Role of protein kinase C-δ in isoproterenol-induced amylase release in rat parotid acinar cells

In parotid acinar cells, β-adrenergic receptor activation results in accumulation of intracellular cAMP. Subsequently, cAMP-dependent protein kinase (PKA) is activated and consequently amylase release is provoked. In this paper, we investigated involvement of protein kinase C-δ(PKCδ), a novel isoform of PKC, in amylase release induced by β-adrenergic receptor stimulation. Amylase release stimulated with the β-agonsit isoproterenol (IPR) was inhibited by rottlerin, an inhibitor of PKCδ. IPR activated PKCδ and the effect of IPR were inhibited by a PKA inhibitor, H89. Myristoylated alanine-rich C kinase substrate (MARCKS), a major cellular substrate for PKC, was detected in rat parotid acinar cells, and a MARCKS inhibitor, MARCKS-related peptide, inhibited the IPR-induced amylase release. IPR stimulated MARCKS phosphorylation, which was found to be inhibited by H89 and rottlerin. These observations suggest that PKCδ activation is a downstream pathway of PKA activation and is involved in amylase release via MARCKS phosphorylation in rat parotid acinar cells stimulated with β-adrenergic agonist

The thiol-oxidizing agent diamide reduces isoproterenolstimulated amylase release in rat parotid acinar cells

In parotid acinar cells, activation of β-adrenergic receptors provokes exocytotic amylase release via the accumulation of intracellular cAMP. Cellular redox status plays a pivotal role in the regulation of various cellular functions. Cellular redox imbalance caused by the oxidation of cellular antioxidants, as a result of oxidative stress, induces significant biological damages. In this study, we examined effect of diamide, a thioloxidizing reagent, on amylase release in rat parotid acinar cells. In the presence of diamide, isoproterenol (IPR)-induced cAMP formation and amylase release were partially reduced. Diamide had no effect on amylase release induced by forskolin and mastoparan, an adenylate cyclase activator and heterotrimeric GTP binding protein activator, respectively. In the cells pretreated with diamide, the binding affinity of [3H]dihydroalprenolol to β-receptors was reduced. These results suggest that oxidative stress results in reduction of binding affinity of ligand on β-receptor and consequently reduces protein secretory function in rat parotid acinar cells

Species identification, antifungal susceptibility, and clinical feature association of Aspergillus section Nigri isolates from the lower respiratory tract

Species of Aspergillus section Nigri are generally identified by molecular genetics approaches, whereas in clinical practice, they are classified as A. niger by their morphological characteristics. This study aimed to investigate whether the species of Aspergillus section Nigri isolated from the respiratory tract vary depending on clinical diagnosis. Forty-four Aspergillus section Nigri isolates isolated from the lower respiratory tracts of 43 patients were collected from February 2012 to January 2017 at the National Hospital Organization (NHO) Tokyo National Hospital. Species identification was carried out based on β-tubulin gene analysis. Drug susceptibility tests were performed according to the Clinical and Laboratory Standards Institute (CLSI) M38 3rd edition, and the clinical characteristics were retrospectively reviewed. A. welwitschiae was isolated most frequently, followed by A. tubingensis. More than half of the A. tubingensis isolates exhibited low susceptibility to azoles in contrast to only one A. welwitschiae isolate. Approximately three quarters of the patients from whom A. welwitschiae was isolated were diagnosed with colonization, whereas more than half the patients from whom A. tubingensis was isolated were diagnosed with chronic pulmonary aspergillosis (CPA). More attention needs to be given to the drug choice for patients with CPA with Aspergillus section Nigri infection because A. tubingensis, which was found to be frequently azole-resistant, was the most prevalent in these patients

Effect of itraconazole and fluconazole on the pharmacokinetics of valemetostat: An open‐label, phase I study in healthy subjects

Abstract Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non‐Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P‐glycoprotein (P‐gp [itraconazole]) in drug–drug interaction studies. Valemetostat is a substrate of CYP3A and P‐gp in vitro. This phase I, open‐label, single‐sequence crossover study (JapicCTI‐183902) assessed the pharmacokinetics (PK) of valemetostat when co‐administered with itraconazole (a strong CYP3A inhibitor and P‐gp inhibitor) or fluconazole (a moderate CYP3A inhibitor) in healthy Japanese male participants 20–45 years of age. Participants were equally allocated to receive two doses of valemetostat 25 mg, once alone and once with either itraconazole or fluconazole (400‐mg induction and 200‐mg once daily maintenance). Valemetostat PK parameters with versus without itraconazole or fluconazole were compared using analysis of variance models. Overall, 32 participants were enrolled. Co‐administration with itraconazole increased valemetostat peak concentration (Cmax) by 2.9‐fold and area under the plasma concentration–time curve extrapolated to infinity (AUCinf) by 4.2‐fold compared with valemetostat alone. When co‐administered with fluconazole, the Cmax and AUCinf of valemetostat were each increased by 1.6‐fold. No treatment‐related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P‐gp dual inhibitors

Comparison of textural properties and structure of gels prepared from cooked rice grain under different conditions

The objective of this study was to investigate the effects of rice variety, water content, and preparation temperature on the textural properties of gels processed from cooked rice grains via high‐speed shear homogenization. Rice gels were prepared from seven high‐amylose rice varieties. The results demonstrated the significant differences in rice gel hardness and hardening rates during storage based on the rice variety used. The proportion of short chains of amylopectin was negatively correlated with the hardness of the rice gel. The sample temperature before shear treatment also influenced the rice gel hardness. Rice gels prepared from cooked rice maintained at 75°C prior to homogenization showed a higher breaking force than those from cooked rice at 25°C. Observation using scanning electron microscopy demonstrated the tendency of the cooked rice sample maintained at 75°C to form a finer gel network after homogenization than those at 25°C from the same rice variety

Impact of decreased estimated glomerular filtration rate on Japanese acute stroke and its subtype

著者最終原稿版Objective In hypertensive patients with typical chest pain but absence of coronary stenosis the coronary microcirculation may be impaired, thus, our study aimed to appraise, in these subjects, the role of the coronary microcirculation, assessed by Myocardial Blush Grade (MBG) and Thrombolysis in Myocardial Infarction (TIMI) Frame Count (TFC). Methods A total of 95 subjects with chest pain and uninjured coronary arteries were recruited into the study: 80 subjects were hypertensive while 15 subjects were normotensive. The hypertensive subjects were divided into two subgroups: hypertensive subjects with positive scintigraphy and hypertensive subjects with negative scintigraphy. The TFC, a quantitative method of assessing coronary artery flow, the MBG, an assessment of the level of tissue perfusion, and the Total Myocardial Blush Score (TMBS), the sum of the myocardial blush grades of each coronary territory, were evaluated on the coronary angiogram of every patient. Results The TFC was higher (p<0.05) in hypertensive subjects than in normotensive subjects. The MBG and the TMBS were lower (p<0.05) in hypertensive subjects than in normotensive subjects. The TFC was higher (p<0.05) in positive scintigraphy than in negative scintigraphy. The MBG was lower (p<0.05) in positive scintigraphy than in negative scintigraphy. The Spearman rank correlation test showed that the TFC and the MBG was inversely associated. Conclusion The hypertensive subjects had impaired coronary artery flow and myocardial perfusion, documented by the TFC, MBG and myocardial perfusion scintigraphy. These methods may be universally applicable, in fact they are validated and most catheterization laboratories have access to them

Retrospective Comparison of the Efficacy of Tonsillectomy with and without Steroid-pulse Therapy in IgA Nephropathy Patients.

著者最終原稿版Objective Tonsillectomy and steroid-pulse (TSP) therapy have been proposed as a curative treatment for immunoglobulin A nephropathy (IgAN) in Japan. However, we sometimes encounter patients who reject steroid-pulse therapy because of concerns about the side effects of corticosteroids. Here, we examined the efficacy of TSP therapy and tonsillectomy alone for IgAN with urinary abnormalities. Methods Data on 40 IgAN patients diagnosed by renal biopsies, who presented glomerular hematuria and proteinuria at baseline and underwent bilateral palatine tonsillectomy, were analyzed retrospectively. Twenty of them underwent TSP therapy (TSP group), and 20 underwent tonsillectomy alone (T group). We examined associations between therapies, changes in urinary findings and renal function, and subsequent clinical remission (CR), defined as negative proteinuria and urinary erythrocytes of less than 5/high-power field. Results TSP group showed a significant decrease in proteinuria and hematuria earlier than T group. The rates of CR were significantly higher in TSP group compared with T group on the final observation period (75% vs. 45%, p<0.05). There was a significant difference between CR group and non-CR group only in the rate of receiving TSP therapy. Conclusion TSP therapy significantly increased the probability of CR compared with tonsillectomy alone in IgAN patients with urinary abnormalities