Effects of switching weekly alendronate or risedronate to monthly minodronate in patients with rheumatoid arthritis: a 12-month prospective study

Summary: Switching weekly ALN or RIS to monthly MIN in patients with RA, of whom two-thirds were treated with low-dose PSL, significantly decreased bone turnover markers and increased BMD at 12 months, suggesting that monthly MIN may be an effective alternative treatment option of oral bisphosphonate treatment. Introduction: The aim of this prospective, observational study was to evaluate the effects of switching weekly alendronate (ALN 35 mg) or risedronate (RIS 17.5 mg) to monthly minodronate (MIN 50 mg) in patients with rheumatoid arthritis (RA). Methods: Patient characteristics were as follows: n = 172; 155 postmenopausal women, age 65.5 (44–87) years; T-score of lumbar spine (LS), −1.4; total hip (TH), −1.8; femoral neck (FN), −2.1; dose and rate of oral prednisolone (2.3 mg/day), 69.1 %; prior duration of ALN or RIS, 46.6 months; were allocated, based on their preference, to either the (1) continue group (n = 88), (2) switch-from-ALN group (n = 44), or (3) switch-from-RIS group (n = 40). Results: After 12 months, increase in BMD was significantly greater in group 3 compared to group 1: LS (4.1 vs 1.2 %; P < 0.001), TH (1.9 vs −0.7 %; P < 0.01), and FN (2.7 vs −0.5 %; P < 0.05); and in group 2 compared to group 1: LS (3.2 vs 1.2 %; P < 0.05) and TH (1.5 vs −0.7 %; P < 0.01). The decrease in bone turnover markers was significantly greater in group 3 compared to group 1: TRACP-5b (−37.3 vs 2.5 %; P < 0.001), PINP (−24.7 vs −6.2 %; P < 0.05), and ucOC (−39.2 vs 13.0 %; P < 0.05); and in group 2 compared to group 1: TRACP-5b (−12.5 vs 2.5 %; P < 0.05) at 12 months. Conclusions: Switching weekly ALN or RIS to monthly MIN in patients with RA may be an effective alternative treatment option of oral bisphosphonate treatment.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00198-015-3369-6Ebina K., Noguchi T., Hirao M., et al. Effects of switching weekly alendronate or risedronate to monthly minodronate in patients with rheumatoid arthritis: a 12-month prospective study. Osteoporosis International 27, 351 (2016); https://doi.org/10.1007/s00198-015-3369-6

Yokukansan Inhibits Neuronal Death during ER Stress by Regulating the Unfolded Protein Response

Recently, several studies have reported Yokukansan (Tsumura TJ-54), a traditional Japanese medicine, as a potential new drug for the treatment of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is known to play an important role in the pathogenesis of AD, particularly in neuronal death. Therefore, we examined the effect of Yokukansan on ER stress-induced neurotoxicity and on familial AD-linked presenilin-1 mutation-associated cell death.We employed the WST-1 assay and monitored morphological changes to evaluate cell viability following Yokukansan treatment or treatment with its components. Western blotting and PCR were used to observe the expression levels of GRP78/BiP, caspase-4 and C/EBP homologous protein.Yokukansan inhibited neuronal death during ER stress, with Cnidii Rhizoma (Senkyu), a component of Yokukansan, being particularly effective. We also showed that Yokukansan and Senkyu affect the unfolded protein response following ER stress and that these drugs inhibit the activation of caspase-4, resulting in the inhibition of ER stress-induced neuronal death. Furthermore, we found that the protective effect of Yokukansan and Senkyu against ER stress could be attributed to the ferulic acid content of these two drugs.Our results indicate that Yokukansan, Senkyu and ferulic acid are protective against ER stress-induced neuronal cell death and may provide a possible new treatment for AD

Effects of DHA- Rich n-3 Fatty Acid Supplementation on Gene Expression in Blood Mononuclear Leukocytes: The OmegAD Study

Background: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e. g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e. g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells. Methods and Findings: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up-and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e. g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e. g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels. Conclusions: We suggest that 6 months of dietary n-3 FA supplementatio

R-SNARE Homolog MoSec22 Is Required for Conidiogenesis, Cell Wall Integrity, and Pathogenesis of Magnaporthe oryzae

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins mediate intracellular vesicle fusion, which is an essential cellular process of the eukaryotic cells. To investigate the role of SNARE proteins in the rice blast fungus Magnaporthe oryzae, MoSec22, an ortholog of Saccharomyces cerevisiae SNARE protein Sec22, was identified and the MoSEC22 gene disrupted. MoSec22 restored a S. cerevisiae sec22 mutant in resistance to cell wall perturbing agents, and the ΔMosec22 mutant also exhibited defects in mycelial growth, conidial production, and infection of the host plant. Treatment with oxidative stress inducers indicated a breach in cell wall integrity, and staining and quantification assays suggested abnormal chitin deposition on the lateral walls of hyphae of the ΔMosec22 mutant. Furthermore, hypersensitivity to the oxidative stress correlates with the reduced expression of the extracellular enzymes peroxidases and laccases. Our study thus provides new evidence on the conserved function of Sec22 among fungal organisms and indicates that MoSec22 has a role in maintaining cell wall integrity affecting the growth, morphogenesis, and virulence of M. oryzae