Effect of Bakumondo-to on cytochrome P450 activities in rat liver microsomes

AbstractBakumondo-to is a traditional herbal medicine. It has been widely used for the treatment of chronic airway diseases. Recently, it was reported that several herbal medicines affected cytochrome P450 (CYP). However, there is little information about the effects of Bakumondo-to on CYP activities. In this study, we evaluated the effects of Bakumondo-to on CYP activities in rat liver microsomes. Rats were orally treated twice a day with Bakumondo-to at doses of 2.0g/kg body weight/day for 4days. CYP activities were determined in liver microsomes isolated from treated rats. CYP1A2, CYP2C, and CYP3A activities were measured using their specific substrates [7-methoxyresorufin, 7-methoxy-4-(trifluoromethyl)-coumarin, and 7-benzyloxyquinoline, respectively]. Bakumondo-to decreased CYP1A2 activity by 42.5±7.8%, increased CYP2C activity by 158.0±29.6%, and decreased CYP3A activity to 81.5±7.8% of the control level. Activities were expressed as percentages of the control.Bakumondo-to induced CYP2C activity and decreased CYP1A2 activity; it may cause drug-herbal interactions. It is suggested that combinations of Bakumondo-to and drugs that are metabolized by CYP1A2 and CYP2C should be carefully used in clinical settings

Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBVencoded RNA.We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-a, and arginase 1, suggesting the immune regulatory role of BART miRNAs.The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma.These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV1 B-cell lymphoma. (Blood. 2018;131(23):2552-2567)

Changes in Glaucoma Medication during the Past Eight Years and Future Directions in Japan Based on an Insurance Medical Claim Database

Purpose. To investigate changes in the status of glaucoma care between 2006 and 2013 and to predict future directions of glaucoma care in Japan. Subjects and Methods. Japanese subjects registered in the largest national insurance claim database in Japan from 2006 to 2013 were analyzed. Estimations of the number of glaucoma patients during the past eight years and of the number of future patients were calculated. Changes in prescription trends among the same patients in the three-year period after initiating antiglaucoma medication were also investigated. Results. There was a total of 3,016,000 subjects in the database. The proportion of glaucoma patients increased consistently from 2.5% in 2006 to 4.5% in 2013. This trend was predicted to continue until 2025, followed by a constant decrease with age. The most frequently prescribed antiglaucoma medications were prostaglandin analogues (PGs); however, in recent years, fixed combination therapy has emerged as a major treatment. Among 2856 newly diagnosed glaucoma patients; 94.7% of the patients initially received a single medication, but 25% of the patients received additional medications within 3 years. Conclusions. The prevalence of glaucoma patients has significantly increased during the past eight years. The number of antiglaucoma medications continuously increased during the treatment period

Targeted Deletion of Capn4 in Cells of the Chondrocyte Lineage Impairs Chondrocyte Proliferation and Differentiation▿

Calpains are calcium-dependent intracellular cysteine proteases, which include ubiquitously expressed μ- and m-calpains. Both calpains are heterodimers consisting of a large catalytic subunit and a small regulatory subunit. The calpain small subunit encoded by the gene Capn4 directly binds to the intracellular C-terminal tail of the receptor for the parathyroid hormone (PTH) and PTH-related peptide and modulates cellular functions in cells of the osteoblast lineage in vitro and in vivo. To investigate a physiological role of the calpain small subunit in cells of the chondrocyte lineage, we generated chondrocyte-specific Capn4 knockout mice. Mutant embryos had reduced chondrocyte proliferation and differentiation in embryonic growth plates compared with control littermates. In vitro analysis further revealed that deletion of Capn4 in cells of the chondrocyte lineage correlated with impaired cell cycle progression at the G1/S transition, reduced cyclin D gene transcription, and accumulated cell cycle proteins known as calpain substrates. Moreover, silencing of p27Kip1 rescued an impaired cell growth phenotype in Capn4 knockdown cells, and reintroducing the calpain small subunit partially normalized cell growth and accumulated cyclin D protein levels in a dose-dependent manner. Collectively, our findings suggest that the calpain small subunit is essential for proper chondrocyte functions in embryonic growth plates

Investigation of visual and physical factors associated with inadequate instillation of eyedrops among patients with glaucoma.

PurposeThe aim of this study was to investigate the frequency of eyedrop instillation failure and its related physical and visual function factors among glaucoma patients who used hypotensive eyedrops daily.Subjects and methodsPatients with a history of self-instillation of one or more ocular hypotensive ophthalmic solutions for six or more months were enrolled. Definitions of instillation failure were eyedrop instillation other than on the eye surface; eyedrop contact with eyelashes; eyedrop bottle tip contact with the eyelashes, eye surface or ocular adnexa; or two or more drops instilled with one instillation trial. To clarify factors related to instillation failure, we used visual function tests and investigated cervical spine extension angles during instillation, pinching strength, physical ataxia (evaluated using the Scale for the Assessment and Rating of Ataxia), motor dysfunction of the upper limbs (evaluated using the Disabilities of the Arm, Shoulder and Hand questionnaire), and vision quality (evaluated using the National Eye Institute Visual Function Questionnaire 25).ResultsOf 103 total subjects, 61.2% satisfied the definition of instillation failure. Instillation of the eyedrop other than at the cul-desac (76.2%) was the most frequent reason for failure, followed by contact of the tip of the eyedrop bottle (22.2%) and instillation of the same or more than two eyedrops in a single attempt (11.1%). Advanced age, a shallow cervical spine extension angle, weak pinching strength, poor motor dysfunction of the upper limbs, the degree of ataxia, poor best-corrected visual acuity, and visual field scores were significant risk factors for instillation failure. Vision quality may have some relation to instillation failure.ConclusionIt is highly recommended that instillation failure be routinely investigated even among patients with adequate experience using eyedrops and that correct therapies are chosen in a patient-based fashion