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"Saito, Satoru"
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Impact of Sarcopenia on Non-Alcoholic Fatty Liver Disease
With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) and the aging of the population, sarcopenia is attracting attention as one of the pathological conditions involved in the development and progression of NAFLD. In NAFLD, sarcopenia is closely associated with insulin resistance and results from the atrophy of skeletal muscle, an insulin target organ. In addition, inflammatory cytokines that promote skeletal muscle protein breakdown, low adiponectin levels leading to decreased insulin sensitivity, and hyperleptinemia are also involved in NAFLD pathogenesis. The presence of sarcopenia is a prognostic factor and increases the risk of mortality in patients with cirrhosis and post-treatment liver cancer. Sarcopenia, the presence of which mainly occurs due to decreased muscle mass, combined with increased visceral fat, can lead to sarcopenia-associated obesity, which increases the risk of NASH, liver fibrosis, and cardiovascular disease. In order to treat sarcopenia, it is necessary to properly evaluate sarcopenia status. Patients with high BMI, as in sarcopenic obesity, may improve with caloric restriction. However, inadequate oral intake may lead to further loss of muscle mass. Aerobic and resistance exercise should also be used appropriately.
Journal Article
Risk of cardiovascular disease in patients with fatty liver disease as defined from the metabolic dysfunction associated fatty liver disease or nonalcoholic fatty liver disease point of view: a retrospective nationwide claims database study in Japan
BackgroundNonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction associated fatty liver disease (MAFLD) have important associations with cardiovascular disease (CVD). The main objective of this study was to compare the frequency of incidence rate of CVD in the NAFLD or MAFLD patients utilizing a large claims database.MethodsUsing the JMDC database from April 2013 to March 2019, we retrospectively analyzed data for 1,542,688 and 2,452,949 people to estimate the relationship between CVD and NAFLD, MAFLD, respectively.ResultsThe incidence rates of CVD were 0.97 (95% CI 0.94–1.01) and 2.82 (95% CI 2.64–3.01) per 1000 person-years in the non-NAFLD and NAFLD groups, respectively, and 1.01 (95% CI 0.98–1.03) and 2.69 (95% CI 2.55–2.83) per 1000 person-years in the non-MAFLD and MAFLD groups, respectively. The overall prevalence of hypertriglyceridemia and diabetes mellitus (DM) was 13.1, and 4.2%, respectively, in the non-NAFLD group and 63.6, and 20.2%, respectively, in the NAFLD group. The overall prevalenceof hypertriglyceridemia and DM was 13.6 and 4.3%, respectively, in the non-MAFLD group and 64.1, and 20.6%, respectively, in the MAFLD group. HRs for CVD increased with hypertriglyceridemia and DM.ConclusionsResults indicated that incident rate of CVD increased with NAFLD/MAFLD; the complication rate of DM and hypertriglyceridemia among NAFLD/MAFLD patients is high and may affect the development of CVD.
Journal Article
The Selective SGLT2 Inhibitor Ipragliflozin Has a Therapeutic Effect on Nonalcoholic Steatohepatitis in Mice
In recent years, nonalcoholic steatohepatitis (NASH) has become a considerable healthcare burden worldwide. Pathogenesis of NASH is associated with type 2 diabetes mellitus (T2DM) and insulin resistance. However, a specific drug to treat NASH is lacking. We investigated the effect of the selective sodium glucose cotransporter 2 inhibitor (SGLT2I) ipragliflozin on NASH in mice.
We used the Amylin liver NASH model (AMLN), which is a diet-induced model of NASH that results in obesity and T2DM. AMLN mice were fed an AMLN diet for 20 weeks. SGLT2I mice were fed an AMLN diet for 12 weeks and an AMLN diet with 40 mg ipragliflozin/kg for 8 weeks.
AMLN mice showed steatosis, inflammation, and fibrosis in the liver as well as obesity and insulin resistance, features that are recognized in human NASH. Ipragliflozin improved insulin resistance and liver injury. Ipragliflozin decreased serum levels of free fatty acids, hepatic lipid content, the number of apoptotic cells, and areas of fibrosis; it also increased lipid outflow from the liver.
Ipragliflozin improved the pathogenesis of NASH by reducing insulin resistance and lipotoxicity in NASH-model mice. Our results suggest that ipragliflozin has a therapeutic effect on NASH with T2DM.
Journal Article
Asymmetric negative transfer effects of working memory training
Gathercole et al. (
Journal of Memory and Language
,
105
, 19–42,
2019
) presented a cognitive routine framework for explaining the underlying mechanisms of working memory (WM) training and transfer. This framework conceptualizes training-induced changes as the acquisition of novel cognitive routines similar to learning a new skill. We further infer that WM training might not always generate positive outcomes because previously acquired routines may affect subsequent task performance in various ways. Thus, the present study aimed to demonstrate the negative effects of WM training via two experiments. We conducted Experiment 1 online using a two-phase training paradigm with only three training sessions per phase and replicated the key findings of Gathercole and Norris (
in prep
.) that training on a backward circle span task (a spatial task) transferred negatively to subsequent training on a backward letter span task (a verbal task). We conducted Experiment 2 using a reversed task order design corresponding to Experiment 1. The results indicated that the transfer from backward letter training to backward circle training was not negative, but rather weakly positive, suggesting that the direction of the negative transfer effect is asymmetric. The present study therefore found that a negative transfer effect can indeed occur under certain WM training designs. The presence of this asymmetric effect indicates that backward circle and backward letter tasks require different optimal routines and that the locus of negative transfer might be the acquisition process of such optimal routines. Hence, the routines already established for backward circle might hinder the development of optimal routines for backward letter, but not vice versa.
Journal Article
Prediction of outcomes in patients with metabolic dysfunction-associated steatotic liver disease based on initial measurements and subsequent changes in magnetic resonance elastography
Background
The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with liver fibrosis. We aimed to investigate whether liver stiffness measurement (LSM) and changes in LSM (ΔLSM) on magnetic resonance elastography (MRE) can predict clinical events in patients with MASLD.
Methods
We included 405 patients with MASLD who underwent at least two MREs. The patients were divided into five groups corresponding to fibrosis stages (0–4) based on initial LSM and classified as progressors (ΔLSM ≥ 19%) or non-progressors (ΔLSM < 19%) based on the difference between the first and last LSM.
Results
The mean follow-up period was 72.6 months, and the mean interval between MREs was 23.5 months. There were 52 (12.8%) progressors and 353 (87.2%) non-progressors. The initial LSM was significantly associated with the cumulative probabilities of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related events, extrahepatic malignancies, and overall mortality but not with cardiovascular disease. Progressors had significantly higher hazard ratios (HRs) for decompensated cirrhosis, HCC, and liver-related events but not for extrahepatic malignancies, cardiovascular disease, or overall mortality. Among patients without cirrhosis, the HR for developing cirrhosis among progressors was 60.15. Progressors had a significantly higher risk of liver-related events, even in the low initial LSM (fibrosis stage 0–2) subgroups.
Conclusions
Both initial LSM and ΔLSM can predict liver-related events in patients with MASLD, even for low initial LSM. This integrated assessment can allow more detailed risk stratification compared with single LSM assessments and identify high-risk patients with MASLD among those previously considered as low risk.
Journal Article
The Hebb repetition effect in complex span tasks: Evidence for a shared learning mechanism with simple span tasks
The Hebb repetition effect on serial-recall task refers to the improvement in the accuracy of recall of a repeated list (e.g., repeated in every 3 trials) over random non-repeated lists. Previous research has shown that both temporal position and neighboring items need to be the same on each repetition list for the Hebb repetition effect to occur, suggesting chunking as one of its underlying mechanisms. Accordingly, one can expect absence of the Hebb repetition effect in a complex span task, given that the sequence is interrupted by distractors. Nevertheless, one study by Oberauer, Jones, and Lewandowsky (
2015
,
Memory & Cognition
,
43
[6], 852–865) showed evidence of the Hebb repetition effect in a complex span task. Throughout four experiments, we confirmed the Hebb repetition effect in complex span tasks, even when we included distractors in both encoding and recall phases to avoid any resemblance to a simple span task and minimized the possibility of chunking. Results showed that the Hebb repetition effect was not affected by the distractors during encoding and recall. A transfer cycle analysis showed that the long-term knowledge acquired in the complex span task can be transferred to a simple span task. These findings provide the first insights on the mechanism behind the Hebb repetition effect in complex span tasks; it is at least partially based on the same mechanism that improves recall performance by repetition in simple span tasks.
Journal Article
Involvement of Periodontal Disease in the Pathogenesis and Exacerbation of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis: A Review
The increasing incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), along with global lifestyle changes, requires further in-depth research to elucidate the mechanisms and develop new treatment strategies. In addition, the number of patients with periodontal disease has increased recently, suggesting that periodontal disease is sometimes associated with systemic conditions. In this review, we summarize recent studies linking periodontal disease and NAFLD, the concept of the mouth–gut–liver axis, oral and intestinal microbiota, and liver disease. We suggest new research directions toward a detailed mechanistic understanding and novel targets for treatment and prevention. Forty years have passed since the concepts of NAFLD and NASH were first proposed. however, no effective prevention or treatment has been established. We also found that the pathogenesis of NAFLD/NASH is not limited to liver-related diseases but has been reported to be associated with various systemic diseases and an increasing number of causes of death. In addition, changes in the intestinal microbiota have been shown to be a risk factor for periodontal diseases, such as atherosclerosis, diabetes, rheumatoid arthritis, nonalcoholic fatty liver disease, and obesity.
Journal Article
Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis
The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.
Journal Article
Palmitate-induced lipotoxicity is crucial for the pathogenesis of nonalcoholic fatty liver disease in cooperation with gut-derived endotoxin
Although previous studies have indicated important roles of palmitate, a saturated fatty acid, in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), it remains unclear how palmitate contributes to inflammation and fibrosis in the liver. Administration of palmitate in high fat diet (HFD)-fed but not basal diet (BD)-fed mice resulted in an increase in serum alanine aminotransferase (ALT) levels. Surprisingly, combined administration of very low dose lipopolysaccharide in palmitate-treated mice led to a marked increase in serum ALT levels despite BD-fed conditions. Administration of palmitate alone in BD-fed mice caused inflammatory cell infiltration and liver fibrosis mediated by the toll-like receptor 4 pathway without ALT elevation. In addition, a significant correlation between serum free fatty acid levels and liver fibrosis stage was observed in patients with NAFLD. These results indicate that palmitate may play crucial roles in the pathogenesis of NAFLD in the presence of gut-derived endotoxin.
Journal Article