Glioblastoma is the most common malignant brain tumor and has a poor prognosis. Tachykinin receptor neurokinin-1 (NK1R) is a promising target in glioblastoma therapy because of its overexpression in human glioblastoma. NK1R agonists promote glioblastoma cell growth, whereas NK1R antagonists efficiently inhibit cell growth both and However, the molecular mechanisms involved in these effects are incompletely understood. β-Arrestins (ARRBs) serve as scaffold proteins and adapters to mediate intracellular signal transduction. Here we show that the ARRB1-mediated signaling pathway is essential for NK1-mediated glioblastoma cell proliferation. ARRB1 knockdown significantly inhibited NK1-mediated glioblastoma cell proliferation and induced G/M phase cell cycle arrest. ARRB1 knockdown cells showed remarkable down-regulation of CDC25C/CDK1/cyclin B1 activity. We also demonstrated that ARRB1 mediated prolonged phosphorylation of ERK1/2 and Akt in glioblastoma cells induced by NK1R activation. ERK1/2 and Akt phosphorylation are involved in regulating CDC25C/CDK1/cyclin B1 activity. The lack of long-term ERK1/2 and Akt activation in ARRB1 knockdown cells was at least partly responsible for the delayed cell cycle progression and proliferation. Moreover, we found that ARRB1-mediated ERK1/2 and Akt phosphorylation regulated the transcriptional activity of both NF-κB and AP-1, which were involved in cyclin B1 expression. ARRB1 deficiency increased the sensitivity of glioblastoma cells to the treatment of NK1R antagonists. Taken together, our results suggest that ARRB1 plays an essential role in NK1R-mediated cell proliferation and G/M transition in glioblastoma cells. Interference with ARRB1-mediated signaling via NK1R may have potential significance for therapeutic strategies targeting glioblastoma.
As numerous clinical isolates are resistant to most conventional antibiotics, infections caused by multidrug-resistant bacteria are associated with a higher death rate. Antimicrobial peptides show great potential as new antibiotics. However, a major obstacle to the development of these peptides as useful drugs is their low stability. To overcome the problem of the natural antimicrobial peptide CPF-C1, we designed and synthesized a series of analogs. Our results indicated that by introducing lysine, which could increase the number of positive charges, and by introducing tryptophan, which could increase the hydrophobicity, we could improve the antimicrobial activity of the peptides against multidrug-resistant strains. The introduction of d-amino acids significantly improved stability. Certain analogs demonstrated antibiofilm activities. In mechanistic studies, the analogs eradicated bacteria not just by interrupting the bacterial membranes, but also by linking to DNA, which was not impacted by known mechanisms of resistance. In a mouse model, certain analogs were able to significantly reduce the bacterial load. Among the analogs, CPF-9 was notable due to its greater antimicrobial potency in vitro and in vivo and its superior stability, lower hemolytic activity, and higher antibiofilm activity. This analog is a potential antibiotic candidate for treating infections induced by multidrug-resistant bacteria.
Pseudomonas aeruginosa is particularly difficult to treat because it possesses a variety of resistance mechanisms and because it often forms biofilms. Antimicrobial peptides represent promising candidates for future templates of antibiotic-resistant bacterial infections due to their unique mechanism of antimicrobial action. In this study, we first found that the antimicrobial peptide Feleucin-K3 has potent antimicrobial activity against not only the standard strain of P. aeruginosa but also against the multidrug-resistant strains isolated from clinics. Then, the structure-activity relationship of the peptide was investigated using alanine and D-amino acid scanning. Among the analogs synthesized, FK-1D showed much more potent antimicrobial activity, superior stability, and very low toxicity, and it was able to permeabilize bacterial membranes. Furthermore, it exhibited significant anti-biofilm activity. More importantly, FK-1D showed excellent antimicrobial activity in vivo, especially against clinical multidrug-resistant bacteria, in contrast to ceftazidime. Our results suggested that FK-1D could be subjected to fixed-point modification in the first and fourth sites to further optimize its medicinal properties and potential as a lead compound for the treatment of infections caused by multidrug-resistant P. aeruginosa and the associated biofilms.
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