Search

Obesity appears to be a major contributing factor for many health problems. Effective treatments for reducing weight gain, other than caloric restriction and exercise, are limited. The consumption of sugars is a major factor in the development of obesity in part by stimulating the transcription factor, carbohydrate response element binding protein (ChREBP), a process that is driven by

Cancer pain is a significant issue in terminally ill cancer patients (TICPs). The fentanyl patch (FP) is used extensively for treating cancer pain, but FP requirements vary between patients. We aimed to identify determinants of FP requirements in TICPs and propose effective pain relief using a FP. In a retrospective chart review, we investigated cancer patients admitted to our hospital from April 2012 to July 2015 and used FP until death. The time course of FP use in TICPs until death was examined. The primary endpoint was the final dose of FP use (FDFP). In total, 79 patients were included the analysis. FDFP was inversely correlated with age (R= -0.262

The carbohydrate response element‐binding protein (ChREBP), a glucose‐responsive transcription factor that plays a critical role in the glucose‐mediated induction of genes involved in hepatic glycolysis and lipogenesis, exists as two isoforms: ChREBPα and ChREBPβ. However, the mechanism responsible for regulating the expression of both ChREBPα and β, as well as the mechanism that determines which specific isoform is more responsive to different stimuli, remains unclear. To address this issue, we compared the effects of several stimuli, including oxidative stress, on the mRNA and protein expression levels of ChREBPα and β in the hepatocyte cell line, HepG2. We found that H2O2 stimulation suppressed the expression of both mRNA and protein in HepG2 cells, but the mRNA expression level of ChREBPβ was, The carbohydrate response element binding protein (ChREBP) is a glucose‐responsive transcription factor that strongly regulates glycolysis and lipogenesis. In this study, we showed that oxidative stress, including STS and TPA treatment, suppressed the expression of both ChREBPα and β through activation of ERK signaling in HepG2 cells.

Post-exposure prophylaxis (PEP) for healthcare workers is one of the effective strategies for preventing nosocomial outbreaks of influenza. However, PEP adherence in healthcare workers is rarely analysed, and no strategies have been established to improve adherence to PEP for healthcare workers. We aimed to retrospectively analyse adherence to PEP and the factors associated with non-adherence in healthcare workers. A survey of 221 healthcare workers who were eligible for PEP at Tokushima University Hospital in the 2016/2017 season was conducted. Once-daily oseltamivir (75 mg for 10 d) was used as the PEP regimen. Of the 221 healthcare workers, 175 received PEP and were surveyed for adherence using a questionnaire. Of the 130 healthcare workers who responded to the questionnaire, 121 (93.1%) had been vaccinated. In this survey, 82 healthcare workers (63.1%) did not fully complete PEP. Multiple logistic regression analysis revealed that physicians (odds ratio: 4.62, 95% confidence interval [CI]: 2.08-10.25) and non-vaccination (odds ratio: 9.60, 95% CI: 1.12-82.25) were the factors for non-adherence to PEP. Of the 47 healthcare workers who responded to the item regarding reasons for non-adherence, 36 (76.6%) reported forgetting to take oseltamivir or discontinuing it due to a misguided self-decision that continuation of PEP was unnecessary, and 5 (10.6%) reported discontinuing treatment due to adverse effects. In conclusion, healthcare workers, particularly physicians, had low PEP adherence owing to forgetting or stopping to take oseltamivir due to a misguided self-decision. To obtain the maximum preventive effect of PEP, medication education should be provided to endorse PEP compliance.

Immune checkpoint inhibitor‐induced diabetes mellitus is a rare immune‐related adverse event. This report illustrates clinical data and insulin secretory ability before and after the onset of immune checkpoint inhibitor‐induced diabetes.

Viet Nam is currently one of the most dynamic economies increasing greenhouse gas (GHG) emissions. The country faces multiple challenges such as meeting energy demand, changing the energy mix as well as responding to climate change. In order to address how policies can contribute to creating synergies between climate change and the sustainable development goals (SDGs), this chapter focuses on SDG7 (affordable and clean energy). More concretely, key questions are how Viet Nam plans to achieve transition to green growth by scaling up renewable energy and where major barriers lie. Based on the recent progress in this policy area, it considers prospects for closer cooperation on sustainable development, climate change and renewable energy between the EU and Viet Nam.

The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that increases the transcription of multiple genes. ChREBP is highly localized in the liver, where it upregulates the expression of genes that code for glycolytic and lipogenic enzymes, resulting in the conversion of excess carbohydrate into storage fat. ChREBP knockout (KO) mice display an anti-obese phenotype. However, at this time, role of ChREBP in adipose tissue remains unclear. Therefore, the energy metabolism and morphology of mitochondrial brown adipose tissue (BAT) in ChREBP KO mice was examined. We found increased expression levels of electron transport system proteins including the mitochondrial uncoupling protein (UCP1), and mitochondrial structural alterations such as dysplasia of the cristae and the presence of small mitochondria in BAT of ChREBP KO mice. Mass spectrometry analyses revealed that fatty acid synthase was absent in the BAT of ChREBP KO mice, which probably led to a reduction in fatty acids and cardiolipin, a regulator of various mitochondrial events. Our study clarified the new role of ChREBP in adipose tissue and its involvement in mitochondrial function. A clearer understanding of ChREBP in mitochondria could pave the way for improvements in obesity management.

Team-based learning (TBL) is an active learning method used in many educational institutions. However, there are few examples of its use in basic medicine, such as biochemistry in medical schools. This study used TBL to teach glucose metabolism to first-year medical students. The process was in four phases: preclass preparation, readiness assurance tests, advanced questions, and a TBL test, with peer evaluation and a questionnaire. There were positive correlations between the TBL test, peer evaluation, and individual readiness test performance. Tests were taken immediately after learning and 2 weeks later, and scores decreased significantly less with TBL than traditional lectures (-2.3% vs. -17.5%). This suggests that TBL was more effective than traditional lectures in supporting knowledge retention. We used a Moodle system to facilitate communication between students and teachers, and this was evaluated positively by both groups. It was particularly useful for managing TBL. These findings suggest that TBL could be used to improve student performance in biochemistry.

Caffeine intake is associated with a reduced risk developing non-alcoholic fatty liver disease (NAFLD), but the underlying molecular mechanisms remain to be fully elucidated. We report here that caffeine markedly improved high fat diet-induced NAFLD in mice resulting in a 10-fold increase in circulating IL-6 levels, leading to STAT3 activation in the liver. Interestingly, the expression of IL-6 mRNA was not increased in the liver, but increased substantially in the muscles of caffeine-treated mice. Caffeine was found to stimulate IL-6 production in cultured myotubes but not in hepatocytes, adipocytes, or macrophages. The inhibition of p38/MAPK abrogated caffeine-induced IL-6 production in muscle cells. Caffeine failed to improve NAFLD in IL-6 and hepatocyte-specific STAT3 knockout mice, indicating that the IL-6/STAT3 pathway is vital for the hepatoprotective effects of caffeine in NAFLD. The possibility that IL-6/STAT3-mediated hepatic autophagosome induction and hepatocytic oxygen consumption are involved in the anti-NAFLD effects of caffeine cannot be excluded, based on the findings presented here. Our results reveal that caffeine ameliorates NAFLD via crosstalk between muscle IL-6 production and liver STAT3 activation.

We identified a waterborne pseudo-outbreak of Mycobacterium chimaera in our stem cell transplantation center, which likely resulted from biofilm on the aerators of the handwashing machines in each patient’s room. Regular replacement of faucet parts can prevent biofilm formation and pseudo-outbreaks of M. chimaera through aerators.

Background Japan has an aging population and an increasing number of patients who reside in long-term care and mental health facilities. Both pneumococcal pneumonia and influenza B infection outbreaks have been observed in these populations, although no reports have described concurrent outbreaks of pneumococcal pneumonia and influenza B infection in these facilities. Case presentation Six patients and two staffs were initially diagnosed with influenza B infection at a mental health facility on March 14, 2015. By March 21, influenza B infection was diagnosed in 26 patients and 10 staff; all individuals received anti-influenza drugs. On March 19, two patients were diagnosed with pneumococcal pneumonia, and seven patients had developed pneumococcal pneumonia by March 24. Six of these seven patients also had influenza B infection. All individuals who developed pneumococcal pneumonia were hospitalized and treated using ampicillin/sulbactam at our hospital, and their symptoms subsequently subsided. Among the seven pneumococcal strains that were frozen and stored, two strains were type 3 and five strains were type 11A/E. Pulsed-field gel electrophoresis testing revealed that each of the serum types were from the same clone. Conclusion It appears that an outbreak of influenza B infection was followed by the spread of multi-clone pneumococcal pneumonia among elderly patients at a mental health facility. Therefore, it may be prudent to use vaccinations to prevent the spread of pneumococcal pneumonia among elderly patients and this diagnosis should be actively considered during outbreaks of influenza infection at elder care facilities.

We identified a waterborne pseudo-outbreak of Mycobacterium chimaera in our stem cell transplantation center, which likely resulted from biofilm on the aerators of the handwashing machines in each patient's room. Regular replacement of faucet parts can prevent biofilm formation and pseudo-outbreaks of M. chimaera through aerators.

Background Liver cancer is the fifth cause of cancer-related deaths in Japan. The BioBank Japan (BBJ) project included 200,000 patients with 47 diseases and samples; their clinical information can be used for further studies. Methods Patients diagnosed with liver cancer (n = 1733; 1316 men, 417 women) were included. Histology, patient characteristics, clinical characteristics, and causes of death were collected. Cumulative and relative survival rates for liver cancer were calculated. Results Of the 1354 patients with available liver cancer histology, 91.9% had hepatocellular carcinoma (HCC). Compared with the National Health and Nutrition Examination Survey, greater proportions of the male patients in this cohort were daily alcohol consumers (26%), and a greater proportion of the men was overweight/obesity (22%). Although Japan is the only Asian country with a predominance of hepatitis C virus (HCV)-related HCC, the prevalence of HCV infection (44%) was lower than that in a previous study. The 3-, 5-, and 10-year cumulative survival rates were 57%, 47%, and 25% in men, respectively, and 49%, 41%, and 27% in women, respectively. Conclusions The present results provide an overview of the patients with liver cancer in the BBJ project. We are planning further analyses combined with various high-throughput ‘omics’ technologies., Highlights • Liver cancer is the second leading cause of death worldwide. • We aimed to provide an overview of patients with liver cancer. • Based on liver cancer histology, 91.9% had hepatocellular carcinoma. • The 10-year relative survival rates were 34% in men and 38% in women. • Future studies will help develop preventive programs for liver cancer.

Background The aim of the present study was to evaluate spleen volume (SV) and the factors influencing it after adult-to-adult living donor liver transplantation (A2LDLT) using a left lobe. Methods Pretransplant computed tomography (CT) and post-transplant CT 2 years after A2LDLT were examined by volumetric analysis in 24 patients. We divided the recipients into the following 2 groups according to the post-transplant SV: >500 mL (Group A) and ≤500 mL (Group B). The factors affecting the change in post-transplant SV were compared between the 2 groups. Results The mean pretransplant SV decreased significantly after A2LDLT. Platelet counts after living donor liver transplantation increased significantly relative to the pretransplant values. Post-transplant SV was >500 mL in 9 patients (Group A) and ≤500 mL in 15 (Group B). Pretransplant SV, platelet count, anhepatic time, operative time, intraoperative blood loss, post-transplant portal vein pressure >20 mm Hg, and post-transplant portal vein flow >250 mL/min/100 g graft weight showed significant differences between the 2 groups. Actual graft volume (GV) and GV/standard liver volume ratio showed no intergroup differences. Multivariate analysis showed that the only significant factor related to a post-transplant SV of >500 mL was the pretransplant SV. Post-transplant platelet counts were significantly increased from the pretransplant values in both Group A and Group B. Conclusions Pretransplant SV is the only significant factor predicting a SV of >500 mL after A2LDLT. However, even in patients with a SV of >500 mL, the platelet count increased significantly from the pretransplant value.

University lectures are mainly passive in nature, and there are few subjects in which students need to learn and function independently. Tutorial education and related activities at universities that specialize in medical and pharmaceutical training have been actively carried out, and lectures in conjunction with practical skills are gradually being developed, although progress has been slow in this area. In past years, our biochemistry practice classes have been evaluated in reports dealing with experiments and written examinations, as is done in other universities. However, using this methodology, we are not able to evaluate the extent to which students master biochemical experimental skills. To address this, we introduced a basic skill test to our biochemical curriculum for the first time. Our exams contributed to a deeper understanding of student skills and could be good tools for evaluating the degree of understanding of the students. The students understood the contents of the training well and felt interested in research in the field of basic medicine. Thus, we conclude that introducing practical testing to biochemical practice was effective for medical students in the field of biochemistry. © 2019 International Union of Biochemistry and Molecular Biology, 47(3):279-287, 2019.

Under certain conditions, amyloid-like fibrils can develop into three-dimensional networks and form hydrogels by a self-assembly process. When Cu/Zn superoxide dismutase (SOD1), an anti-oxidative enzyme, undergoes misfolding, fibrillar aggregates are formed, which are a hallmark of a certain form of familial amyotrophic lateral sclerosis (ALS). However, the issue of whether SOD1 fibrils can be assembled into hydrogels remains to be tested. Here, we show that the SOD1 polypeptides undergo hydrogelation accompanied by the formation of thioflavin T-positive fibrils at pH 3.0 and 4.0, but not at pH 5.0 where precipitates are formed. The results of viscoelastic analyses indicate that the properties of SOD1 hydrogels (2%) were similar to and slightly more fragile than a 0.25% agarose gel. In addition, monitoring by a quartz crystal microbalance with admittance analysis showed that the denaturing of immobilized SOD1 on a sensor under the hydrogelation conditions at pH 3.0 and 4.0 resulted in an increase in the effective acoustic thickness from ~3.3 nm (a folded rigid form) to ~50 and ~100 nm (an extended water-rich state), respectively. In contrast, when SOD1 was denatured under the same conditions at pH 5.0, a compact water-poor state with an effective acoustic thickness of ~10 nm was formed. The addition of physiological concentrations of NaCl to the pH 4.0 sample induced a further extension of the SOD1 with larger amounts of water molecules (with an effective acoustic thickness of ~200 nm) but suppressed hydrogel formation. These results suggest that different denatured intermediate states of the protein before self-assembly play a major role in determining the characteristics of the resulting aggregates and that a conformational change to a suitable level of extended water-rich intermediate state before and/or during intermolecular assembling is required for fibrillation and hydrogelation in the case of globular proteins.

Aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological signature of amyotrophic lateral sclerosis (ALS). Although accumulating evidence suggests the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy, it remains unclear how native TDP-43 is converted to pathogenic forms. To elucidate the role of homeostasis of RRM1 structure in ALS pathogenesis, conformations of RRM1 under high pressure were monitored by NMR. We first found that RRM1 was prone to aggregation and had three regions showing stable chemical shifts during misfolding. Moreover, mass spectrometric analysis of aggregated RRM1 revealed that one of the regions was located on protease-resistant β-strands containing two cysteines (Cys-173 and Cys-175), indicating that this region served as a core assembly interface in RRM1 aggregation. Although a fraction of RRM1 aggregates comprised disulfide-bonded oligomers, the substitution of cysteine(s) to serine(s) (C/S) resulted in unexpected acceleration of amyloid fibrils of RRM1 and disulfide-independent aggregate formation of full-length TDP-43. Notably, TDP-43 aggregates with RRM1-C/S required the C terminus, and replicated cytopathologies of ALS, including mislocalization, impaired RNA splicing, ubiquitination, phosphorylation, and motor neuron toxicity. Furthermore, RRM1-C/S accentuated inclusions of familial ALS-linked TDP-43 mutants in the C terminus. The relevance of RRM1-C/S-induced TDP-43 aggregates in ALS pathogenesis was verified by immunolabeling of inclusions of ALS patients and cultured cells overexpressing the RRM1-C/S TDP-43 with antibody targeting misfolding-relevant regions. Our results indicate that cysteines in RRM1 crucially govern the conformation of TDP-43, and aberrant self-assembly of RRM1 at amyloidogenic regions contributes to pathogenic conversion of TDP-43 in ALS. Background: The role of RRM1 in the pathogenesis of TDP-43 proteinopathy is unclear. Results: RRM1 was aggregate-prone, mediated by a self-assembly at newly identified amyloidogenic β-strands containing cysteines; cysteine substitution(s) replicated diverse cytopathologies of TDP-43 in ALS. Conclusion: RRM1 misfolding may underlie TDP-43 proteinopathy. Significance: This study proposes a novel mechanism and a new in vitro model for TDP-43 proteinopathy.

BACKGROUND Intractable ascites is one of the causes of graft loss after adult-to-adult living donor liver transplantation (LDLT) using a small graft. Identification of factors associated with increasing posttransplant ascites has important implications for prevention and treatment. METHODS All 59 consecutive adult patients who underwent left lobe LDLT without portal inflow modulation between October 2002 and February 2016 were prospectively enrolled. Factors associated with the average daily amount of ascites for 2 weeks after LDLT were assessed. RESULTS The median daily amount of ascites during the 2 weeks was 1052 mL (range, 52-3480 mL). Although 16 of the 59 patients developed intractable ascites, exceeding 1500 mL daily (massive ascites group), the remaining 43 patients produced less than 1500 mL of ascites daily (nonmassive ascites group). The presence of pretransplant ascites (P = 0.001), albumin (P = 0.011), albumin/globulin ratio (P = 0.026), cold ischemia time (P = 0.004), operation time (P = 0.022), and pretransplant portal vein pressure (PVP) (P = 0.047) differed significantly between the 2 groups. Neither posttransplant PVP nor portal vein flow differed between the 2 groups. The variables associated with intractable ascites that remained significant after logistic regression analysis were pretransplant PVP (P = 0.047) and cold ischemia time (P = 0.049). After appropriate fluid resuscitation for intractable ascites, 58 (98%) of the 59 recipients were discharged from hospital after removal of the indwelling drains. CONCLUSIONS It is important to shorten the scold ischemia time to reduce massive ascites after LDLT. Pretransplant portal hypertension is more closely associated with ascites production than posttransplant hemodynamic status.

Copper/zinc superoxide dismutase (SOD1), a primary anti-oxidative enzyme, protects cells against oxidative stress. We report herein on a comparison of behavioral and neurobiological changes between SOD1 knockout (KO) and wild-type mice, in an attempt to assess the role of SOD1 in brain functions. SOD1 KO mice exhibited impaired motivational behavior in both shuttle-box learning and three-chamber social interaction tests. High levels of dopamine transporter protein and an acceleration of serotonin turnover were also detected in the cerebrums of the SOD1 KO mice. These findings suggest that SOD1 deficiency disturbs monoaminergic neurotransmission leading to a decrease in motivational behavior.

NMR active nuclei, 1H, 13C and 15N, are usually used for determination of protein structure. However, solution 17O-NMR application to proteins is extremely limited although oxygen is an essential element in biomolecules. Proteins are oxidized through cysteine residues by two types of oxidation. One is reversible oxidation such as disulphide bonding (Cys-S-S-Cys) and the other is irreversible oxidation to cysteine sulfinic acid (Cys-SO 2H) and cysteine sulfonic acid (Cys-SO 3H). Copper,Zinc-superoxide dismutase (SOD1) is a key enzyme in the protection of cells from the superoxide anion radical. The SH group at Cys 111 residue in human SOD1 is selectively oxidized to -SO 2H and -SO 3H with atmospheric oxygen, and this oxidized human SOD1 is also suggested to play an important role in the pathophysiology of various neurodegenerative diseases, probably mainly via protein aggregation. Therefore, information on the structural and the dynamics of the oxidized cysteine residue would be crucial for the understanding of protein aggregation mechanism. Although the -SO 3H group on proteins cannot be directly detected by conventional NMR techniques, we successfully performed the site-specific 17O-labeling of Cys 111 in SOD1 using \(^{17}\textit {O}_{2}\) gas and the 17O-NMR analysis for the first time. We observed clear 17O signal derived from a protein molecule and show that 17O-NMR is a sensitive probe for studying the structure and dynamics of the 17O-labeled protein molecule. This novel and unique strategy can have great impact on many research fields in biology and chemistry.

Background: Emergency admissions and emergency department visits (EAs/EDVs) have been used as quality indicators of home care in terminally ill cancer patients. We established a cancer transitional care (CTC) program to monitor and manage terminally ill cancer patients receiving care at home. The purpose of this study was to evaluate the effectiveness of CTC by the frequency of EAs/EDVs. Methods: In a retrospective chart review, we identified 133 patients with cancer admitted to our department, of whom 56 met study eligibility criteria. The CTC consisted of at least 1 or more following components: (1) a 24-hour hotline for general physicians or home care nurses to reach hospital-based physicians, (2) periodic phone calls from an expert hospital-based oncology nurse to home care medical staff, and (3) reports sent to our department from home care medical staff. The primary outcome variable was the frequency of EAs/EDVs. Results: There were 32 EAs/EDVs and 69 planned admissions during the observation period. In the last 30 days of life, 16 patients (28.6%) had 1 EA/EDV and none had multiple EAs/EDVs. Compared with previous studies, our study found a similar or lower frequency of EAs/EDVs. Conclusion: Our findings suggest that the implementation of CTC reduces the number of EAs/EDVs by replacing them with planned admissions. Further prospective studies to evaluate CTC are warranted.

Cu,Zn SOD1 (superoxide dismutase 1) is implicated in FALS (familial amyotrophic lateral sclerosis) through the accumulation of misfolded proteins that are toxic to neuronal cells. Loop VI (residues 102–115) of the protein is at the dimer interface and could play a critical role in stability. The free cysteine residue, Cys111 in the loop, is readily oxidized and alkylated. We have found that modification of this Cys111 with 2-ME (2-mercaptoethanol; 2-ME-SOD1) stabilizes the protein and the mechanism may provide insights into destabilization and the formation of aggregated proteins. Here, we determined the crystal structure of 2-ME-SOD1 and find that the 2-ME moieties in both subunits interact asymmetrically at the dimer interface and that there is an asymmetric configuration of segment Gly108 to Cys111 in loop VI. One loop VI of the dimer forms a 310-helix (Gly108 to His110) within a unique β-bridge stabilized by a hydrogen bond between Ser105-NH and His110-CO, while the other forms a β-turn without the H-bond. The H-bond (H-type) and H-bond free (F-type) configurations are also seen in some wild-type and mutant human SOD1s in the Protein Data Bank suggesting that they are interconvertible and an intrinsic property of SOD1s. The two structures serve as a basis for classification of these proteins and hopefully a guide to their stability and role in pathophysiology.

Converging evidence indicates that SOD1 aggregation is a common feature of mutant SOD1-linked fALS, and seems to be directly related to the gain-of-function toxic property. However, the mechanism inducing the aggregation is not understood. To study the contribution of oxidative modification of cysteine residues in SOD1 aggregation, we systematically examined the redox state of SOD1 cysteine residues in the G37R transgenic mouse model at different stages of the disease and under oxidative stress induced by H₂O₂. Our data suggest that under normal circumstance, cysteine 111 residue in SOD1 is free; however, under oxidative stress, it is prone to oxidative modification by providing the thiolate anion (S-). With the progression of the disease, increased levels of oxidative insults facilitated the oxidation of thiol groups of cysteine residues; human mutant SOD1 could generate an upper shift band in reducing SDS-PAGE, which turned out to be a Cys111-peroxidized SOD1 species. We also detected the formation of SOD1 multimers at different stages of the disease, and found that accumulated oxidative stress facilitated the formation of aggregates, which were not mediated by disulfide bond. This oxidative modification of cysteine 111 therefore promotes the formation of disulfide bond-independent aggregation of SOD1.

Micronutrient deficiencies such as vitamin A, iron, zinc, and selenium have been known to occur as a consequence of pancreaticoduodenectomy (PD), but vitamin B6 deficiency has not been previously reported. We report two post-PD patients who developed anemias attributed to vitamin B6 deficiency. Oral supplementations of vitamin B6 significantly improved anemias in both cases. Micronutrients including vitamin B6 should be monitored in post-PD patients, and supplementations should be carried out when necessary.

The oxidative modification hypothesis postulates that oxidative stress is one of the major factors in aging and the development of age-related disorders, including cardiovascular diseases. In this scenario, the oxidative modification of lipids, proteins and nucleic acids in vascular walls contributes to the etiology of cardiovascular disease, implying that consumption or therapeutic use of antioxidants could prevent the onset of such pathological disorders. Because of this, a number of studies have been conducted to address the question of whether cardiovascular diseases can be modulated by antioxidant treatment or consumption. Although some of the earliest data, collected in animal studies and epidemiologic studies have shown a measure of success, numerous clinical trials indicate that this approach is of minimal or no benefit. These conclusions represent a challenge to design more sensitive antioxidant trials in order to confirm or alter these conclusions. The focus of this review is on the benefits and disadvantages associated with the use of antioxidants, such as vitamins C and E, polyphenols, or antioxidant therapies, including hormone replacement therapy and iron reduction therapy, on overall vascular health.

Copper/zinc-superoxide dismutase (SOD1) plays a protective role in cells by catalyzing the conversion of the superoxide anion into molecular oxygen and hydrogen peroxide. Although SOD1 knockout (KO) mice exhibit a reduced life span and an elevated incidence of dysfunctions in old age, young SOD1 KO mice grow normally and exhibit no abnormalities. This fact leads to the hypothesis that other antioxidative proteins prevent oxidative stress, compensating for SOD1. Differently expressed genes in 3-week-old SOD1 KO and littermate wild-type mice were explored. A gene remarkably elevated in SOD1 KO mouse kidneys was identified as the glutathione S-transferase Alpha 4 gene (Gsta4), which encodes the GSTA4 subunit. The GSTA4 protein level and activity were also significantly increased in SOD1 KO mouse kidneys. The administration of an iron complex, a free radical generator, induced GSTA4 expression in wild-type mouse kidneys. Iron deposition detected in SOD1 KO mouse kidney is thought to be an inducer of GSTA4. In addition, overexpression of mouse GSTA4 cDNA in human embryonic kidney cells decreased cell death caused by both 4-hydroxynonenal and hydrogen peroxide. These findings suggest that compensatory induced GSTA4 plays a protective role against oxidative stress in young SOD1 KO mouse kidneys.

The serological prevalence of IgG antibody to seven NoV strains (GI.1, GI.4, GII.3, GII.4, GII.10, GII.12 and GII.15) among inhabitants aged 1-62 years of Aichi Prefecture, Japan was studied. Age-related seroprevalence was measured by ELISA using baculovirus-expressed recombinant VLP antigens. Seropositive rates for all seven VLP antigens gradually increased with age. Among the tested antigens, the highest seropositive rate was for the GII.4 strain. This result is consistent with the recent epidemic of NoV infection due to GII.4 strain in Japan.