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Myostatin, a muscle-specific TGF-β, negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin binds to and inhibits the C-terminal myostatin mature domain (ligand). We previously identified the myostatin inhibitory core (IC) composed of 29 amino acids in the myostatin prodomain that not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. However, systemic administration of the IC peptide failed to alleviate muscle atrophy in a mouse model of caveolin 3-deficient limb-girdle muscular dystrophy (LGMD) 1C. Here, we designed stapled peptides derived from the IC by alkyne-to-Cys linkage between the side chains of two separate amino acid residues. We optimized them using by in vitro myostatin-induced transcriptional activity assay and in silico structural analysis. The optimized stapled peptide exhibited a 10-fold increase of myostatin inhibitory activity (IC50: 230nM), when compared to the IC peptide. We administered the optimized stapled peptide to DBA/2-mdx mice, a severe model of Duchenne muscular dystrophy (DMD). Intravenous injection of the peptide improved muscle mass and grip strength in the mice. Surprisingly, peptide significantly ameliorated dystrophic changes (necrosis, incomplete regeneration, fibrosis, and fatty regeneration) in the DBA/2-mdx mice. This stapled IC peptide combats the dystrophic process, demonstrating its potential as a disease-modifying therapy for muscular dystrophies. We are investigating the molecular mechanisms by which the IC peptide improves dystrophic pathology. [ABSTRACT FROM AUTHOR]

Background: Policies, such as stay home, bubbling, and stay with your community, recommending that individuals reduce contact with diverse communities, including families and schools, have been introduced to mitigate the spread of the COVID-19 pandemic. However, these policies are violated if individuals from various communities gather, which is a latent risk in a real society where people move among various unreported communities., Objective: We aimed to create a physical index to assess the possibility of contact between individuals from diverse communities, which serves as an indicator of the potential risk of SARS-CoV-2 spread when considered and combined with existing indices., Methods: Moving direction entropy (MDE), which quantifies the diversity of moving directions of individuals in each local region, is proposed as an index to evaluate a region's risk of contact of individuals from diverse communities. MDE was computed for each inland municipality in Tokyo using mobility data collected from smartphones before and during the COVID-19 pandemic. To validate the hypothesis that the impact of intercommunity contact on infection expansion becomes larger for a virus with larger infectivity, we compared the correlations of the expansion of infectious diseases with indices, including MDE and the densities of supermarkets, restaurants, etc. In addition, we analyzed the temporal changes in MDE in municipalities., Results: This study had 4 important findings. First, the MDE values for local regions showed significant invariance between different periods according to the Spearman rank correlation coefficient (>0.9). Second, MDE was found to correlate with the rate of infection cases of COVID-19 among local populations in 53 inland regions (average of 0.76 during the period of expansion). The density of restaurants had a similar correlation with COVID-19. The correlation between MDE and the rate of infection was smaller for influenza than for COVID-19, and tended to be even smaller for sexually transmitted diseases (order of infectivity). These findings support the hypothesis. Third, the spread of COVID-19 was accelerated in regions with high-rank MDE values compared to those with high-rank restaurant densities during and after the period of the governmental declaration of emergency (P<.001). Fourth, the MDE values tended to be high and increased during the pandemic period in regions where influx or daytime movement was present. A possible explanation for the third and fourth findings is that policymakers and living people have been overlooking MDE., Conclusions: We recommend monitoring the regional values of MDE to reduce the risk of infection spread. To aid in this monitoring, we present a method to create a heatmap of MDE values, thereby drawing public attention to behaviors that facilitate contact between communities during a highly infectious disease pandemic., (©Yukio Ohsawa, Yi Sun, Kaira Sekiguchi, Sae Kondo, Tomohide Maekawa, Morihito Takita, Tetsuya Tanimoto, Masahiro Kami. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 21.08.2024.)

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666., (© 2024. The Author(s).)

Objectives: Several therapeutic agents have been developed and used for the clinical treatment of systemic lupus erythematosus (SLE). In cases where SLE is accompanied by severe organ failures, such as neuropsychiatric lupus erythematosus (NPSLE) and acute onset of lupus nephritis, the use of potent immunosuppressive drugs, such as cyclophosphamide, is necessary. However, potent immunosuppressive drugs are known to increase infection risks. Thus, the development of therapeutic agents with novel mechanisms is urgently required. Previously, we reported that treatment with lysophosphatidic acid (LPA) prevents depression-like behaviours by suppressing microglial activation in MRL/lpr mice. In this study, we examined whether the treatment with LPA improves glomerulonephritis by affecting systemic immunity in MRL/lpr mice., Methods: Eighteen-week-old MRL/lpr mice were treated with a vehicle or LPA for 3 weeks. After treatment, the glomerular inflammation and damage parameters were compared between the 2 groups. Moreover, we examined the effects of LPA on immune cells by flow cytometry using isolated splenocytes., Results: LPA treatment in MRL/lpr mice significantly reduced the daily urinary albumin content and suppressed the CD68-positive cells and Periodic acid-Schiff (PAS)-positive areas in the glomeruli. The treatment also suppressed plasma anti-dsDNA antibodies and inflammatory cytokines in MRL/lpr mice. Although LPA did not significantly affect the total number of splenocytes, the treatment significantly reduced CD11b+Ly6G-Ly6C- cells (mature macrophages), as well as CD11b+Ly6G-Ly6C-CD68+ cells (activated mature macrophages)., Conclusions: These results suggest that LPA may improve glomerulonephritis by suppressing macrophage activation in MRL/lpr mice.