Emerging roles of long non-coding RNAs in osteosarcoma.

Osteosarcoma (OS) is a highly aggressive and lethal malignant bone tumor that primarily afflicts children, adolescents, and young adults. However, the molecular mechanisms underlying OS pathogenesis remain obscure. Mounting evidence implicates dysregulated long non-coding RNAs (lncRNAs) in tumorigenesis and progression. These lncRNAs play a pivotal role in modulating gene expression at diverse epigenetic, transcriptional, and post-transcriptional levels. Uncovering the roles of aberrant lncRNAs would provide new insights into OS pathogenesis and novel tools for its early diagnosis and treatment. In this review, we summarize the significance of lncRNAs in controlling signaling pathways implicated in OS development, including the Wnt/ß-catenin, PI3K/AKT/mTOR, NF-κB, Notch, Hippo, and HIF-1α. Moreover, we discuss the multifaceted contributions of lncRNAs to drug resistance in OS, as well as their potential to serve as biomarkers and therapeutic targets. This review aims to encourage further research into lncRNA field and the development of more effective therapeutic strategies for patients with OS.

Design of SC PEP with enhanced stability against pepsin digestion and increased activity by machine learning and structural parameters modeling.

Prolyl endopeptidases from Sphingomonas capsulata (SC PEP) has attracted much attention as promising oral therapy candidate for celiac sprue, however, its low stability in the gastric environment leads to unsatisfactory clinical results. Therefore, improving its stability against pepsin digestion at low pH is crucial for clinical applications, but challenging. In this study, machine learning and physical parameter model were combined to design SC PEP mutants. After iterations, 20 mutants had higher hydrolysis activity in stomach environment, which was up to 14.1-fold compared with wild-type SC PEP. Mutant M24 involving stable and active mutations and pegylated M24 (M24-PEG) had higher activity of hydrolyzing immunogen in bread than wild-type SC PEP in vitro and in vivo, and residual immunogens in simulated gastric environment were only 1/8 and 1/10 of that in the wild-type SC PEP group. The total residual immunogens in the gastrointestinal tract of mice in the M24 and M24-PEG groups were <20 ppm, reaching the standard of non-toxic food. Our results indicate that the combination of M24 (or M24-PEG) with EP-B2 may be a promising candidate for celiac disease, and the strategies developed in this study provide a paradigm for the design of SC PEP stability mutants.

Effect of Lacticaseibacillus paracasei N1115 on Immunomodulatory and Gut Microbial Composition in Young Children: A Randomized, Placebo-Controlled Study.

Lactobacillus paracasei N1115 (Lp N1115) was isolated from fermented milk products. The administration of Lp N1115 is safe and well tolerated in Chinese children, but its effectiveness among young Chinese children is still unclear. To investigate the efficacy of Lp N1115 as a probiotic to enhance gut development in Chinese infants and toddlers born by cesarean section, 109 healthy and cesarean-delivered infants aged 6-24 months were recruited for a 12-week randomized, placebo-controlled trial, with 101 finally completing the study. Saliva and stool samples were collected and detected at weeks 0, 4, 8, and 12 of the intervention. Statistical analyses were performed by using a per-protocol (PP) approach. After 12 weeks of intervention, the fecal pH in the control group increased (p = 0.003), while the fecal pH in the experimental group did not change. Salivary cortisol decreased from baseline in the experimental group (p = 0.023), while the control group showed little change. In addition, Lp N1115 increased the fecal sIgA content of infants aged 6-12 months (p = 0.044) but had no obvious effect on fecal calprotectin and saliva sIgA. At week 4, the increase in Lactobacillus relative to baseline was higher in the experimental group than in the control group (p = 0.019). Further analysis showed a trend toward a higher detection rate of Lactobacillus in the experimental group than in the control group (p = 0.039). In conclusion, Lp N1115 was able to enhance the content of Lactobacillus and maintain fecal pH levels. Its beneficial effects on gut development were more obvious in 6-12-month-old infants.

Design SMAP29-LysPA26 as a Highly Efficient Artilysin against Pseudomonas aeruginosa with Bactericidal and Antibiofilm Activity.

Antimicrobial resistance (AMR) is a major issue to global health. The multidrug-resistant (MDR) Gram-negative infections, particularly infected by carbapenem-resistant pathogens, urgently need efficient antibiotics and novel therapy. However, the scientific challenges of aiming for innovative approaches against Gram-negative bacteria have hindered the research and development of antibiotic drugs. Phage-derived endolysins are bacteriolytic and specific for a bacterial species or genus, providing a promising antibiotic strategy. However, the outer membrane of Gram-negative bacteria could prevent the peptidoglycan layer from the hydrolysis of endolysins. Antimicrobial peptides usually destabilize the outer membrane and could enhance the antibiotic activity of endolysins. In this study, we designed new artilysins with antimicrobial-peptide SMAP29 fusion at the N-terminal of LysPA26 (named as AL-3AA, AL-9AA, and AL-15AA), and evaluated them. The results showed artilysin AL-3AA to be highly bactericidal; even 0.05 mg/mL AL-3AA could reduce 5.81 log units P. aeruginosa without EDTA in 60 min. It killed P. aeruginosa rapidly and dose-dependently through cell lysis. AL-3AA inhibited P. aeruginosa PAO1 biofilm formation and significantly decreased mature P. aeruginosa biofilms. It also had potential broad-spectrum activity against susceptible Gram-negative bacteria in the hospital, including K. pneumoniae and E. coli. The antibacterial mechanism investigation has provided valuable information about the antibacterial action of AL-3AA, which can lyse and disintegrate the bacterial quickly. These results suggested AL-3AA could be a new and promising antimicrobial agent for the combat of P. aeruginosa. IMPORTANCE Antimicrobial resistance (AMR) is a major issue to global health, particularly the multidrug-resistant (MDR) Gram-negative infections, which pose great challenges. Even new antibiotics research is ongoing, antibiotics used to treat Gram-negative bacteria in the clinical are limited in a small set of molecular scaffolds, and biomolecular categories of antibiotics are urgently needed. In this study, we designed new proteins by combining antimicrobial peptides and endolysins for synergistic bactericidal effects. One of designed proteins, named AL-3AA, showed highly bactericidal, and killed P. aeruginosa rapidly and dose-dependently through cell lysis. It also killed Klebsiella pneumoniae and Escherichia coli, showing potential broad-spectrum activity against susceptible Gram-negative bacteria in the hospital. All results suggest AL-3AA could be a new and promising antimicrobial agent for the combat of P. aeruginosa.