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Wong, F. Preterm infants on inotropes have different cerebral oxygen metabolism measured by near infrared spectroscopy. Quantification of adult cerebral blood volume using the NIRS tissue oxygenation index. Spatially resolved blood oxygenation measurements using time resolved photo-acoustic spectroscopy.

Spatially resolved measurements of blood oxygen saturation in a tissue phantom using photoacoustic spectroscopy. Estimation of cerebral oxy- and deoxy-haemoglobin concentration changes in a layered adult head model using near-infrared spectroscopy and multivariate statistical analysis. Physics in Medicine and Biology, 50 , In vitro measurements of absolute blood oxygen saturation using pulsed photoacoustic near infrared photoacoustic spectroscopy: accuracy and resolution. Investigation of the cerebral haemoglobin and cytochrome signals using near infrared spectroscopy during head up tilt in patients with orthostatic hypotension.

Brain, 25 , S Investigation of the changes in cerebral tissue oxygenation measured with near infrared spectroscopy in response to moderate hypercapnia. Measurement of CMRO2 in neonates undergoing intensive care using near infrared spectroscopy. Okunieff, J. Williams,, Y. Chen Eds. Non-invasive monitoring of carbon dioxide reactivity: spatially resolved spectroscopy near infrared spectroscopy and transcranial Doppler. European Journal of Anaesthesiology, 22 Suppl.

Optimal determination of detector placement in cerebral NIR spectroscopy of neonates using chemometric techniques. Rate of change in cerebral oxygenation and blood pressure in response to passive changes in posture: a comparison between pure autonomic failure patients and controls. Regional measurements of CMRO2 in neonates undergoing intensive care using near infrared spectroscopy. Austin, T. Relationship between cerebral oxygen delivery, cerebral metabolic rate and the mean cerebral oxygen saturation in preterm infants.

A new method for the measurement of cerebral blood volume and total circulating blood volume using near infrared spatially resolved spectroscopy and indocyanine green: application and validation in neonates. Pediatric Research, 55 1 , Changes in cerebral total haemoglobin and cytochrome oxidase redox state during deep apnoeas in patients with obstructive sleep apnoea.

Investigation of cerebral haemodynamics by near-infrared spectroscopy in young healthy volunteers reveals posture- dependent spontaneous oscillations.

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Physiological Measurement, 25 2 , Mean cerebral oxygen saturation increases with gestational age in preterm infants. Measurement of the optical properties of the adult human head with spatially resolved spectroscopy and changes of posture. Csibra, G. Near infrared spectroscopy reveals neural activation during face perception in infants and adults.

Journal of Pediatric Neurology, 2 , Non invasive measurement of absolute cerebral blood volume in adults using a tissue oxygen index. Journal of Neurosurgical Anesthesiology, 16 , Posture dependence of spontaneous oscillations in cerebral haemodynamics. Anesthesia and Analgesia, 98 , S Pulsed near-infrared photoacoustic spectroscopy of blood.

Oxygen Sensing Molecule to Man Advances in Experimental Medicine and Biology

Mean cerebral saturation is an index of neonatal cerebral blood flow. Pediatric Research, 54 4 , ?. McGown, A. Measurement of changes in cytochrome oxidase redox state during obstructive sleep apnea using near-infrared spectroscopy. Sleep, 26 6 , Measurement of the optical properties of the adult human head with spatially resolved spectroscopy and changes in posture. Mcleod, A. Measuring cerebral oxygenation during normobaric hyperoxia: A comparison of tissue microprobes, near-infrared spectroscopy, and jugular venous oximetry in head injury. Anesthesia and Analgesia, 97 3 , Simultaneous measurement of cerebral tissue oxygenation over the adult frontal and motor cortex during rest and functional activation.

Spectral characteristics of spontaneous oscillations in cerebral haemodynamics are posture dependent. Thavasothy, M. Anaesthesia, 57 10 , Bleasdale-Barr, K. Mathias, C. Changes in cerebral oxygen saturation on postural change in patients with autonomic failure and orthostatic hypotension and controls. Clinical Autonomic Research, 12 , Changes in cerebral tissue oxygenation during postural hypotension in patients with autonomic failure. Journal of Neurosurgical Anesthesiology, 14 , ?. Gora, F. Noninvasive measurement of cerebral blood flow in adults using near-infrared spectroscopy and indocyanine green: A pilot study.

Journal of Neurosurgical Anesthesiology, 14 3 , A day in the Life of a Research Medical Physicist. The Biochemist, 22 2 , Lovell, A. Changes in cerebral blood volume with changes in position in awake anaesthetized subjects. Anesthesia and Analgesia, 90 2 , Lee, T. Washington DC. Meek, J. Abnormal cerebral haemodynamics in perinatally asphyxiated neonates related to outcome.

Continuous measurement of cerebral oxygenation by near infrared spectroscopy during induction of anesthesia. Anesthesia and Analgesia, 88 3 , Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage. Measurement of cerebral blood flow in adults using near infrared spectroscopy and indocyanine green. Journal of Neurosurgical Anesthesiology, 11 , ?. Owen-Reece, H. Near infrared spectroscopy. British Journal of Anaesthesia, 82 3 , Oscillations in cerebral haemodynamics - implications for functional activation studies.

Visually evoked haemodynamic responses in infants with cerebral pathology. Cerebral blood flow increases over the first three days of life in extremely preterm neonates. Archives of Disease in Childhood, 78 , FF Tyszczuk, L. Cerebral blood flow is independent of mean arterial blood pressure in preterm infants undergoing intensive care. Pediatrics, , Changes in cerebral blood volume measured by near infrared spectroscopy.

Acta Anaesthesiol Scand, 42 , Firbank, M. Experimental and theoretical comparison of NIR spectroscopy measurements of cerebral hemoglobin changes. Journal of Applied Physiology, 85 5 , Regional haemodynamic responses to visual stimulation in awake infants. Pediatric Research, 43 6 , pp. Regional hemodynamic responses to visual stimulation in awake infants. Pediatr Res, 43 6 , An analytical method for determining cerebrovascular transit time using near infrared spectroscopy.

Changes in cerebral blood volume with change in posture measured by near infrared spectroscopy. Anesthiol, 9 , ?. Comparison of the immediate effects of induction of anaesthesia with etomidate, propofol and thiopentone on cerebral haemodynamics. British Journal of Anaesthesia, 78 , P-?. Continuous measurement of cerebral oxygenation by NIRS during induction of anaesthesia. Jugular venus bulb oxygen saturation compared with cerebral saturation measured by near infrared spectroscopy.

Analgesia, 84 , S?. Measurement of cerebral venous saturation in adults using near infrared spectroscopy. Oscillations in arterial saturation: implications for the measurement of cerebral blood flow with near infrared spectroscopy.


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Anaesth, 78 , P-?. Predicting oscillation in arterial saturation from cardiorespiratory variables. Implications for the measurement of cerebral blood flow with NIRS during anaesthesia. Cooper, C. The cytochrome oxidase redox state in vivo. These results suggest that TRS may be useful to study language function and to assess hemispheric dominance for language. Hamamatsu, Japan. Skip to main content.

1. Introduction

Advertisement Hide. Conference paper First Online: 24 October This is a preview of subscription content, log in to check access. Carrington et al. Therefore, this complex offered anti-breast cancer activity through unique light-controlled CO delivery [ 24 ]. In a later study, Carrington et al.


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  6. The results suggested that this manganese photo-CORM was able to deliver CO to biological targets upon irradiation with visible light, provoke CO-induced apoptosis in human breast cancer cells, and offer the ability to track CO delivery within the cells, because of the highly fluorescent pbt included in the complex [ 26 ]. The anticancer potential of these complexes was investigated against a human invasive ductal breast carcinoma MCF-7 cell line and all of them displayed promising IC 50 values of low micromolecular range.

    It seems that compounds 1, 3, and 5 exert cytotoxic effect on MCF-7 cells, and UV irradiation does not enhance cytotoxicity of these compounds. On the contrary, compounds 2 and 4 express a UV-dependent cytotoxicity, following the principles of photo-CORMs design. Therefore, compounds 2 and 4 may provide photodynamic agents for anticancer therapy with controlled CO release profiles [ 27 ]. Prostate cancer is the most common type of cancer in males.


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    Jackson et al. Also, the authors found that this complex possesses a suitable ligand structure for peptide attachment [ 28 ]. In addition, Pierri et al. However, the experiments demonstrated a significant aggregation in the cytoplasm, but not within the nucleus [ 29 ]. Niesel et al. According to cellular uptake studies, this complex was suggested to enter the cells by passive diffusion rather than active transport and thus may be useful for cellular delivery of CO. The differential cytotoxicity of the complex with or without irradiation was tested on HT29 colon cancer cells via the crystal violet assay.

    Therefore, this complex may serve as a PDT agent against colon cancer [ 30 ]. The cytotoxicity of these complexes was tested on Hct human colon carcinoma cells and compared to that of CORM However the researchers concluded that it was not a direct result of CO release, because the toxicities of the two complexes remained the same with or without irradiation. This study demonstrated the feasibility of developing ligand functionalized polymers as carrier systems for Mn CO 3 -based CORMs for the passive delivery of these CORMs to tumour tissues or other sites [ 31 ].

    FRET-like fluorophore-nanoparticle complex for highly specific cancer localization

    The manganese complex fac- [MnBr azpy CO 3 ], previously mentioned in the breast cancer section, was also tested for inhibitory effects on a cervical cancer cell line, that is, HeLa cells [ 24 ]. This complex exhibited similar anticancer effects on the cervical cells as those against the breast cancer cell line upon irradiation with visible light. The complex caused certain morphological changes to the cervical cancer cells, indicating an apoptotic cell state, suggesting a potential use as an anticancer agent for breast or cervical cancers, with the advantage of a favourable light-controlled CO release [ 24 ].

    Hu and colleagues [ 32 ] designed a series of N-substituted molybdenum, tungsten, and manganese carbonyl complexes containing various heterocycles Figure 3 C which were tested for cytotoxicity on HeLa cells.

    1. Introduction

    Apart from complex 4, the rest of series complexes exert modest inhibitory effects on HeLa cells, without significant cytotoxicity. Among them, complex 3 was the most potent, with an IC 50 of The mechanism of action was further studied, revealing a concentration-dependent apoptotic effect of complexes 1 and 6, mainly in the later stage. Hence, they hypothesised that the antiproliferative activity of the synthesised compounds resulted from the binding of CO to proteins of the mitochondrial electron transfer chain leading to an intracellular ROS level increase, as well as the release of cobalt species that can bind to endogenous substrates interrupting cell cycle and provoking apoptosis [ 33 ].

    CORM-2 was also able to substantially affect de novo angiogenesis via suppressing Akt phosphorylation, a significant contributor to cancer neovascularisation. Schwer et al. Being a common histopathological feature in pancreatic cancer, fibrosis has been shown to be significantly affected by both processes of translation and protein synthesis. The anti-inflammatory and antiproliferative effects of CORM-2 could hence be via repressing global protein synthesis [ 35 ]. The antiphotocarcinogenic properties of CO were established in another study by Allanson and Reeve [ 36 ].

    They explored whether CO signalling has an anti-skin cancer function. All the effects of CORMs were dose-dependent, even though not always following the expected pattern. CORM-2 also appeared to significantly reduce average tumour multiplicity [ 36 ]. HO-1 was shown to inhibit lung adenocarcinoma cell growth via generation of CO [ 8 ]. CO gas could not enhance the sensitivity of ARho o , the mitochondria-depleted A cells, to doxorubicin, suggesting that CO gas may rapidly enhance mitochondrial activity of cancer cells, resulting in metabolic exhaustion and cellular collapse under intense oxidative stress and thus tumour regression [ 8 ].

    A cells were derived from the lung tumour Kras mouse model. Loureiro et al. To take advantage of the ability of the nanocarriers to affect the pharmacokinetics and drug distribution to different tissues, PEGylated and folic acid- FA- functionalized BSA nanoemulsions were generated, which could specifically deliver CORM-2 into FA receptor-positive cancer cells.

    The study by Schlawe et al. The authors generated some iron-containing nucleoside analogues Figure 4 A and tested them for their cytotoxic activity against a lymphoma B cell line, namely, BJAB cells. The antileukemic potency of the new nucleosides was also evaluated, with one particular complex efficiently inducing apoptosis in an ex vivo DNA-fragmentation assay involving primary leukemic lymphoblasts. However, the mechanism of action needs to be further elucidated but may involve CO release as well [ 38 ]. The authors tested these micelle-encapsulated organic photo-CORMs for effects on leukemic KG1 cell proliferation and viability by flow cytometry.

    Their results showed that the viability of the cells was not altered by the photo-CORMs or the anthracene based fluorophore. Also, no photodamage was observed. Therefore, this study revealed a new approach in the designing and synthesis of new photo-CORMs, beyond their potential use as anticancer agents, which can prove well suited for possible targeted delivery of CO to biological systems [ 39 ].

    Toxic effects of CO are due to its high affinity for the reduced iron-heme in haemoglobin, crucial for the delivery of oxygen O 2 to tissues. Thus, CO can compete with O 2 for the binding site of heme on the mitochondrial cytochrome c oxidase, one of its central targets, and become harmful for cellular respiration [ 40 ]. CO has also been shown to increase mitochondrial biogenesis and ATP and ROS generation, which also affects cellular behaviour [ 4 , 7 , 8 ].

    A proof-of-concept study by Lo Iacono et al. The iCORM-3 unable to release CO could not exert the same effects, suggesting that the uncoupling effect and inhibition of mitochondrial respiration caused by CORM-3 are most likely due to CO rather than the rest of the molecule.

    Takano et al. CORMs have also been considered against other cancer-related pathological conditions, most commonly side effects caused by other anticancer drugs. In that scope, Soni et al. These cardioprotective effects were probably derived from the CORMinduced reduction in the serum levels of creatine kinase CK and lactate dehydrogenase LDH , leading to further attenuation of oxidative stress and cardiomyocyte apoptosis. A notorious side effect of cisplatin CP-a widely used anticancer drug is nephrotoxicity. Tayem et al. From another point of view, Tong et al.

    Different studies report contradicting results based on the types of tumours studied. They conclude that these agents have either a pro- or antiangiogenic effect based on the type of cells involved. Choi et al. This effect is directly linked to the inhibitory activity of CO on mitochondrial complex IV, involved in the respiratory system of these organelles [ 1 , 45 ]. Similarly, CORM-2 could provoke a paracrine-style of proangiogenic activity.

    Fang et al. Other papers reported similar results that CO could induce VEGF expression or enhance its angiogenic activity [ 49 — 51 ]. In contrast, there are reports suggesting that both HO-1 and CO could have variable functions, based on the different cellular microenvironments [ 48 , 49 , 51 , 52 ]. Some of these reports described an antiangiogenic effect of HO-1 and CO on cancer cells [ 19 , 34 , 52 ]. Ahmad et al.

    In pancreatic cancer, CO inhibited endothelial proliferation and reduced microvascular density of xenon cancer models [ 34 ]. The study by Skrzypek et al. Loboda et al. The authors thoroughly examined both potential types of effects that may be modulated by heme oxygenase-1 HO-1 and CO regarding angiogenesis. First they make the point that 1 induction of angiogenesis is mainly supported by an increase in growth factors synthesis and activation, an inhibition of the differentiation of cancer stem cells, and a boost in VEGF expression and release and 2 angiogenesis may be attenuated via a decreased synthesis of angiogenic mediators, an inhibition on the phosphorylation of key kinases, and a metabolic switch from glycolysis towards the pentose phosphate pathway.

    In this review as well as all others, CO is suggested to influence tumour angiogenesis in opposite ways. It has been reported to increase the synthesis of growth factors and improve the viability of endothelial cells and may be linked to cancer initiating cells. Indeed, as mentioned above antiangiogenic activities of CO were reported in various studies, as well as antiproliferative effects and inhibition of xenotransplanted tumours.

    Only in this way could CORMs be considered for more personalised therapies, potentially as additional therapeutic agents for cancer patients [ 18 ]. So, the question now is, what is next? There is a growing interest in developing novel CO-based therapeutics, and as the understanding of CO biology increases every day we expect to see CORMs becoming a new class of therapeutics against various diseases soon [ 55 ]. There have been many obstacles for CORMs to develop as clinically useful agents, though.

    The main problem is obviously solubility, but researchers have been able to address this problem successfully. Nevertheless, there are many other issues to be dealt with, such as stability in air and water, biocompatibility, how to ensure low or no toxicity of the metal-fragment left after the release of CO, and favourable pharmacokinetics [ 1 , 2 , 4 , 7 ]. Apart from the properties of absorption, distribution, metabolism, and excretion ADME required for all drug-like substances, the most important feature of effective CORMs is to be able to reach the appropriate disease sites where they can release CO via a certain trigger or stimulus in the proper amount and time [ 1 , 2 , 10 ].

    Moreover, the half-life of the CORM in the circulation and the release of CO are crucial for the desired therapeutic effect. The design of new CORMs should be based on finding suitable ligands capable of tuning the half-life of the CO release [ 2 , 4 , 13 ]. The ligand sphere determines the kinetics and stoichiometry of the CO release, given a proper metal core, whereas the drug sphere should provide the CORM with desired characteristics, such as favourable ADME and tissue-specific targeting elements [ 1 , 13 ].

    Comprehensive reviews of conceptualising novel CORM structures are introduced by many researchers [ 4 , 10 , 13 ]. The most important aspects of designing new CORMs include the number of releasable CO groups, the kinetics of the CO release, and the trigger mechanisms required for initiation. The chemical versatility of these compounds is their most significant advantage over CO gas. The appropriate targeting ligands conjugated to the metal-carbonyl scaffold allow for their spatial distribution in the various body fluids and tissues, even in different cell subpopulations [ 4 , 13 ].

    As for the special class of photo-CORMs, additional properties are required, such as photoreactivity at specific wavelengths where the penetration depth is optimal, that may allow for total control of the delivery and activation of these compounds. This could only be achieved by suitable metal and coligand combinations [ 15 , 55 , 56 ]. Further development of metal-based CORMs is on its way and we expect to see more advanced and well-targeted molecules arising in the near future.

    In this perspective, it would be even possible to select the proper CORM for the therapeutic action needed, according to its CO-releasing profile and pharmacokinetic behaviour. Overall, appropriate designing and synthesis of novel molecules could prove invaluable towards a more personalised cancer treatment and a reduced drug load for cancer patients [ 4 ].

    National Center for Biotechnology Information , U. Oxid Med Cell Longev. Published online Feb Malamati Kourti , Wen G. Wen G. Author information Article notes Copyright and License information Disclaimer. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC.