No abstract

Public health is confronting the threat caused by antibiotic resistance and this means new antibacterial strategies must be developed urgently. Antimicrobial peptides (AMPs) have been considered as promising therapeutic candidates against infection in the post-antibiotic era. In this paper, we dismissed the significance of “Rana box” in the natural nigrocin-HL identified from skin secretion of Hylarana latouchii by comparing its activity with nigrocin-HLD without the motif. By substituting the “Rana box” sequence with an amidated phenylalanine residue, the natural peptide was modified into a shorter AMP nigrocin-HLM. Activities and toxicities of these two peptides in vitro and in vivo were compared. As a result, nigrocin-HLM not only displayed significantly increased potency against several representative microbes, but also high activity against the antibiotic-resistant methicillin-resistant S. aureus (MRSA, NCTC 12493 and ATCC43300 and several clinical isolates) as evidenced by markedly reduced minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), and minimum biofilm eradication concentration (MBEC). More strikingly, nigrocin-HLM exhibited prominent inhibition against MRSA infection in a pneumonia mice model. In addition, the substitution attenuated the toxicity of nigrocin-HLM as evidenced by precipitously decreased hemolytic and cytotoxic activities in vitro, and acute toxicity to mice in vivo. Taken these results into consideration, nigrocin-HLM should be a promising therapeutic candidate for anti-infection. And in addition to dismiss an indispensable role of “Rana box” in maintaining antimicrobial activity of nigrocin-HL, our data provided an inspired strategy for peptide optimization.

Atopic dermatitis (AD) is a prevalent inflammatory skin disease characterized by its chronic nature and relapse. Ample evidence suggests that non-coding RNAs play a major role in AD pathogenesis. However, the mechanism remains unknown, particularly in AD recurrence. Dynamic morphological and cytokine changes were measured throughout the whole course of an FITC-induced AD recurrence murine model. Microarray assay and integrative analysis were performed to comprehensively explore long non-coding RNA (lncRNA), messenger RNA (mRNA), and microRNA (miRNA) networks. Our results showed that an AD recurrence model was established. Overall, 5766 lncRNAs, 4025 mRNAs, and 202 miRNAs changed after elicitation, whereas, 419 lncRNAs, 349 mRNAs, and more notably, only 23 miRNAs, were dysregulated in the remission phase. Gene ontology (GO) and KEGG pathway enrichment analyses were used to investigate the potential functions of the dysregulated genes. The altered regulation of seven miRNAs and seven lncRNAs were validated in different stages of the model. The competing endogenous RNA (ceRNA) network inferred that lncRNA humanlincRNA0490+ could compete for miR-155-5p binding, through which it might affect Pkiα expression. Altogether, our findings have provided a novel perspective on the potential roles of non-coding RNAs in AD, and suggest that specific non-coding RNAs could be new therapeutic targets against AD recurrence.

Atopic dermatitis (AD) is a common chronic pruritic inflammatory skin disorder characterized by recurrent eczematous lesions. Interleukin (IL)−33, a cytokine of the IL-1 family, was found to play an important role in the pathogenesis of AD. As a key component of the inflammasome, NLRP3 has been mostly described in myeloid cells that to mediate inflammasome activation conducted proinflammatory cytokine production of the IL-1 family. However, the role of NLRP3 inflammasome in the pathogenesis of AD, as well as IL-33 processing are highly controversial. Whether NLRP3 can mediate IL-33 expression and secretion independently of the inflammasome in the epithelium of AD has remained unclear. In this article, we found the mRNA expression of Il33 and Nlrp3 were notably increased in the lesional skin of AD patients compared to healthy controls. We then found a significant positive correlation between the expression of Nlrp3 and Il33 in the epithelium of MC903-mediated AD mice model, but no changes were observed for Il36α, Il36γ, Il1β, or Il18 mRNA expression, as well as IL-1β or IL-18 production. Overexpression of NLRP3 in human immortalized epithelial cells increased IL-33 expression, whereas siRNA targeting NLRP3 abolished IL-33 expression. In addition, inhibition of NLRP3 inflammasome activation or caspase-1 activity with MCC950 or VX-765 showed no effect on the expression and secretion of IL-33 in AD mice. Unlike myeloid cells, NLRP3 predominantly located in the nucleus of epithelial cells, which could directly bind to Il33 specific-promoters and transactivate it through an interaction with transcription factor IRF4. Furthermore, NLRP3 deficient mice exhibited a significant alleviated epidermis inflammation and decreased mRNA expression and secretion of IL-33 in MC903-mediated AD mice without interfering with TSLP and IL-1β production. Our results demonstrate a novel ability of NLRP3 to function as a crucial transcription factor of IL-33 in epithelium independently of inflammasome that to mediate the pathological process of AD.