Search

Background Sarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD‐related muscular atrophy. Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress. However, the role of AOPPs on CKD‐induced muscle atrophy remains unclear. Methods In a retrospective case–control clinical study, we evaluated the relationship between serum AOPPs levels and muscle strength in haemodialysis patients with sarcopenia (n = 26, mean age ± SEM: 78.5 ± 1.4 years for male patients; n = 22, mean age ± SEM: 79.1 ± 1.5 for female patients), pre‐sarcopenia (n = 12, mean age ± SEM: 73.8 ± 2.0 years for male patients; n = 4, mean age ± SEM: 74.3 ± 4.1 for female patients) or without sarcopenia (n = 12, mean age ± SEM: 71.3 ± 1.6 years for male patients; n = 7, mean age ± SEM: 77.7 ± 1.6 for female ). The molecular mechanism responsible for the AOPPs‐induced muscle atrophy was investigated by using 5/6‐nephrectomized CKD mice, AOPPs‐overloaded mice, and C2C12 mouse myoblast cells. Results The haemodialysis patients with sarcopenia showed higher serum AOPPs levels as compared with the patients without sarcopenia. The serum AOPPs levels showed a negative correlation with grip strength (P

Currently, the gold standard for diagnosing diabetic kidney disease (DKD) is the measurement of the urinary albumin-to-creatinine ratio (UACR), but it has been clarified that there are many cases of decreased renal function and atypical nephropathy without the development of albuminuria (1,2). Given these diversified pathologies of DKD, it is necessary to identify new biomarkers that can predict renal prognosis at an earlier disease stage. In this retrospective case-control study, we performed posttranslational modification analysis of plasma albumin by electrospray ionization time-of-flight mass spectrometry (3,4) in 257 outpatients with type 2 diabetes at a single center to evaluate association between the posttranslational modifications of albumin and DKD progression. In fact, 257 patients with type 2 diabetes (179 men and 78 women) aged 49–80 years (mean ± SD 67.1 ± 10.7) who visited the Jinnouchi Clinic, Diabetes Care Center, in Kumamoto, Japan, between April 2014 and June 2017 were enrolled, and the follow-up period was 2 years. According to Kidney Disease: Improving Global Outcomes (KDIGO) glomerular filtration rate (GFR) categories in chronic kidney disease, the subjects were classified into five estimated (e)GFR stages (Fig. 1 A ). Figure 1 A : Characteristics of patients enrolled in this study ( n = 257; 179 men, 78 women). B : The mass peaks of each posttranslational form of serum albumin in patients with type 2 diabetes. C and …

Parathyroid hormone-related protein (PTHrP), which is secreted from a tumor, contributes to the progression of cachexia, a condition that is observed in half of all cancer patients. Although drug clearance was reported to decrease in patients with cancer cachexia, the details have not been clarified. The present study reports on an investigation of whether PTHrP is involved in the alternation of drug metabolism in cases of cancer cachexia. Cancer cachexia model rats with elevated serum PTHrP levels showed a significant decrease in hepatic and intestinal CYP3A2 protein expression. When midazolam, a CYP3A substrate drug, was administered intravenously or orally to the cancer cachexia rats, its area under the curve (AUC) was increased by about 2 and 5 times, as compared to the control group. Accordingly, the bioavailability of midazolam was increased by about 3 times, thus enhancing its pharmacological effect. In vitro experiments using HepG2 cells and Caco-2 cells showed that the addition of serum from cancer cachexia rats or active PTHrP (1-34) to each cell resulted in a significant decrease in the expression of CYP3A4 mRNA. Treatment with a cell-permeable cAMP analog also resulted in a decreased CYP3A4 expression. Pretreatment with protein kinase A (PKA), protein kinase C (PKC), and nuclear factor-kappa B (NF-κB) inhibitors recovered the decrease in CYP3A4 expression that was induced by PTHrP (1-34). These results suggest that PTHrP suppresses CYP3A expression via the cAMP/PKA/PKC/NF-κB pathway. Therefore, it is likely that PTHrP would be involved in the changes in drug metabolism observed in cancer cachexia.

Orexins (orexin-A and orexin-B) are neuropeptides that are reduced in narcolepsy, a sleep disorder that is characterized by excessive daytime sleepiness, sudden sleep attacks and cataplexy. However, it remains unclear how orexins in the brain and orexin neurons are reduced in narcolepsy. Orexin-A has two closely located intramolecular disulfide bonds and is prone to misfolding due to the formation of incorrect disulfide bonds. Protein disulfide isomerase (PDI) possesses disulfide interchange activity. PDI can modify misfolded orexin-A to its native form by rearrangement of two disulfide bonds. We have previously demonstrated that sleep deprivation and a high fat diet increase nitric oxide in the brain. This increase triggers S-nitrosation and inactivation of PDI, leading to aggregation of orexin-A and reduction of orexin neurons. However, the relationship between PDI inactivation and loss of orexin neurons has not yet been fully elucidated. In the present study, we used a PDI inhibitor, cystamine, to elucidate the precise molecular mechanism by which PDI inhibition reduces the number of orexin neurons. In rat hypothalamic slice cultures, cystamine induced selective depletion of orexin-A, but not orexin-B and melanin-concentrating hormone. Moreover, cystamine triggered aggregation of orexin-A, but not orexin-B in the Golgi apparatus of hypothalamic slice cultures and in vivo mouse brains. However, cystamine did not induce endoplasmic reticulum (ER) stress, and an ER stress inducer did not trigger aggregation of orexin-A in slice cultures. Finally, we demonstrated that cystamine significantly decreased extracellular secretion of orexin-A in AD293 cells overexpressing prepro-orexin. These findings suggest that cystamine-induced PDI inhibition induces selective depletion, aggregation in the Golgi apparatus and impaired secretion of orexin-A. These effects may represent an initial step in the pathogenesis of narcolepsy.

This paper is described on the charging characteristics of floating electrode modeled on Vacuum Interrupter (VI). The experimental sample has a floating electrode between two ceramics cylinders. We prepared two kinds of samples which are equipped with or without shield rings inside of the floating electrode to relax an electric field around the triple junction of floating electrode. A charging signal was measured by a surface potential meter as a charging potential.As a result, in case of low voltage application, only an induced voltage in the floating electrode was measured depending on the capacitive dividing voltage of the sample and grounded objects around the sample. In case of high voltage application, not only induced voltage but also a positively charging potential was observed in the floating electrode regardless of sample configuration or polarity of applied voltage. This is due to the field electron emission from the floating electrode itself. The positive charging potential was increased almost linearly to the applied voltage. Comparing the samples, it was found that the sample without shield rings began to form a positive charge at a lower voltage application rather than the sample with shield rings.

In a vacuum interrupter (VI), surface flashover events are one of the obstacles for improving its higher voltage performance. To suppress the vacuum flashover along the insulator surface, field relaxation rings apply to it around the connection point between the metal and alumina insulator, which is called as Triple Junction (TJ) in order to reduce the high field around the TJ point. To obtain higher voltage performance in vacuum interrupter, it is necessary to optimize the shape of field relaxation rings for example, its length, tip radius and gap length etc. In this study, we investigated the vacuum flashover voltage in model vacuum interrupter samples which were equipped with the field relaxation rings inside cylindrical alumina insulator. We carried out the flashover tests for the model samples changing the length of field relaxation rings. As a result, it was confirmed that the install of field relaxation ring increased the vacuum flashover voltage in vacuum interrupter. But in case of the short ring length, the flashover performance was inferior to that of sample having a certain length ring. On the other hand, in case of applying a long ring length, the flashover voltage also decreased rather than the certain appropriate ring length. Therefore, the design of ring length is necessary to select the appropriate length considering the field relaxation for TJ point and the tip of shield rings.

This paper deals with charging characteristics on the insulator surface in vacuum after the AC voltage application. In designing Vacuum Interrupters (VIs) which is current interruption parts of Vacuum Circuit Breakers (VCBs), one of the consideration points is the control of surface flashover events in vacuum. It is believed that such a flashover occurs via charging on the insulator surface. In this study, we measured the charge distributions of cylindrical alumina insulators in vacuum after the AC voltage application. Those insulator samples are equipped with electric field relaxing shield rings (shields) at both ends of the insulator to relax electric field around the triple junction (TJ), and we prepared three kind of shield rings which have different gap length from the alumina insulator surface. As a result, positive charges were formed on the insulator surface of all samples by voltage application. The amount of charge was increased almost linearly to the applied voltage. In addition, when repeating high voltage application test under same condition, the amount of charge was gradually decreased by conditioning effect of shields, and finally reached a stable value by repeating voltage application tests. After that, when a higher voltage rather than above conditioning voltage was applied to the experimental sample, the charge amount was slightly increased.

In vacuum devices such as vacuum interrupters (VIs), surface flashover events are one of the obstacles for developing their higher performance. It is believed that such a surface flashover in vacuum has a close relationship with a charging phenomenon on the insulator surface. Therefore, it is important to grasp the charging characteristics on the inner surface of the VI. In this study, we have measured the charge distribution characteristics inside a cylindrical type insulator employed as a model insulator of VI after the AC voltage (50 Hz) application. This cylindrical insulator has shield rings to relax the electric field at triple junction at both ends of the insulator. We investigate the charging characteristics for samples having different gaps between the shield and insulator. As a result, in the case of first AC voltage application to each sample, the vacuum side of the cylindrical insulators were charged to a certain value. As repeating the AC voltage application several times, the amount of electric charge on the insulator surface was gradually reduced in each sample. However the reduction rate of the sample with the narrow clearance is larger than wide one. In addition, the sample with the wide clearance was charged on a larger surface area than that of the narrow clearance.