•LC/ESI–MS/MS has been widely used for the quantification of endogenous steroids.•However, the ESI efficiency and fragmentation behavior of some steroids are poor.•Chemical derivatization is ...effective for enhancing detectability of steroids.•This article reviews chemical derivatization for LC/ESI–MS/MS of steroids.•Stable isotope-coded derivatization for the steroid analysis is also described.
Sensitive and specific methods for the detection, characterization and quantification of endogenous steroids in body fluids or tissues are necessary for the diagnosis, pathological analysis and treatment of many diseases. Recently, liquid chromatography/electrospray ionization–tandem mass spectrometry (LC/ESI–MS/MS) has been widely used for these purposes due to its specificity and versatility. However, the ESI efficiency and fragmentation behavior of some steroids are poor, which lead to a low sensitivity. Chemical derivatization is one of the most effective methods to improve the detection characteristics of steroids in ESI–MS/MS. Based on this background, this article reviews the recent advances in chemical derivatization for the trace quantification of steroids in biological samples by LC/ESI–MS/MS. The derivatization in ESI–MS/MS is based on tagging a proton-affinitive or permanently charged moiety on the target steroid. Introduction/formation of a fragmentable moiety suitable for the selected reaction monitoring by the derivatization also enhances the sensitivity. The stable isotope-coded derivatization procedures for the steroid analysis are also described.
•Poor throughput becomes a major issue in the metabolite quantification by LC/MS/MS.•Multiplexing of samples in a single LC/MS run can be the answer for this issue.•This article reviews the ...derivatization-based sample-multiplexing strategy.•Applications of this strategy to relative and absolute quantifications are outlined.•Combination of the multiple derivatization can expand the coverage of metabolites.
The quantification of metabolites in various samples, including body fluids, tissues, cells, and foodstuffs, contributes to our understanding of their biological activities and roles in the body, diagnosis for many diseases, drug and biomarker discovery, and many aspects of human health. Liquid chromatography (LC)/tandem mass spectrometry (MS/MS) is the most powerful and reliable methodology for the quantification of metabolites due to its high specificity and sensitivity, and broad coverage of various compounds. Derivatization often makes the quantification power of LC/MS/MS stronger due to the desirable LC behavior and enhanced MS/MS detectability of the derivatized metabolites. On the other hand, LC/MS/MS-based quantification has room for improvement regarding its analysis throughput. Derivatization is also a promising approach to overcome this drawback; the multiplexing of samples in the same LC/MS/MS injection, which is achieved by derivatization of multiple samples with multiple well-designed reagents, can enhance the throughput. Based on this background, this article reviews the derivatization-based sample-multiplexing strategy, especially the characteristics and applications of the derivatization reagents, for the LC/MS/MS quantification of metabolites. This strategy has been used for the relative and absolute quantification of a variety of metabolites, and expansion of the coverage of metabolites.
•Insufficient sensitivity becomes a major problem in the LC/ESI-MS(/MS) of metabolites.•Limited availability of stable isotope-labeled ISs is also a problem.•Stable isotope-coded derivatization can ...be the answer to these problems.•This article reviews the isotope-coded ESI-enhancing derivatization (ICEED) reagents.•Applications of ICEED reagents to biological sample analysis are outlined.
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The analysis of the qualitative and quantitative changes of metabolites in body fluids and tissues yields valuable information for the diagnosis, pathological analysis and treatment of many diseases. Recently, liquid chromatography/electrospray ionization-(tandem) mass spectrometry LC/ESI-MS(/MS) has been widely used for these purposes due to the high separation capability of LC, broad coverage of ESI for various compounds and high specificity of MS(/MS). However, there are still two major problems to be solved regarding the biological sample analysis; lack of sensitivity and limited availability of stable isotope-labeled analogues (internal standards, ISs) for most metabolites. Stable isotope-coded derivatization (ICD) can be the answer for these problems. By the ICD, different isotope-coded moieties are introduced to the metabolites and one of the resulting derivatives can serve as the IS, which minimize the matrix effects. Furthermore, the derivatization can improve the ESI efficiency, fragmentation property in the MS/MS and chromatographic behavior of the metabolites, which lead to a high sensitivity and specificity in the various detection modes. Based on this background, this article reviews the recently-reported isotope-coded ESI-enhancing derivatization (ICEED) reagents, which are key components for the ICD-based LC/MS(/MS) studies, and their applications to the detection, identification, quantification and profiling of metabolites in human and animal samples. The LC/MS(/MS) using the ICEED reagents is the powerful method especially for the differential analysis (relative quantification) of metabolites in two comparative samples, simultaneous quantification of multiple metabolites whose stable isotope-labeled ISs are not available, and submetabolome profiling.
In this manuscript, we present the guideline for use of meta-
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At astatobenzylguanidine (
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At MABG), a newly introduced alpha emitting radiopharmaceutical to the up-coming World’s first ...clinical trial for targeted alpha therapy (TAT) at Fukushima Medical University in Japan, focusing on radiation safety issues in Japan. This guideline was prepared based on a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on Oct. 5th, 2021. The study showed that patients receiving
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At MABG do not need to be admitted to a radiotherapy room and that TAT using
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At MABG is possible on an outpatient basis. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers or patient’s family members. In this guideline, the following contents are also included: precautions for patients and their families, safety management associated with the use of
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At MABG, education and training, and disposal of medical radioactive contaminants. TAT using
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At MABG in Japan should be carried out according to this guideline. Although this guideline is based on the medical environment and laws and regulations in Japan, the issues for radiation protection and evaluation methodology presented in this guideline are useful and internationally acceptable as well.
Saliva has recently been attracting attention as a patient-friendly available bio-fluid and an alternative to serum/plasma for hormone tests. LC coupled with atmospheric pressure ionization-MS/MS, ...especially electrospray ionization (ESI)-MS/MS, has been recently valued as a highly specific method in the analysis of salivary hormones. In this article, LC/ESI-MS/MS assays for salivary hormones are overviewed according to the papers that have been published during the last 5 years. Practical derivatization to enhance the detectabilities of hormones in ESI-MS/MS is also discussed, because a major disadvantage of using saliva is low hormone concentrations.
In alpha radionuclide therapy, an optical fiber-based alpha particle detector is a new tool that could possibly be employed for the direct detection of alpha particles in subjects. Thus, in the ...present study, we developed an optical fiber-based alpha particle detector. The alpha particle detector was made of a 1mm diameter, 10 cm long plastic double clad optical fiber drilled a 0.7 mm diameter, 2 mm depth open space at the one end of the fiber. Silver-doped zinc sulfide (ZnS (Ag)) was painted inside this open space to form a ZnS(Ag) small scintillation chamber. To conduct performance comparisons, we also developed a fiber detector using the same fiber in which a Ce-doped Lu1.8Y0·2SiO5 (LYSO(Ce)) scintillator with dimensions of 0.32 mm × 0.5 mm × 5 mm was inserted. Both fiber detectors were wrapped in aluminized Mylar and optically coupled to a position sensitive photomultiplier tube, before calculating the two-dimensional distributions, energy, and pulse shape spectra. For 5.5-MeV alpha particles, the ZnS(Ag) fiber detector produced ~ 5 times larger pulse heights and the count rate was ~2 times higher compared with those using the LYSO(Ce) fiber detector. For the maximum energy 2.28-MeV beta particles and 0.66-MeV gamma photons, the ZnS(Ag) fiber detector produced no counts, but it yielded small counts from natural alpha particles. Our results confirmed that the ZnS(Ag) fiber detector developed in this study could selectively detect alpha particles and it was insensitive to beta particles and gamma photons.
•Optical fiber-based ZnS(Ag) alpha particle detector was developed.•Performance compared with that of a Lu1.8Y0·2SiO5(Ce) fiber detector.•About five times larger pulse height and two times higher count rate with ZnS(Ag).•ZnS(Ag) fiber detector produced no counts with beta and gamma.
The measurements of the serum/plasma concentrations of vitamin D metabolites are widely used for the diagnostic assessment and follow-up of several diseases, such as chronic renal failure and ...osteoporosis. These metabolites have usually been measured by protein binding assays, such as radioimmunoassay and radioreceptor assay. Although these techniques will doubtless continue to be the methods of choice for routine use in the clinical field, their specificity and accuracy are sometimes poor due to interference from other metabolites and lipids. Among the alternative methods, liquid chromatography (LC) coupled with mass spectrometry (MS) has been used for the analysis of these metabolites and even synthetic vitamin D analogues (therapeutic agents) due to its sensitivity and selectivity. This article reviews recent advances in the determination of vitamin D metabolites and related compounds in biological samples using LC–MS.
Total redox capacity (TRC) and oxidative stress (OxiStress) of biological objects (such as cells, tissues, and body fluids) are some of the most frequently analyzed parameters in life science. ...Development of highly sensitive molecular probes and analytical methods for detection of these parameters is a rapidly growing sector of BioTech’s R&D industry. The aim of the present study was to develop quantum sensors for tracking the TRC and/or OxiStress in living biological objects using electron-paramagnetic resonance (EPR), magnetic resonance imaging (MRI), and optical imaging. We describe a two-set sensor system: (i) TRC sensor QD@CD-TEMPO and (ii) OxiStress sensor QD@CD-TEMPOH. Both redox sensors are composed of small-size quantum dots (QDs), coated with multinitroxide-functionalized cyclodextrin (paramagnetic CD-TEMPO or diamagnetic CD-TEMPOH) conjugated with triphenylphosphonium (TPP) groups. The TPP groups were added to achieve intracellular delivery and mitochondrial localization. Nitroxide residues interact simultaneously with various oxidizers and reducers, and the sensors are transformed from the paramagnetic radical form (QD@CD-TEMPO) into diamagnetic hydroxylamine form (QD@CD-TEMPOH) and vice-versa, because of nitroxide redox-cycling. These chemical transformations are accompanied by characteristic dynamics of their contrast features because of quenching of QD fluorescence by nitroxide radicals. The TRC sensor was applied for EPR analysis of cellular redox-status in vitro on isolated cells with different proliferative indexes, as well as for noninvasive MRI of redox imbalance and severe oxidative stress in vivo on mice with renal dysfunction.
Cancer metabolism is an extensively studied field since the discovery of the Warburg effect about 100 years ago and continues to be increasingly intriguing and enigmatic so far. It has become clear ...that glycolysis is not the only abnormally activated metabolic pathway in the cancer cells, but the same is true for the fatty acid synthesis (FAS) and mevalonate pathway. In the last decade, a lot of data have been accumulated on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. In this article, we discuss how mFAO can escape normal regulation under certain conditions and be overactivated. Such abnormal activation of mitochondrial β-oxidation can also be combined with mutations in certain enzymes of the Krebs cycle that are common in cancer. If overactivated β-oxidation is combined with other common cancer conditions, such as dysfunctions in the electron transport complexes, and/or hypoxia, this may alter the redox state of the mitochondrial matrix. We propose the idea that the altered mitochondrial redox state and/or inhibited Krebs cycle at certain segments may link mitochondrial β-oxidation to the citrate-malate shuttle instead to the Krebs cycle. We call this abnormal metabolic condition “β-oxidation shuttle”. It is unconventional mFAO, a separate metabolic pathway, unexplored so far as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and ultimately a source of proliferation. It is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathway.
Liquid chromatography/electrospray ionization–tandem mass spectrometry (LC/ESI-MS/MS) enables the accurate and precise quantification of various analytes at very low concentrations, but it has room ...for improvement in analysis throughput. Multiplexing of samples in the same injection could be a promising procedure for enhancing the analysis throughput. This could be achieved by derivatization of the multiple samples with multiple isotopologous reagents. In this study, a sample-multiplexed LC/ESI-MS/MS assay using the 1-(4-dimethylaminophenyl)carbonylpiperazine (DAPPZ) isotopologues (2H0-, 2H3-, and 2H6-forms) was developed and validated for the simultaneous determination of primary bile acids in three different plasma samples in a single run. The developed method had satisfactory intra- and inter-assay precisions (≤ 2.3 and ≤ 4.2%, respectively) and accuracy (99.0 – 100.3%), and could reduce the total LC/ESI-MS/MS run time by more than 60% for 42 samples compared to the conventional method. Thus, the derivatization with the DAPPZ isotopologues worked well for enhancing the throughput of the LC/ESI-MS/MS assay of the bile acids.
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