Three multicentre studies of reference intervals were conducted recently in Japan. The Committee on Common Reference Intervals of the Japan Society of Clinical Chemistry sought to establish common ...reference intervals for 40 laboratory tests which were measured in common in the three studies and regarded as well harmonized in Japan.
The study protocols were comparable with recruitment mostly from hospital workers with body mass index ≤28 and no medications. Age and sex distributions were made equal to obtain a final data size of 6345 individuals. Between-subgroup differences were expressed as the SD ratio (between-subgroup SD divided by SD representing the reference interval). Between-study differences were all within acceptable levels, and thus the three datasets were merged.
By adopting SD ratio ≥0.50 as a guide, sex-specific reference intervals were necessary for 12 assays. Age-specific reference intervals for females partitioned at age 45 were required for five analytes. The reference intervals derived by the parametric method resulted in appreciable narrowing of the ranges by applying the latent abnormal values exclusion method in 10 items which were closely associated with prevalent disorders among healthy individuals. Sex- and age-related profiles of reference values, derived from individuals with no abnormal results in major tests, showed peculiar patterns specific to each analyte.
Common reference intervals for nationwide use were developed for 40 major tests, based on three multicentre studies by advanced statistical methods. Sex- and age-related profiles of reference values are of great relevance not only for interpreting test results, but for applying clinical decision limits specified in various clinical guidelines.
Oxidative damage results in protein modification and is observed in many diseases, such as heart failure and renal insufficiency. Human serum albumin is an index of oxidative change and is ...conventionally measured using high-performance liquid chromatography (HPLC). Although this method is more sensitive than the colorimetric method, it is time-consuming for clinical practice and the sera must be stored at –80°C before analysis. To overcome these limitations, in the present study we developed a new reagent for a more rapid and convenient quantification of oxidative stress, involving determination of the ratio of human nonmercaptalbumin to total albumin using a colorimetric method with bromocresol purple. The clinical utility of the developed reagent was confirmed by demonstrating the consistently higher oxidative stress levels in dialysis patients than in healthy control subjects, matching the results of the conventional HPLC method. This novel approach could be a valuable tool for immediate estimation of the state of oxidative stress during the course of disease and treatment, and could aid clinical treatment decisions.
Patients with congenital protein S (PS) deficiency show a hereditary predisposition for thrombosis, and PS deficiency is prevalent among Japanese populations. Diagnosis is based on symptoms of ...thrombosis and reduced PS activity. Three reagents that use different measurement principles for determining PS activity are available in Japan. This study aimed to confirm the possibility of harmonization of these three reagents to establish a universal standard for PS activity in Japanese populations. Commercial normal plasma and plasma samples obtained from healthy individuals and healthy pregnant women were tested at three facilities using three reagents for measuring PS: STA-Staclot Protein S (STA-PS), HemosIL Protein S (Clotting) (IL-PS), and a total PS assay (SNT-PS). The within-run precision of each reagent was good, as each had a coefficient of variation of ≤ 3.8%. The dilution linearity for each reagent was also good. The correlation coefficient was 0.94 for STA-PS vs. IL-PS, 0.93 for SNT-PS vs. STA-PS, and 0.90 for SNT-PS vs. IL-PS, indicating a good correlation. Although the three reagents available in Japan for measuring PS activity use different measurement methods, each showed good performance, and large differences were not observed between the obtained values. Harmonization among them appears possible.
Chemical acetylation is postulated to occur in mitochondria. Mitochondrial transcription factor A (TFAM or mtTFA), a mitochondrial transcription initiation factor as well as the major mitochondrial ...nucleoid protein coating the entire mitochondrial genome, is proposed to be acetylated in animals and cultured cells. This study investigated the properties of human TFAM, in conjunction with the mechanism and effects of TFAM acetylation in vitro. Using highly purified recombinant human TFAM and 3 kb circular DNA as a downsized mtDNA model, we studied how the global TFAM–DNA interaction is affected/regulated by the quantitative TFAM–DNA relationship and TFAM acetylation. Results showed that the TFAM–DNA ratio strictly affects the TFAM property to unwind circular DNA in the presence of topoisomerase I. Mass spectrometry analysis showed that in vitro chemical acetylation of TFAM with acetyl-coenzyme A occurs preferentially on specific lysine residues, including those reported to be acetylated in exogenously expressed TFAM in cultured human cells, indicating that chemical acetylation plays a crucial role in TFAM acetylation in mitochondria. Intriguingly, the modification significantly decreased TFAM’s DNA-unwinding ability, while its DNA-binding ability was largely unaffected. Altogether, we propose TFAM is chemically acetylated in vivo, which could change mitochondrial DNA topology, leading to copy number and gene expression modulation.
•A case-control blood biomarker study for drug-free MDD.•We classified all the subjects into three groups by personality traits.•Classification improved discriminating MDD patients from healthy ...subjects.•Plasma tryptophan, serotonin, and kynurenine may be biased by personality traits.•Plasma sarcosine, serine and alanine may be independent from personality traits.
The relationship between depression and personality has long been suggested, however, biomarker investigations for depression have mostly overlooked this connection.
We collected personality traits from 100 drug-free patients with major depressive disorders (MDD) and 100 healthy controls based on the Five-Factor Model (FFM) such as Neuroticism (N) and Extraversion (E), and also obtained 63 plasma metabolites profiles by LCMS-based metabolome analysis.
Partitional clustering analysis using the NEO-FFI data classified all subjects into three major clusters. Eighty-six subjects belonging to Cluster 1 (C1: less personality-biased group) constituted half of MDD patients and half of healthy controls. C2 constituted 50 subjects mainly MDD patients (N high + E low), and C3 constituted 64 subjects mainly healthy subjects (N low + E high). Using metabolome information, the machine learning model was optimized to discriminate MDD patients from healthy controls among all subjects and C1, respectively. The performance of the model for all subjects was moderate (AUC = 0. 715), while the performance was extremely improved when limited to C1 (AUC = 0. 907). Tryptophan-pathway plasma metabolites including tryptophan, serotonin and kynurenine were significantly lower in MDD patients especially among C1. We also validated metabolomic findings using a social-defeat mice model of stress-induced depression.
A case-control study design and sample size is not large.
Our results suggest that personality classification enhances blood biomarker analysis for MDD patients and further translational investigations should be conducted to clarify the biological relationship between personality traits, stress and depression.
Some mutations of the DHODH (dihydro-orotate dehydrogenase) gene lead to postaxial acrofacial dysostosis or Miller syndrome. Only DHODH is localized at mitochondria among enzymes of the de novo ...pyrimidine biosynthesis pathway. Since the pyrimidine biosynthesis pathway is coupled to the mitochondrial RC (respiratory chain) via DHODH, impairment of DHODH should affect the RC function. To investigate this, we used siRNA (small interfering RNA)-mediated knockdown and observed that DHODH knockdown induced cell growth retardation because of G₂/M cell-cycle arrest, whereas pyrimidine deficiency usually causes G₁/S arrest. Inconsistent with this, the cell retardation was not rescued by exogenous uridine, which should bypass the DHODH reaction for pyrimidine synthesis. DHODH depletion partially inhibited the RC complex III, decreased the mitochondrial membrane potential, and increased the generation of ROS (reactive oxygen species). We observed that DHODH physically interacts with respiratory complexes II and III by IP (immunoprecipitation) and BN (blue native)/SDS/PAGE analysis. Considering that pyrimidine deficiency alone does not induce craniofacial dysmorphism, the DHODH mutations may contribute to the Miller syndrome in part through somehow altered mitochondrial function.
Human ATP-dependent Lon protease (LONP1) forms homohexameric, ring-shaped complexes. Depletion of LONP1 causes aggregation of a broad range of proteins in the mitochondrial matrix and decreases the ...levels of their soluble forms. The ATP hydrolysis activity, but not protease activity, of LONP1 is critical for its chaperone-like anti-aggregation activity. LONP1 forms a complex with the import machinery and an incoming protein, and protein aggregation is linked with matrix protein import. LONP1 also contributes to the degradation of imported, aberrant, unprocessed proteins using its protease activity. Taken together, our results show that LONP1 functions as a gatekeeper for specific proteins imported into the mitochondrial matrix.
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disorder caused by overnutrition and can lead to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The ...transcription factor Forkhead box K1 (FOXK1) is implicated in regulation of lipid metabolism downstream of mechanistic target of rapamycin complex 1 (mTORC1), but its role in NAFLD-NASH pathogenesis is understudied. Here, we show that FOXK1 mediates nutrient-dependent suppression of lipid catabolism in the liver. Hepatocyte-specific deletion of Foxk1 in mice fed a NASH-inducing diet ameliorates not only hepatic steatosis but also associated inflammation, fibrosis, and tumorigenesis, resulting in improved survival. Genome-wide transcriptomic and chromatin immunoprecipitation analyses identify several lipid metabolism-related genes, including Ppara, as direct targets of FOXK1 in the liver. Our results suggest that FOXK1 plays a key role in the regulation of hepatic lipid metabolism and that its inhibition is a promising therapeutic strategy for NAFLD-NASH, as well as for HCC.
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•FOXK1 deficiency in the liver ameliorates NAFLD-NASH pathogenesis•Hepatic FOXK1 deficiency also alleviates NASH-associated HCC and improves survival•FOXK1 suppresses fatty acid oxidation in an mTORC1-dependent manner•Inhibition of FOXK1 is a promising therapeutic approach for NASH
Fujinuma et al. show that FOXK1 suppresses hepatic fatty acid oxidation in an mTORC1-dependent manner and its ablation attenuates the pathogenesis of NAFLD-NASH, as well as consequent cirrhosis and hepatocarcinogenesis, by enhancing lipid catabolism in hepatocytes.
•Metabolomics of repetitive transcranial magnetic stimulation (rTMS) for depression.•Analysis of changes in 72 metabolites of cerebrospinal fluid (CSF) by rTMS.•rTMS significantly increased CSF ...niacinamide, kynurenine, and creatinine levels.•rTMS significantly decreased CSF cystine levels.
Repetitive transcranial magnetic stimulation (rTMS) improves depressive symptoms in treatment-resistant depression (TRD). This study aimed to analyze changes in cerebrospinal fluid (CSF) metabolites in patients with TRD after rTMS. Five patients with TRD were enrolled in a high frequency (10-Hz) rTMS study. The concentration of 72 CSF metabolites were measured at baseline and at the end of the 6-week rTMS treatment. rTMS significantly increased CSF niacinamide, kynurenine, and creatinine levels and significantly decreased CSF cystine levels, but not the levels of the other 68 CSF metabolites. This is the first CSF metabolomics study on patients with TRD who underwent rTMS.
The quantitative assay of protein S can help in rapidly identifying carriers of abnormal protein S molecules through a simple procedure (by determining the total protein S mass, total protein S ...activity, and protein S-specific activity in blood), without genetic testing. To clarify the relationship between venous thromboembolism (VTE) and protein S-specific activity, and its role in the diagnosis of thrombosis in Japanese persons, the protein S-specific activity was measured and compared between patients with thrombosis and healthy individuals. The protein S-specific activity of each participant was calculated from the ratio of total protein S activity to total protein S antigen level. Plasma samples were collected from 133 healthy individuals, 57 patients with venous thrombosis, 118 patients with arterial thrombosis, and 185 non-thrombotic patients. The protein S-specific activity of one-third of the patients with VTE was below the line of Y = 0.85X (−2 S.D.). Most protein S activities in the plasma of non-thrombotic patients were near the Y = X line, as observed in healthy individuals. In conclusion, it was clearly shown that monitoring protein S activity and protein S-specific activity in blood is useful for predicting the onset and preventing venous thrombosis in at least the Japanese population.
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