A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways

Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial

bbsag20 dataset: total 30,851 single-cell genomes, 51 metagenomes, and 1,544 metagenome-assembled genomes from the human oral/gut microbiota

READMEThis is the large single amplified genome calatog (bbsag20) corresponding to the publication below:Title: "Single Amplified Genome Catalog Reveals the Dynamics of Mobilome and Resistome in the Human Microbiome" (preprint: 10.1101/2023.12.06.570492)Authors: Tetsuro Kawano-Sugaya, Koji Arikawa, Tatsuya Saeki, Taruho Endoh, Kazuma Kamata, Ayumi Matsuhashi, and Masahito HosokawaResearch abstractThe increase in metagenome-assembled genomes (MAGs) has significantly advanced our understanding of the functional characterization and taxonomic assignment within the human microbiome. However, MAGs, as population consensus genomes, often mask heterogeneity among species and strains, thereby obfuscating the precise relationships between microbial hosts and mobile genetic elements (MGEs). In contrast, single amplified genomes (SAGs) derived via single-cell genome sequencing can capture individual genomic content, including MGEs. We present the bbsag20 dataset, which encompasses 17,202 human-associated prokaryotic SAGs and 869 MAGs, spanning 647 gut and 312 oral bacterial species. The SAGs revealed diverse bacterial lineages and MGEs with a broad host range that were absent in the MAGs and traced the translocation of oral bacteria to the gut. Importantly, our SAGs linked individual mobilomes to resistomes and meticulously charted a dynamic network of antibiotic resistance genes (ARGs) on MGEs, pinpointing potential ARG reservoirs in the microbial community.This dataset contains four types of data:mg: Fecal metagenome from x51 samples (QLF001-064)mag: Fecal metagenome-assembled genome from x51 samples (QLF001-064; x1,544 genomes containing x869 HQ/MQ genomes)QLFsag: Fecal single amplified genome from x51 samples (QLF001-064; x19,042 genomes containing x10,066 HQ/MQ genomes)QLSsag: Oral single amplified genome from x32 samples (QLS001-033; x11,809 genomes containing x7,136 HQ/MQ genomes)Details of genomes (e.g. assembly statistics, quality, taxonomy classification, and number of mobile genetic elements) are described in summary.tsvThe raw data produced in this study were deposited at NCBI under BioProject ID PRJNA1030952.</p

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5.

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM

心室性期外収縮に対するMexiletineの臨床効果およびその消化器系副作用の対策について

雑誌掲載版抗不整脈薬mexiletine (MX) 300 mgおよび450 mg/日の心室性期外収縮(VPC)に対する臨床効果を,39例の患者について,主にホルター心電図を用いて検討した.また消化器症状改善剤オキセサゼイン(OX)およびマレイン酸トリメプチン(TM)の,MXの消化器系副作用に対する効果も併せて検討した.VPC数減少率からみれば,MXの有効率は61.6%であった.VPC重症度も加味した不整脈改善度では,66.7%の症例が「有効」以上と判定された.消化器症状は少なからず出現したが,OXあるいはTM,特にTMはその予防効果が大きく,MXの継続投与を可能ならしめるものと考えられ