Publications by authors named "Hiroshi Watanabe"

1,033 Publications

  • Page 1 of 1

Comparison of renal remission and relapse-free rate in initial- and delayed-onset lupus nephritis.

Int J Rheum Dis 2021 Oct 11. Epub 2021 Oct 11.

Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan.

Introduction: Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE) which contributes to significant morbidity and mortality. It is unclear whether the timing of LN onset influences renal outcome. This study aimed to investigate differences in clinical features-particularly the relapse-free rate-in remission duration from induction therapies for LN and the onset timing of LN after the development of SLE.

Methods: We enrolled 66 LN patients from January 2004 to March 2020. We collected the following: demographic data, laboratory data, renal histology data, and LN induction therapy data. Renal remission and relapse-free rates were calculated for each group.

Results: Patients were first divided into early remission group (achieved renal remission in <12 months [n = 44]) and others (n = 22). There were no significant differences in clinical data, treatments, and relapse-free rate of LN. Patients were then divided into initial-onset LN (<12 months after development of SLE [n = 49]) and delayed-onset LN (≥12 months after development of SLE [n = 17]). Kaplan-Meier analysis showed that the relapse-free rate was significantly higher in all patients with initial-onset LN than those with delayed-onset LN (P = .0094).

Conclusion: The relapse-free rate was significantly higher in the initial-onset LN group than the delayed-onset LN group of patients with LN of various histopathological backgrounds. These data suggest that delayed-onset LN is a risk factor for the relapse of LN.
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http://dx.doi.org/10.1111/1756-185X.14228DOI Listing
October 2021

Advanced oxidation protein products contribute to chronic kidney disease-induced muscle atrophy by inducing oxidative stress via CD36/NADPH oxidase pathway.

J Cachexia Sarcopenia Muscle 2021 Oct 2. Epub 2021 Oct 2.

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

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 < 0.01 for male patients, P < 0.01 for female patients) and skeletal muscle index (P < 0.01 for male patients). Serum AOPPs levels showed a positive correlation with cysteinylated albumin (Cys-albumin), a marker of oxidative stress (r  = 0.398, P < 0.01). In the gastrocnemius of CKD mice, muscle AOPPs levels were also increased, and it showed a positive correlation with atrogin-1 (r  = 0.538, P < 0.01) and myostatin expression (r  = 0.421, P < 0.05), but a negative correlation with PGC-1α expression (r  = 0.405, P < 0.05). Using C2C12 cells, AOPPs increased atrogin-1 and myostatin expression through the production of reactive oxygen species via CD36/NADPH oxidase pathway, and decreased myotube formation. AOPPs also induced mitochondrial dysfunction. In the AOPPs-overloaded mice showed that decreasing running time and hanging time accompanied by increasing AOPPs levels and decreasing cross-sectional area in gastrocnemius.

Conclusions: Advanced oxidation protein products contribute to CKD-induced sarcopenia, suggesting that AOPPs or its downstream signalling pathway could be a therapeutic target for the treatment of CKD-induced sarcopenia. Serum AOPPs or Cys-albumin levels could be a new diagnostic marker for sarcopenia in CKD.
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http://dx.doi.org/10.1002/jcsm.12786DOI Listing
October 2021

Bulk-sensitive spin-resolved resonant electron energy-loss spectroscopy (SR-rEELS): Observation of element- and spin-selective bulk plasmons.

Rev Sci Instrum 2021 Sep;92(9):093103

High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.

We have developed spin-resolved resonant electron energy-loss spectroscopy with the primary energy of 0.3-1.5 keV, which corresponds to the core excitations of 2p-3d absorption of transition metals and 3d-4f absorption of rare-earths, with the energy resolution of about 100 meV using a spin-polarized electron source as a GaAs/GaAsP strained superlattice photocathode. Element- and spin-selective carrier and valence plasmons can be observed using the resonance enhancement of core absorptions and electron spin polarization. Furthermore, bulk-sensitive electron energy-loss spectroscopy spectra can be obtained because the primary energy corresponds to the mean free path of 1-10 nm. The methodology is expected to provide us with novel information about elementary excitations by resonant inelastic x-ray scattering and resonant photoelectron spectroscopy.
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http://dx.doi.org/10.1063/5.0055435DOI Listing
September 2021

Sustained Long-Term Retention Rates of Abatacept in Combination with Conventional Synthetic Disease-Modifying Antirheumatic Drugs in Elderly Patients with Rheumatoid Arthritis.

Medicina (Kaunas) 2021 Aug 31;57(9). Epub 2021 Aug 31.

Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Fukushima, Japan.

: Treatment for elderly (aged ≥75 years) patients with rheumatoid arthritis (RA) is important because they usually have several complications and organ dysfunction and are more susceptible to drug-related adverse events. Abatacept (ABT) treatment is relatively safe in elderly RA patients; however, the real-world data of efficacy and long-term retention of ABT is sparse in such patients. This study aimed to investigate the clinical efficacy and long-term retention rates of ABT in elderly Japanese RA patients. : This 10-year retrospective observational cohort study was performed in two centers in Fukushima, Japan. We reviewed the clinical features of elderly RA patients who received ABT and investigated the differences in retention rates with concomitant administration of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The clinical characteristics of younger (<75 years old, 39 cases) and elderly (≥75 years old, 20 cases) RA patients were generally similar. Although the efficacy was also similar, the concomitant administration of csDMARDs with ABT differed between the two groups. Younger patients significantly decreased methotrexate (MTX) administration than elderly patients ( < 0.01), and elderly patients significantly received tacrolimus (TAC) ( < 0.01) or salazosulfapyridine (SASP; = 0.01) than younger patients. The overall retention and infection-free survival rates were similar between the two groups. Elderly RA patients showed sustained retention rates compared to younger RA patients. TAC and SASP can help to maintain sustained retention rates in elderly RA patients.
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http://dx.doi.org/10.3390/medicina57090914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469009PMC
August 2021

Comprehensive efficacy of ipragliflozin on various conditioned type 2 diabetes compared with dipeptidyl peptidase-4 inhibitors and with both agents, based on a real-world multicenter trial.

Diabetol Int 2021 Oct 11;12(4):364-378. Epub 2021 Feb 11.

Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma Japan.

Aims: The effects of ipragliflozin, the first sodium-glucose co-transporter 2 inhibitors (SGLT2i) launched in Japan in 2014, and with dipeptidyl peptidase-4 inhibitors (DPP-4i) on glycemic control and metabolic changes were investigated comprehensively on various conditioned type 2 diabetes (T2DM) by evaluating various clinical parameters in a real-world setting.

Materials And Methods: A total of 101 patients with T2DM aged 20-80 years with 7.0% ≤ HbA1c < 10.0% were followed in this 52-week, open-label, prospective, real-world, multicenter study.

Results: HbA1c decreased significantly in all groups. In ipragliflozin using groups, body weight, waist circumference, blood pressure, HOMA-IR, AST, ALT, γ-GTP, uric acid and leptin levels decreased, in contrast, HDL-cholesterol, total ketone bodies, blood urea nitrogen, creatinine, RBC, hemoglobin and hematocrit levels increased, however, in DPP-4i sole group, no significant trends were observed in these parameters. Change in leptin positively correlated with insulin, while change in total ketone bodies inversely correlated with ALT in ipragliflozin using groups. Fasting active gastric inhibitory polypeptide levels decreased in ipragliflozin sole group. Glucagon showed no changes. No significant safety concerns were observed in this study.

Conclusions: Ipragliflozin is useful and safe, showing some contrastive effects on several clinical parameters which are not shown with DPP-4i, resulting several clinical benefits. The co-administration of ipragliflozin and a DPP-4i has a better clinical outcome than either single-agent therapy.
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http://dx.doi.org/10.1007/s13340-021-00492-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413408PMC
October 2021

The relationship between severity of varus osteoarthritic knees and contracture of the medial structures.

J Nippon Med Sch 2021 Sep 14. Epub 2021 Sep 14.

Department of Orthopaedic Surgery, Nippon Medical School.

Background: Severe varus osteoarthritic knee has possibility of medial structure contracture. There is no report concerning the relationship between severity of varus deformity and contracture of medial structure. We aimed to reveal a threshold angle that could be corrected in proportion to the width of medial osteophyte removal, and to examine correction differences between larger and smaller than the threshold angle in total knee arthroplasty.

Methods: This study included 27 varus osteoarthritic knees scheduled for total knee arthroplasty (TKA). Each knee was measured the hip-knee-ankle angles (HKA) using a navigation system, at maximum extension, 30˚ and 60˚ flexion before and after osteophyte removal, with and without external 10 N-m valgus torque loads. Subsequently, resected osteophyte widths were measured. Mean correction angle per 1 mm osteophyte removal was calculated, and the threshold angle was calculated using the receiver operating characteristic curve. HKA differences were compared against larger and smaller deformity than the threshold angle.

Results: Mean osteophyte width was 7.1±2.20 mm. Osteophyte removal produced a mean 3.1° correction, which equaled a 0.4° correction per 1 mm osteophyte width removal. The varus deformity threshold angle was 9.5°, however, when comparing the groups larger and smaller than the threshold, there were no significant differences in HKA differences between each step and flexion angle.

Conclusions: The threshold angle for expected correction with medial osteophyte removal was 9.5˚. However, with no differences in correction between those with larger or smaller than this angle, medial structure contracture seemed to be unrelated to severity of deformity.
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http://dx.doi.org/10.1272/jnms.JNMS.2022_89-113DOI Listing
September 2021

MIHARI project, a preceding study of MID-NET, adverse event detection database of Ministry Health of Japan-Validation study of the signal detection of adverse events of drugs using export data from EMR and medical claim data.

PLoS One 2021 8;16(9):e0255863. Epub 2021 Sep 8.

Hamamatsu University School of Medicine, Shizuoka, Japan.

We studied the effectiveness of the direct data collection from electronic medical records (EMR) when it is used for monitoring adverse drug events and also detection of already known adverse events. In this study, medical claim data and SS-MIX2 standardized storage data were used to identify four diseases (diabetes, dyslipidemia, hyperthyroidism, and acute renal failure) and the validity of the outcome definitions was evaluated by calculating positive predictive values (PPV). The maximum positive predictive value (PPV) for diabetes based on medical claim data was 40.7% and that based on prescription data from SS-MIX2 Standardized Storage was 44.7%. The PPV for dyslipidemia was 50% or higher under either of the conditions. The PPV for hyperthyroidism based on disease name data alone was 20-30%, but exceeded 60% when prescription data was included in the evaluation. Acute renal failure was evaluated using information from medical records in addition to the data. The PPV for acute renal failure based on the data of disease names and laboratory examination results was slightly higher at 53.7% and increased to 80-90% when patients who previously had a high serum creatinine (Cre) level were excluded. When defining a disease, it is important to include the condition specific to the disease; furthermore, it is very useful if laboratory examination results are also included. Therefore, the inclusion of laboratory examination results in the definitions, as in the present study, was considered very useful for the analysis of multi-center SS-MIX2 standardized storage data.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255863PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425565PMC
September 2021

TAFRO syndrome complicated by porto-sinusoidal vascular liver disease with portal hypertension: a case report.

Clin J Gastroenterol 2021 Sep 6. Epub 2021 Sep 6.

Department of Gastroenterology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Porto-sinusoidal vascular liver disease (PSVD) is a disorder that can cause portal hypertension without liver cirrhosis. TAFRO syndrome is a systemic inflammatory disorder with a background of immunological abnormalities. We report a case of TAFRO syndrome complicated by PSVD with portal hypertension. A 39-year-old man developed refractory ascites and esophageal varices. Lymph node histology revealed multicentric Castleman disease-like features. Intravenous methylprednisolone and tocilizumab therapy improved ascites and renal dysfunction, but the patient developed severe infections. The diagnosis of TAFRO syndrome in patients complicated by PSVD with portal hypertension encourages the consideration of appropriate treatment for these patients.
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http://dx.doi.org/10.1007/s12328-021-01515-2DOI Listing
September 2021

The Therapeutic Effect of Human Serum Albumin Dimer-Doxorubicin Complex against Human Pancreatic Tumors.

Pharmaceutics 2021 Aug 5;13(8). Epub 2021 Aug 5.

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.

Human serum albumin (HSA) is a versatile drug carrier with active tumor targeting capacity for an antitumor drug delivery system. Nanoparticle albumin-bound (nab)-technology, such as nab-paclitaxel (Abraxane), has attracted significant interest in drug delivery research. Recently, we demonstrated that HSA dimer (HSA-d) possesses a higher tumor distribution than HSA monomer (HSA-m). Therefore, HSA-d is more suitable as a drug carrier for antitumor therapy and can improve nab technology. This study investigated the efficacy of HSA-d-doxorubicin (HSA-d-DOX) as next-generation nab technology for tumor treatment. DOX conjugated to HSA-d via a tunable pH-sensitive linker for the controlled release of DOX. Lyophilization did not affect the particle size of HSA-d-DOX or the release of DOX. HSA-d-DOX showed significantly higher cytotoxicity than HSA-m-DOX in vitro. In the SUIzo Tumor-2 (SUIT2) human pancreatic tumor subcutaneous inoculation model, HSA-d-DOX could significantly inhibit tumor growth without causing serious side effects, as compared to the HSA binding DOX prodrug, which utilized endogenous HSA as a nano-drug delivery system (DDS) carrier. These results indicate that HSA-d could function as a natural solubilizer of insoluble drugs and an active targeting carrier in intractable tumors with low vascular permeability, such as pancreatic tumors. In conclusion, HSA-d can be an effective drug carrier for the antitumor drug delivery system against human pancreatic tumors.
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http://dx.doi.org/10.3390/pharmaceutics13081209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402024PMC
August 2021

Clinical relevance for circulating cold-inducible RNA-binding protein (CIRP) in patients with adult-onset Still's disease.

PLoS One 2021 5;16(8):e0255493. Epub 2021 Aug 5.

Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan.

Background: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease in which danger-associated molecular patterns (DAMPs)-mediated inflammasome activation seems to be involved in the disease pathogenesis. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cellular stress and has been identified as a DAMP that triggers the inflammatory response. The aim of this study is to investigate the clinical significance of serum CIRP levels in AOSD.

Methods: Serum samples were obtained from 44 patients with active AOSD or 50 patients with rheumatoid arthritis (RA), 20 patients with systemic lupus erythematosus (SLE), and 15 healthy control patients (HCs). Serum levels of CIRP and IL-18 were determined using enzyme-linked immunosorbent assay. Results were compared among AOSD patients, RA patients, SLE patients and HCs. Results were also analyzed according to the clinical features of AOSD.

Results: Serum CIRP levels were significantly higher in AOSD patients compared with RA patients (median: 9.6 ng/mL, IQR [5.7-14.4] versus 3.2 ng/mL, IQR [1.9-3.8]; p < 0.001) and with HCs (2.8 ng/mL, [IQR; 1.4-4.9], p < 0.001). There was a significant positive correlation between serum CIRP levels and AOSD disease activity score (Pouchot's score r = 0.45, p = 0.003) as well as between AOSD-specific biomarkers ferritin and IL-18. However, there was no significant difference in the serum CIRP levels among AOSD patients with three different disease phenotypes.

Conclusions: These results suggest that CIRP may play a significant role in the pathophysiology of AOSD and could be a potential biomarker for monitoring the disease activity of AOSD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341607PMC
August 2021

Diagnostic and prognostic significance of serum angiopoietin-1 and -2 concentrations in patients with pulmonary hypertension.

Sci Rep 2021 07 29;11(1):15502. Epub 2021 Jul 29.

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Several biomarkers for detecting pulmonary hypertension (PH) have been reported. However, these biomarkers are deemed insufficient to detect PH in its early stages. We evaluated the utility of serum angiopoietin (ANGP), a glycoprotein related to angiogenesis, as a diagnostic and prognostic biomarker of PH. Patients with PH who underwent right-heart catheterization, were retrospectively studied. Serum concentrations of ANGP-1 and ANGP-2 were measured using an enzyme-linked immunosorbent assay in patients with PH (n = 32), those with idiopathic pulmonary fibrosis (IPF) without PH (as a disease control, n = 75), and age-matched healthy controls (HC, n = 60). Nineteen patients (59.4%) with PH had World Health Organization group 3 PH. Serum ANGP-2 concentration, but not ANGP-1, in patients with PH was significantly higher compared with that in HC (p = 0.025) and in patients with IPF without PH (p = 0.008). Serum ANGP-2 concentration in patients with PH positively and significantly correlated with N-terminal pro-B-type natriuretic peptide (r = 0.769, p < 0.001), right ventricular diameter on echocardiography (r = 0.565, p = 0.035), and mean pulmonary arterial pressure (r = 0.449, p = 0.032) and pulmonary vascular resistance (r = 0.451, p = 0.031) on right-heart catheterization. ANGP-1 and ANGP-2 were expressed on lung vascular endothelial cells, as shown by immunohistochemistry. Patients with PH with higher ANGP-2 concentration (≥ 2.48 ng/mL) had significantly worse survival (p = 0.022). Higher ANGP-2 concentration was a significant worse prognostic factor (hazard ratio = 6.063, p = 0.037), while serum ANGP-1 concentration was not. In conclusion, serum ANGP-2 may be a useful diagnostic and prognostic biomarker in patients with PH, especially in patients with group 3 PH.
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http://dx.doi.org/10.1038/s41598-021-94907-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322335PMC
July 2021

Omeprazole suppresses endothelial calcium response and eNOS Ser1177 phosphorylation in porcine aortic endothelial cells.

Mol Biol Rep 2021 Jul 21;48(7):5503-5511. Epub 2021 Jul 21.

Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Japan.

Background: Although high doses of proton pump inhibitors can elicit an anticancer effect, this strategy may impair vascular biology. In particular, their effects on endothelial Ca signaling and production of endothelium-derived relaxing factor (EDRF) are unknown. To this end, we investigated the effects of high dosages of omeprazole on endothelial Ca responses and EDRF production in primary cultured porcine aortic endothelial cells.

Methods And Results: Omeprazole (10-1000 μM) suppressed both bradykinin (BK)- and thapsigargin-induced endothelial Ca response in a dose-dependent manner. Furthermore, omeprazole slightly attenuated Ca mobilization from the endoplasmic reticulum, whereas no inhibitory effects on endoplasmic reticulum Ca-ATPase were observed. Omeprazole decreased BK-induced phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and tended to decrease BK-induced nitric oxide production. Production of prostaglandin I metabolites, especially 6-keto-prostaglandin 1α, also tended to be reduced by omeprazole.

Conclusion: Our results are the first to indicate that high doses of omeprazole may suppress both store-operated Ca channels and partially the G protein-coupled receptor/phospholipase C/inositol 1,4,5-triphosphate pathway, and decreased BK-induced, Ca-dependent phosphorylation of eNOS(Ser1177). Thus, high dosages of omeprazole impaired EDRF production by attenuating intracellular Ca signaling.
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http://dx.doi.org/10.1007/s11033-021-06561-0DOI Listing
July 2021

Effects of polymers on the cavitating flow around a cylinder: A large-scale molecular dynamics analysis.

J Chem Phys 2021 Jul;155(1):014905

Institute for Solid State Physics, The University of Tokyo, Kashiwa, Chiba 277-8581, Japan.

The cavitation flow of linear-polymer solutions around a cylinder is studied by performing a large-scale molecular dynamics simulation. The addition of polymer chains remarkably suppresses cavitation. The polymers are stretched into a linear shape near the cylinder and entrained in the vortex behind the cylinder. As the polymers stretch, the elongational viscosity increases, which suppresses the vortex formation. Furthermore, the polymers exhibit an entropic elasticity owing to stretching. This elastic energy increases the local temperature, which inhibits the cavitation inception. These effects of polymers result in the dramatic suppression of cavitation.
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http://dx.doi.org/10.1063/5.0056988DOI Listing
July 2021

Association of adipokines with frailty in heart failure.

Acta Biomed 2021 07 1;92(3):e2021195. Epub 2021 Jul 1.

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Background Frailty is a multifactorial physiological syndrome most often associated with age but which has received increasing recognition as a component of chronic illnesses such as heart failure. Patients with heart failure are likely to be frail, irrespective of their age. Adipokine dysregulation, which is associated with frailty, occurs in patients with heart failure. In this study, we tested the hypothesis that adipokines are associated with frailty in patients with heart failure. Methods Thirty-five patients with heart failure (age, 67 ± 14 years; 25 males; left ventricular ejection fraction, 45 ± 19%) were included. Serum adipokine levels, physical performance, and body composition were measured. Results Adiponectin and leptin were inversely correlated with grip strength. Adiponectin was inversely correlated with bone mineral density. Leptin was positively correlated with fat mass. Adipokines were not correlated with skeletal muscle mass. Conclusions Adipokines were associated with frailty in patients with heart failure. Adipokine dysregulation may play a role in the development of frailty in heart failure.
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http://dx.doi.org/10.23750/abm.v92i3.9228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343728PMC
July 2021

α-Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages.

Cancer Res 2021 Sep 1;81(17):4545-4559. Epub 2021 Jul 1.

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Blood levels of acute-phase protein α-acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell-derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte-derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL6 production from macrophages, which stimulated proliferation in tumor cells by IL6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages (TAM) on tumor progression. AGP decreased IFNγ secretion from T cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL6 production in macrophages by binding with CD14, a coreceptor for Toll-like receptor 4 (TLR4), and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with TAMs and that AGP might be a target molecule for anticancer therapy. SIGNIFICANCE: AGP-mediated suppression of antitumor immunity contributes to tumor progression by inducing PD-L1 expression and IL6 production in TAMs.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3471DOI Listing
September 2021

Selective Adsorption of Potassium in Seawater by CoHCF Thin Film Electrode and Its Electrochemical Desorption/Regeneration.

Materials (Basel) 2021 Jun 27;14(13). Epub 2021 Jun 27.

Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba 305-8565, Japan.

Cobalt Hexacyanoferrate (CoHCF) was tested for the selective uptake of K from seawater and the electrochemical method was adopted for the desorption and regeneration of the material. Powder form CoHCF could adsorb about 6.5 mmol/g of K from the seawater. For the ease of the electrochemical desorption and regeneration, CoHCF thin film was coated onto the Indium Tin Oxide (ITO) glass to obtain a CoHCF electrode. K adsorption kinetics on CoHCF thin film was found to be well fitted with the intraparticle diffusion model, which was a two-step process. Five consecutive adsorption-desorption-regeneration cycles were carried out to know the gradual decrease in the adsorption capacity owing to changes in the redox states of two metals, Co and Fe, in the material. Fourier Transform Infrared Spectroscopy (FT-IR) and Ultraviolet-Visible (UV-Vis) measurement results corresponded to the color change of CoHCF thin film, indicating the valence change of transition metals and the exchange of alkali metal cations happened on the CoHCF at different operation stages. In order to elucidate the reaction mechanism, composition of the material was analysis in the following steps: adsorption, desorption, and regeneration. It was proved that the system based on CoHCF thin film modified electrode had the potential of recovering potassium from seawater.
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http://dx.doi.org/10.3390/ma14133592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269628PMC
June 2021

Differentiation of cystic lesions in the jaw by conventional magnetic resonance imaging and diffusion-weighted imaging.

Dentomaxillofac Radiol 2021 Jun 16:20210212. Epub 2021 Jun 16.

Department of Oral and Maxillofacial Radiology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.

Objectives: This study aimed to determine the discrimination power of apparent diffusion coefficient (ADC) for cystic lesions in the jaw using MRI.

Methods: We selected 127 cystic lesions, comprising dentigerous cysts (DCs), odontogenic keratocysts (OKCs), and unicystic ameloblastomas (UABs), from our MRI database examined by 3T MRI, including diffusion-weighted imaging sequences, and we reviewed their imaging characteristics. We attempted to discriminate the three types of lesions by ADC values with receiver operator characteristic analysis; however, satisfactory results were not obtained for differentiation between DC and OKC. Therefore, we performed a decision tree analysis.

Results: The imaging characteristics of the lesions were significantly different according to Fisher's exact test, except for differences in sex. The ADC values statistically discriminated the lesions of DC and UAB, OKC and UAB, but not DC and OKC. Thus, differentiation was performed by a decision tree for DC and OKC by evaluating the following points: the attached tooth condition, signal intensity on the weighted image (SI), ADC value, and the cyst site. However, cases showing hypo- or isointense SI with an ADC value under 1.168 × 10 mm/s were difficult to differentiate.

Conclusion: The ADC value helped distinguish UAB from both DC and OKC, but not DC from OKC. However, the decision tree based on ADC value, tooth contact status, and SI helped differentiate DC and OKC to some extent.
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http://dx.doi.org/10.1259/dmfr.20210212DOI Listing
June 2021

Meningoencephalitis in relapsing polychondritis: A case report.

Medicine (Baltimore) 2021 Jun;100(24):e26315

Department of Neurology, Fukushima Medical University School of Medicine, Fukushima.

Rationale: Aseptic meningoencephalitis is a rare central nervous system complication of relapsing polychondritis (RP).

Patient: We report a 61-year-old Japanese male patient with spiking fever and impaired consciousness. Neurological examination revealed meningealirritation, and cerebrospinal fluid (CSF) examination showed lymphocytic pleocytosis with elevated protein (199 mg/dL) and interleukin-6 (3810 pg/mL). Serological analysis showed high levels of anti-type II collagen antibodies, and the result of auricular biopsy was consistent with the diagnosis of RP showing cartilage degeneration surrounded by inflammatory cell infiltrations.

Diagnosis: A clinical diagnosis of RP was made according to the diagnostic criteria established by MacAdams et al.

Intervention: Steroid pulse therapy (methylprednisolone 1000 mg, consecutive 3 days) followed by oral prednisolone (60 mg/day) resolved the patient's high fever and disturbance of consciousness.

Outcomes: The patient rapidly improved after steroid treatments and has a normal quality of life under the maintenance dose of steroid plus methotrexate (4 mg/week).

Lessons: RP-associated meningoencephalitis is a rare complication with significant morbidity and mortality. It should be considered and differentiated in patients with RP with unexplained spiking fever and impaired consciousness. In addition, the assessment of cerebrospinal fluid interleukin-6 levels may be useful to investigate the disease activity of RP-related meningoencephalitis. Further prospective studies are required to confirm this result.
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http://dx.doi.org/10.1097/MD.0000000000026315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213297PMC
June 2021

Phase equilibrium and dielectric relaxation in mixture of 5CB with dilute dimethyl phthalate: effect of coupling between orientation and composition fluctuations on molecular dynamics in isotropic one-phase state.

Soft Matter 2021 Jun;17(25):6259-6272

Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.

Phase equilibrium and dielectric relaxation were examined for mixtures of liquid-crystalline (LC)-forming 4-cyano-4'-pentylbiphenyl (5CB) with dilute dimethyl phthalate (DMP). The mixtures were in an isotropic one-phase state at high temperatures T but were separated into nematic and isotropic phases at low T < TIN (isotropic-to-nematic transition temperature), and the isotropic phase disappeared and a nematic one-phase state was realized on a further decrease of T below another transition temperature . These TIN and data (phase diagram) were described considerably well by a simple model of free energy contributed from a Flory-Huggins type mixing entropy (no enthalpic contribution) and a Landau-de Gennes type nematic interaction. This success of the model, not expected for ordinary (not LC-forming) components exhibiting enthalpically-driven phase separation, suggested that the phase separation in the DMP/5CB mixtures was triggered by the nematic transition of 5CB (possibly governed by the packing entropy) and thus the orientation fluctuation of 5CB molecules was coupled with the composition fluctuation. This coupling was expected to affect the dielectric relaxation detecting the rotational dynamics of 5CB molecules, the major component in the mixtures. This expectation was examined for a representative mixture having the DMP content of wDMP = 3.1 wt% and TIN ≅ 27.0 °C. In a high-T asymptote (T > TIN + 10 °C), the dielectric relaxation of this mixture was close to that of pure 5CB, which suggested no significant effect of the above coupling on 5CB dynamics in the mixture at such high T. Nevertheless, in a significantly wide range of T between TIN and TIN + 10 °C, the dielectric relaxation time τε of the isotropic one-phase mixture increased on cooling much more significantly compared to τε in that high-T asymptote. The kinematic viscosity ν of the mixture exhibited a qualitatively similar increase in the same range of T, but this increase was weaker than that of τε. This difference between the dielectric τε and the rheological ν was attributed to coupling of the orientation and the composition fluctuations mentioned above. Namely, the composition fluctuation enhances the orientation fluctuation in the mixture thereby providing τε (reflecting the orientation fluctuation) with an extra increase. Pure 5CB exhibited similar increases of τε and ν (stronger for the former) but only in a close vicinity of (within 2-3 °C), because the orientation fluctuation in pure 5CB is coupled with the density fluctuation, not with the composition fluctuation being absent in the pure 5CB system. This behavior of pure 5CB in turn suggests an importance of the coupling of orientation and composition fluctuations in the mixture.
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http://dx.doi.org/10.1039/d1sm00496dDOI Listing
June 2021

Prediction of the Area under the Curve Using Limited-Point Blood Sampling in a Cocktail Study to Assess Multiple CYP Activities.

Biol Pharm Bull 2021 ;44(6):762-770

Department of Pharmacy Practice & Science, School of Pharmaceutical Sciences, University of Shizuoka.

A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were <39.5% in Model 1 and <26.2% in Model 2 which were created using 1- and 4-point sampling data. MAE shows larger values in the administration of inducer in compared with the administration of inhibitors. The accuracy of the prediction in Model 2 could be acceptable for screening of inhibitions. MAE for caffeine, dextromethorphan, and midazolam were acceptable in the model that used 4 sampling points from all data. The use of this method could reduce the burden on the subject and make it possible to evaluate each AUC in a minimally invasive manner.
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http://dx.doi.org/10.1248/bpb.b20-00691DOI Listing
January 2021

Randomized phase 2 study comparing irinotecan versus amrubicin as maintenance therapy after first-line induction therapy for extensive disease small cell lung cancer (HOT1401/NJLCG1401).

Thorac Cancer 2021 07 2;12(14):2113-2121. Epub 2021 Jun 2.

Division of Pulmonary Medicine, Allergy, and Rheumatology, Iwate Medical University Faculty of Medicine Graduate School of Medicine Morioka, Iwate, Japan.

Background: A cisplatin plus irinotecan (CPT-11) regimen is used for patients with extensive disease small cell lung cancer (ED-SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open-label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED-SCLC who responded to induction therapy.

Methods: Patients with histologically- or cytologically-confirmed ED-SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m on day 1) plus CPT-11 (60 mg/m on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT-11 (60 mg/m on days 1 and 8) every three weeks, or AMR (35 mg/m on days 1-3) every three weeks.

Results: A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT-11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6-11.8), and the median overall survival was 20.1 months (95% CI: 13.7-not reached). No statistically significant difference in progression-free survival (PFS) were noted between patients treated with CPT-11 and those treated with AMR. There were no treatment-related deaths in this study.

Conclusions: Maintenance therapy with CPT-11 or AMR after induction therapy might be effective in some patients.
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http://dx.doi.org/10.1111/1759-7714.14048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287008PMC
July 2021

Recombinant Long-Acting Thioredoxin Ameliorates AKI to CKD Transition via Modulating Renal Oxidative Stress and Inflammation.

Int J Mol Sci 2021 May 25;22(11). Epub 2021 May 25.

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.

An effective strategy is highly desirable for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Thioredoxin-1 (Trx), a redox-active protein that has anti-oxidative and anti-inflammatory properties, would be a candidate for this but its short half-life limits its clinical application. In this study, we examined the renoprotective effect of long-acting Trx that is comprised of human albumin and Trx (HSA-Trx) against AKI to CKD transition. AKI to CKD mice were created by renal ischemia-reperfusion (IR). From day 1 to day 14 after renal IR, the recovery of renal function was accelerated by HSA-Trx administration. On day 14, HSA-Trx reduced renal fibrosis compared with PBS treatment. At the early phase of fibrogenesis (day 7), HSA-Trx treatment suppressed renal oxidative stress, pro-inflammatory cytokine production and macrophage infiltration, thus ameliorating tubular injury and fibrosis. In addition, HSA-Trx treatment inhibited G2/M cell cycle arrest and apoptosis in renal tubular cells. While renal Trx protein levels were decreased after renal IR, the levels were recovered by HSA-Trx treatment. Together, HSA-Trx has potential for use in the treatment of AKI to CKD transition via its effects of modulating oxidative stress and inflammation.
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http://dx.doi.org/10.3390/ijms22115600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199127PMC
May 2021

Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end-stage renal disease.

Clin Transl Sci 2021 Sep 31;14(5):2034-2042. Epub 2021 May 31.

Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan.

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end-stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact-PTH (iPTH) level with blood tacrolimus concentration in patients with end-stage renal disease just before kidney transplantation. Forty-eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co-administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.
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http://dx.doi.org/10.1111/cts.13065DOI Listing
September 2021

Serum checkpoint molecules in patients with IgG4-related disease (IgG4-RD).

Arthritis Res Ther 2021 05 24;23(1):148. Epub 2021 May 24.

Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.

Background: Immunoglobulin G4-related disease (IgG4-RD) is characterized by increased serum IgG4 concentration and infiltration of IgG4 plasma cells in the affected organs. The present study aimed to characterize the serum levels of coinhibitory checkpoint molecule, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), and its ligand, galectin-9 (Gal-9), among IgG4-related disease in patients with IgG4-RD patients with various organ involvements.

Methods: Serum samples were collected from untreated 59 patients with IgG4-RD, 13 patients with rheumatoid arthritis, and 37 healthy controls (HCs). HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within 7 days. Patients with IgG4-RD (n = 57) were subdivided into those with visceral involvement (n = 38) and those without visceral involvement (n = 21). Serum levels of Gal-9 and soluble TIM-3 (sTIM-3) were determined using enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical phenotypes of IgG4-RD.

Results: In untreated patients with IgG4-RD, serum levels of Gal-9 and sTIM-3 were significantly higher than in RA patients as well as in healthy controls. There were significant correlations between the serum levels of Gal-9 or sTIM-3 and serum levels of IgG, BAFF, or sIL-2R. However, there was no significant correlation between the serum levels of Gal-9 or sTIM-3 and serum IgG4 concentrations. Serum levels of sTIM-3 were significantly higher in a subset of patients with visceral involvements than in those without visceral involvements. However, there was no significant difference in the serum levels of Gal-9 between IgG4-RD patients with and without visceral involvements, although both Gal-9 and sTIM-3 were elevated in untreated IgG4-RD patients, and the levels of these checkpoint molecules remained unchanged after steroid therapy.

Conclusion: Serum levels of Gal-9 and sTIM-3 were significantly elevated in untreated patients with IgG4-RD. Furthermore, serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral involvements. These checkpoint molecules could be a potentially useful biomarker for IgG4-RD and for assessing the clinical phenotypes of IgG4-RD.
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http://dx.doi.org/10.1186/s13075-021-02527-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142499PMC
May 2021

Effective dose estimation in cone-beam computed tomography for dental use by Monte-Carlo simulation optimizing calculation numbers using a step-and-shoot method.

Dentomaxillofac Radiol 2021 Oct 30;50(7):20210084. Epub 2021 Apr 30.

Department of Oral and Maxillofacial Radiology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.

Objective: The objective of this study was to perform effective dose estimation in cone-beam CT for dental use (CBCT) using a Monte-Carlo simulation employing a step-and-shoot method as well as to determine the optimal number of steps.

Methods: We simulated 3DX Accuitomo FPD8 as a CBCT model and estimated the effective doses of a large and a small field of view (FOV) examination against the virtual Rando phantom using a particle and heavy ion transport code system. We confirmed the results compared to those from a thermo-luminescence dosemeter (TLD) system in a real phantom and investigated how the reduced angle calculations could be accepted.

Results: The effective doses of both FOVs estimated with each one degree were almost the same as those estimated from the TLD measurements. Considering the effective doses and the itemized organ doses, simulation with 5° and 10° is acceptable for the large and small FOV, respectively. We tried to compare an effective dose with a large FOV as well as with multiple small FOVs covering the corresponding area and found that the effective dose from six small FOVs was approximately 1.2 times higher than that of the large FOVs.

Conclusion: We successfully performed a Monte-Carlo simulation using a step-and-shoot method and estimated the effective dose in CBCT. Our findings indicate that simulation with 5° or 10° is acceptable based on the FOV size, while a small multiple FOV scan is recommended from a radiation protection viewpoint.
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http://dx.doi.org/10.1259/dmfr.20210084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474132PMC
October 2021

β2-adrenergic receptor agonist counteracts skeletal muscle atrophy and oxidative stress in uremic mice.

Sci Rep 2021 04 28;11(1):9130. Epub 2021 Apr 28.

Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

In patients with chronic kidney disease, skeletal muscle dysfunction is associated with mortality. Uremic sarcopenia is caused by ageing, malnutrition, and chronic inflammation, but the molecular mechanism and potential therapeutics have not been fully elucidated yet. We hypothesize that accumulated uremic toxins might exert a direct deteriorative effect on skeletal muscle and explore the pharmacological treatment in experimental animal and culture cell models. The mice intraperitoneally injected with indoxyl sulfate (IS) after unilateral nephrectomy displayed an elevation of IS concentration in skeletal muscle and a reduction of instantaneous muscle strength, along with the predominant loss of fast-twitch myofibers and intramuscular reactive oxygen species (ROS) generation. The addition of IS in the culture media decreased the size of fully differentiated mouse C2C12 myotubes as well. ROS accumulation and mitochondrial dysfunction were also noted. Next, the effect of the β2-adrenergic receptor (β2-AR) agonist, clenbuterol, was evaluated as a potential treatment for uremic sarcopenia. In mice injected with IS, clenbuterol treatment increased the muscle mass and restored the tissue ROS level but failed to improve muscle weakness. In C2C12 myotubes stimulated with IS, although β2-AR activation also attenuated myotube size reduction and ROS accumulation as did other anti-oxidant reagents, it failed to augment the mitochondrial membrane potential. In conclusion, IS provokes muscular strength loss (uremic dynapenia), ROS generation, and mitochondrial impairment. Although the β2-AR agonist can increase the muscular mass with ROS reduction, development of therapeutic interventions for restoring skeletal muscle function is still awaited.
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http://dx.doi.org/10.1038/s41598-021-88438-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080640PMC
April 2021

Cold-inducible RNA-binding protein (CIRP) potentiates uric acid-induced IL-1β production.

Arthritis Res Ther 2021 04 26;23(1):128. Epub 2021 Apr 26.

Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.

Background: Gout is an autoinflammatory disease driven by interleukin-1 (IL-1) induction in response to uric acid crystals. IL-1β production is dependent on inflammasome activation, which requires a priming signal, followed by an activating signal. The cold-inducible RNA-binding protein (CIRP) has been recently identified as a damage-associated molecular pattern (DAMP). In this study, we evaluated the roles of CIRP in monosodium urate (MSU)-mediated IL-1β secretion using human neutrophils.

Methods: Human neutrophils were stimulated by MSU in the presence or absence of CIRP priming to determine NLRP3 inflammasome activation and subsequent caspase-1 activation and IL-1β production. Cellular supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) to determine the presence of IL-1β or caspase-1 (p20). The cellular supernatants and lysates were also analyzed by immunoblotting using anti-cleaved IL-1β or anti-cleaved caspase-1 antibodies.

Results: Neither CIRP nor MSU stimulation alone induced sufficient IL-1β secretion from neutrophils. However, MSU stimulation induced IL-1β secretion from CIRP-primed neutrophils in a dose-dependent manner. This MSU-induced IL-1β secretion from CIRP-primed neutrophils was accompanied by the induction of cleaved IL-1β (p17), which was inhibited by the pretreatment of MCC950, a specific inhibitor for NLRP3. Furthermore, cleaved caspase-1 was induced in the cellular lysates of CIRP/MSU-treated neutrophils. Additionally, CIRP stimulation induced the protein expression of pro-IL-1β in neutrophils.

Conclusions: Our data indicate that CIRP, an endogenous stress molecule, triggers uric acid-induced mature IL-1β induction as a priming stimulus for NLRP3 inflammasome in human neutrophils. We propose that CIRP acts as an important proinflammatory stimulant that primes and activates inflammasome and pro-IL-1β processing in response to uric acid in innate immune cells.
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http://dx.doi.org/10.1186/s13075-021-02508-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074240PMC
April 2021

Proton transfer in bulk water using the full adaptive QM/MM method: integration of solute- and solvent-adaptive approaches.

Phys Chem Chem Phys 2021 Apr 1;23(14):8344-8360. Epub 2021 Apr 1.

Quantum Computing Center, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.

The quantum mechanical/molecular mechanical (QM/MM) method is a hybrid molecular simulation technique that increases the accessibility of local electronic structures of large systems. The technique combines the benefit of accuracy found in the QM method and that of cost efficiency found in the MM method. However, it is difficult to directly apply the QM/MM method to the dynamics of solution systems, particularly for proton transfer. As explained in the Grotthuss mechanism, proton transfer is a structural interconversion between hydronium ions and solvent water molecules. Hence, when the QM/MM method is applied, an adaptive treatment, namely on-the-fly revisions on molecular definitions, is required for both the solute and solvent. Although several solvent-adaptive methods have been proposed, a full adaptive framework, which is an approach that also considers adaptation for solutes, remains untapped. In this paper, we propose a new numerical expression for the coordinates of the excess proton and its control algorithm. Furthermore, we confirm that this method can stably and accurately simulate proton transfer dynamics in bulk water.
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http://dx.doi.org/10.1039/d1cp00116gDOI Listing
April 2021
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