment showed the NIR-AZA fluorophores to be wavelength compatible and brighter than currently used methylene blue (MB), and that they have the ability to be imaged simultaneously with indocyanine green (ICG) offering a potential for dual colour clinical imaging.


Assuntos
Compostos Aza/química , Compostos de Boro/química , Neoplasias da Mama/diagnóstico por imagem , Corantes Fluorescentes/química , Imagem Óptica , Polietilenoglicóis/química , Porfobilinogênio/análogos & derivados , Animais , Compostos Aza/administração & dosagem , Compostos de Boro/administração & dosagem , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/síntese química , Humanos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Polietilenoglicóis/administração & dosagem , Porfobilinogênio/administração & dosagem , Porfobilinogênio/química , Eliminação Renal , Espectrometria de Fluorescência , Relação Estrutura-Atividade
20.
Biochim Biophys Acta Biomembr ; 1860(11): 2272-2280, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30409523

RESUMO

It is challenging to achieve selective off to on modulation of the emissive state of a fluorophore within a complex and heterogeneous cellular environment. Herein we show that the dis-assembly of a non-fluorescent aggregate to produce individual fluorescent molecules, termed disaggregation induced emission (DIE), can be utilised to achieve this goal with an amphiphilic BF2-azadipyrromethene (NIR-AZA) probe. Optical near-infrared properties of the NIR-AZA probe used in this study include absorption and emission maxima at 700 and 726 nm respectively when in the emissive non-aggregated state. Key to the success of the probe is the bis-sulfonic acid substitution of the NIR-AZA fluorophore, which is atypical for membrane probes as it does not contain zwitterionic lipid substituents. The aggregation/disaggregation properties of the NIR-fluorophore have been investigated in model surfactant and synthetic liposomal systems and shown to be emissive responsive to both. Real-time live cell imaging experiments in HeLa Kyoto and MC3T3 cells showed a rapid switch on of emission specific to the plasma membrane of viable and apoptotic cells attributable to a disaggregation-induced emission of the probe. Image analysis software confirmed localisation of fluorescence to the plasma membrane. Cell membrane staining was also effective for formaldehyde fixed cells, with staining possible either before or after fixation. This study adds new and important findings to recent developments of DIE responsive probes and further applications of this controllable emission-switching event are anticipated.


Assuntos
Membrana Celular/metabolismo , Corantes Fluorescentes , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Células 3T3 , Animais , Células HeLa , Humanos , Camundongos
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