Fasting blood glucose (FBG) and hepatic glucose production are regulated according to a circadian rhythm. An early morning increase in FBG levels, which is pronounced among diabetic patients, is ...known as the dawn phenomenon. Although the intracellular circadian clock generates various molecular rhythms, whether the hepatic clock is involved in FBG rhythm remains unclear. To address this issue, we investigated the effects of phase shift and disruption of the hepatic clock on the FBG rhythm. In both C57BL/6J and diabetic ob/ob mice, FBG exhibited significant daily rhythms with a peak at the beginning of the dark phase. Light-phase restricted feeding altered the phase of FBG rhythm mildly in C57BL/6J mice and greatly in ob/ob mice, in concert with the phase shifts of mRNA expression rhythms of the clock and glucose production–related genes in the liver. Moreover, the rhythmicity of FBG and Glut2 expression was not detected in liver-specific Bmal1-deficient mice. Furthermore, treatment with octreotide suppressed the plasma growth hormone concentration but did not affect the hepatic mRNA expression of the clock genes or the rise in FBG during the latter half of the resting phase in C57BL/6J mice. These results suggest that the hepatic circadian clock plays a critical role in regulating the daily FBG rhythm, including the dawn phenomenon.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Sustained hepatic inflammation is a key driver of the transition from simple fatty liver to ...nonalcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. Hepatic inflammation is orchestrated by chemokines, a family of chemoattractant cytokines that are produced by hepatocytes, Kupffer cells (liver resident macrophages), hepatic stellate cells, endothelial cells, and vascular smooth muscle cells. Over the last three decades, accumulating evidence from both clinical and experimental investigations demonstrated that chemokines and their receptors are increased in the livers of NAFLD patients and that CC chemokine ligand (CCL) 2 and CCL5 in particular play a pivotal role in inducing insulin resistance, steatosis, inflammation, and fibrosis in liver disease. Cenicriviroc (CVC), a dual antagonist of these chemokines’ receptors, CCR2 and CCR5, has been tested in clinical trials in patients with NASH-associated liver fibrosis. Additionally, recent studies revealed that other chemokines, such as CCL3, CCL25, CX3C chemokine ligand 1 (CX3CL1), CXC chemokine ligand 1 (CXCL1), and CXCL16, can also contribute to the pathogenesis of NAFLD. Here, we review recent updates on the roles of chemokines in the development of NAFLD and their blockade as a potential therapeutic approach.
As older adults in an early stage (prefrailty) of frailty may return to a healthy state, it is necessary to examine the prevention of prefrailty. In this context, the number and types of social ...participation activities associated with physical prefrailty in community-dwelling older adults have remained relatively unexplored. This cross-sectional study investigates this issue by analyzing 616 participants living in Okinoshima, Shimane, a rural area of Japan, in 2019. Frailty was assessed using the 5-item frailty phenotype (unintentional weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity). Data on social participation were obtained using a questionnaire based on participants' level of involvement with volunteer groups, sports clubs/groups, neighborhood associations, religious organizations/groups, and community elderly salons; their answers were categorized as "yes" if they answered "several times per year or more" and "no" if they answered "never." Binominal logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prefrailty by the number or types of social participation activities, adjusted for gender, age, body mass index, smoking, medication-taking, educational attainment, working status, and living arrangement. Of the 616 participants, 273 (44.3%) and 28 (4.5%) had prefrailty and frailty, respectively. The analysis showed that the number of social participation activities was significantly associated with lower odds of prefrailty (OR = 0.83; 95% CI, 0.74-0.94). Regarding the types of social participation, sports clubs/groups were associated with lower odds of prefrailty (OR = 0.47; 95% CI, 0.31-0.73). Participation in neighborhood associations was associated with prefrailty/frailty (OR = 0.57; 95% CI, 0.37-0.86). These results suggest that increasing the number of social participation activities or involvement in sports clubs/groups and neighborhood associations may be important to prevent physical prefrailty in the older population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drug-induced nephrotoxicity is a serious problem in patients with hospital-acquired acute kidney injury (AKI). A new renal biomarker is needed because traditional markers are not sensitive for early ...detection of drug-induced AKI. In a recent study, we demonstrated that vanin-1 is a novel candidate biomarker of nephrotoxicant-induced kidney injury. The objective of the present study is to determine whether the increase in urinary vanin-1 is detected before the elevations of serum creatinine or urinary N-acetyl-β-glucosaminidase (NAG), kidney injury molecule-1 (Kim-1), and neutrophil gelatinase-associated lipocalin (NGAL) in the two well established animal models of drug-induced AKI. After the administration of a higher dose of cisplatin (10 mg/kg, a single intraperitoneal dose) or gentamicin (120 mg/kg per day, once daily intraperitoneal dose for 9 days), urinary vanin-1 was detected earlier than the other biomarkers. In rats treated with a lower dose of cisplatin (5 mg/kg, a single intraperitoneal dose) or gentamicin (40 mg/kg per day, once daily intraperitoneal dose for 9 days), serum creatinine and urinary NAG were not changed throughout the study period, whereas urinary vanin-1, Kim-1, and NGAL were significantly increased. The renal vanin-1 protein levels were significantly decreased in rats treated with the higher dose of cisplatin on day 5 and gentamicin on day 9, and the immunofluorescence analyses confirmed that vanin-1 immunoreactivity in tubular cells was reduced with the time after the dose of cisplatin, indicating that urinary vanin-1 was leaked from tubular cells. These results suggest that, compared with urinary Kim-1 and NGAL, urinary vanin-1 is an earlier and equally sensitive biomarker for drug-induced AKI.
Glecaprevir is a substrate for organic anion-transporting polypeptide (OATP) 1B1/1B3, which transports bilirubin. Hyperbilirubinemia is an adverse event during anti-hepatitis C virus treatment with ...glecaprevir and pibrentasvir. Gadoxetic acid is also transported by OATP1B1/1B3, and we aimed to evaluate whether gadoxetic acid-enhanced magnetic resonance (MR) imaging was associated with glecaprevir trough concentrations (C
). We further determined whether this was predictive of hyperbilirubinemia development in a cohort of 33 patients. The contrast enhancement index (CEI), a measure of hepatic enhancement effect on the hepatobiliary image, was assessed. Glecaprevir C
was determined 7 days after administration. Five of the 33 patients (15%) developed Common Terminology Criteria for Adverse Events grade ≥ 2 hyperbilirubinemia. We found a negative relationship between CEI and C
(r = - 0.726, p < 0.001). The partial correlation coefficient between CEI and C
was - 0.654 (p < 0.001), while excluding the effects of albumin, FIB-4 index, and indirect bilirubin at baseline. The C
was significantly higher in patients with hyperbilirubinemia than in those without (p = 0.008). In multivariate analysis, CEI ≤ 1.71 was an independent factor influencing the development of hyperbilirubinemia (p = 0.046). Our findings indicate that gadoxetic acid MR imaging can help predict glecaprevir concentration and development of hyperbilirubinemia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Children with allergy to raw egg white might tolerate low amounts of heated egg. Ovomucoid-specific IgE antibodies have been suggested to be predictors of whether children could tolerate ...heat-treated egg. Objective The aim was to evaluate the clinical usefulness and added diagnostic value of measurements of IgE antibodies to egg white, ovalbumin, and ovomucoid in children with egg allergy. Methods One hundred eight patients (median age, 34.5 months) with suspected egg allergy underwent double-blind, placebo-controlled food challenges with raw and heated egg. The outcomes of the challenges were related to the serum concentration of specific IgE antibodies and total IgE by using ImmunoCAP. Results Reactions to heated egg white were observed in 38 patients (considered allergic to raw and heated egg), 29 patients reacted to only raw egg white, and 41 patients were tolerant. Correlation was observed between the serologic parameters studied. Receiver operating characteristic analysis showed that egg white ImmunoCAP was useful in the diagnosis of allergy to raw egg white. The positive decision point, based on 95% clinical specificity, was 7.4 kUA /L, and the negative decision point, based on 95% clinical sensitivity, was 0.6 kUA /L. For reaction to heated egg white, ovomucoid ImmunoCAP was superior. The positive decision point was 10.8 kUA /L, and the negative decision point was 1.2 kUA /L. Conclusions Quantitative measurements of specific IgE antibodies to both egg white and ovomucoid and the evaluation against the suggested positive and negative decision points for specific IgE will be useful in the diagnosis of egg allergy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Sphingosine 1-phosphate (S1P) has been implicated in brown adipose tissue (BAT) formation and energy consumption; however, the mechanistic role of sphingolipids, including S1P, in BAT remains ...unclear. Here, we showed that, in mice, BAT activation by cold exposure upregulated mRNA and protein expression of the S1P-synthesizing enzyme sphingosine kinase 1 (SphK1) and S1P production in BAT. Treatment of wild-type brown adipocytes with exogenous S1P or S1P receptor subtype-selective agonists stimulated triglyceride (TG) breakdown only marginally, compared with noradrenaline. However, genetic deletion of Sphk1 resulted in hypothermia and diminished body weight loss upon cold exposure, suggesting that SphK1 is involved in thermogenesis through mechanisms different from receptor-mediated, extracellular action of S1P. In BAT of wild-type mice, SphK1 was localized largely in the lysosomes of brown adipocytes. In the brown adipocytes of Sphk1−/− mice, the number of lysosomes was reduced and lysosomal function, including proteolytic activity, acid esterase activity, and motility, was impaired. Concordantly, nuclear translocation of transcription factor EB, a master transcriptional regulator of lysosome biogenesis, was reduced, leading to decreased mRNA expression of the lysosome-related genes in Sphk1−/− BAT. Moreover, BAT of Sphk1−/− mice showed greater TG accumulation with dominant larger lipid droplets in brown adipocytes. Inhibition of lysosomes with chloroquine resulted in a less extent of triglyceride accumulation in Sphk1−/− brown adipocytes compared with wild-type brown adipocytes, suggesting a reduced lysosome-mediated TG breakdown in Sphk1−/− mice. Our results indicate a novel role of SphK1 in lysosomal integrity, which is required for TG breakdown and thermogenesis in BAT.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The selenium (Se)-containing imidazole compound selenoneine (2-selenyl-
N
α
,
N
α
,
N
α
-trimethyl-
l
-histidine) is a strong scavenger of reactive oxygen species (ROS) in the blood and tissues of ...fish. Intravenous injection of selenoneine into yellowtail has been shown to delay changes in meat color and prevent met-myoglobin formation in red muscle. In this study, to determine whether selenoneine can improve stress tolerance and meat quality in fish, we examined the biological antioxidant functions of selenoneine in fish in vivo. Juvenile amberjack (
Seriola dumerili
) were cultured and fed a diet containing selenoneine for 9 weeks. Total Se and selenoneine concentrations increased in amberjack blood and muscles during the study period. We also measured the oxidative–redox potential (ORP) in fish muscle using an ORP electrode and found that muscle ORP and ROS levels were closely correlated with the Se concentration in blood and muscles. We conclude that dietary administration of selenoneine led to its accumulation in amberjack blood and muscles, resulting in reduced ORP and ROS levels in the muscles.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cause fatty liver disease and hepatic insulin resistance. However, because animal ...models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH2-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This prospective study examined the impact of genetic polymorphisms on the pharmacokinetics and clinical efficacy and safety of lenvatinib, a substrate of ATP-binding transporters, in a cohort of 48 ...Japanese patients with hepatocellular carcinoma (HCC). Pharmacokinetic studies were performed at the start of lenvatinib therapy (day 1) and on day 15. The coefficients of variation in AUC0–24h of lenvatinib on days 1 and 15 were 44.0% and 52.4%, respectively. Although the ABCB1 3435C > A, 1236C > T, and 2677G>T/A polymorphisms did not influence pharmacokinetic parameters, the AUC0–24h values on days 1 and 15 of the ABCG2 C/A or A/A group were approximately 1.1-fold and 1.4-fold that in the ABCG2 C/C group (P = 0.164 and 0.024). There were no significant differences in AUC0–24h on days 1 and 15 between the responders (complete or partial response) and non-responders (stable or progressive disease). The AUC0–24h on day 15 in those developing anorexia of any grade was significantly higher than that without such development (P = 0.017). In multivariate analysis, ABCG2 421C > A C/A or A/A was significantly associated with the development of anorexia (odds ratio 9.009, P = 0.009). ABCG2 421C > A polymorphism could affect exposure to lenvatinib and the development of anorexia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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