Shandong Hubble Kisen Biological Technology Co Ltd

Over the past decades, the incidence and modality of invasive fungal infections have been significantly underestimated. And the limited availability of clinically effective antifungals further underscores the need for novel therapeutic agents. In this study, a series of novel 8-hydroxyquinolin-5-ylidene thiosemicarbazone derivatives (A5-A32) were designed and synthesized via a condensation reaction between 5-formyl-8-hydroxyquinoline and substituted hydrazinecarbothioamides. The in vitro antifungal activity of all synthesized compounds was evaluated against a panel of clinically relevant fungal pathogens using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, with minimum inhibitory concentrations (MICs) ranging from 4 to ≤ 0.0313 μg/mL. Notably, compound A14 was the most active, demonstrating the lowest MICs among the compounds against each of the tested seven fungal pathogens. Specifically, A14 exhibited remarkable potency against Cryptococcus gattii, C. neoformans, C. glabrata, and C. auris, with MICs ranging from ≤ 0.0313 to 2 μg/mL. This potency is significantly higher than that of the lead compound 5r (MICs: 0.25- >16 μg/mL) and fluconazole (MICs: 2->16 μg/mL). Furthermore, A14 inhibited hyphal formation in C. albicans SC5314 at 8 μg/mL, and remarkably inhibited biofilm formation in both C. albicans SC5314 and C. neoformans H99, achieving >90 % suppression at 32 μg/mL. The cytotoxic effects of compound A14 on the viability of HUVECs and Caco-2 cells were evaluated using the CCK-8 assay, demonstrating acceptable safety profiles. As an innovative antifungal agent, 8-hydroxyquinolin-5-ylidene thiosemicarbazone A14 warrants further investigation.

In this study, a quercetin-loaded liposome system modified with collagenase was developed to increase QU penetration in the ECM and improve IPF treatment. Quercetin-loaded long circulation liposome (QU-LP) and quercetin-loaded liposome modified with collagenase type I (QU-CLP) were prepared, followed by characterization of the encapsulation efficiency, particle size, morphology, and in vitro drug release. Their effect on the cytotoxicity of A549 cells was detected by the Cell Counting Kit-8, and the cellular uptake was investigated using cellular fluorescence imaging and flow cytometry. TGF-β1 induced A549 cell model was established to mimic pulmonary fibrosis to explore further the anti-pulmonary fibrosis effect of QU-CLP by CCK8 experiment. QU-CLP significantly improves the solubility and bioavailability of QU by encapsulating it in the internal cavity with a high encapsulation efficiency (EE%) of 92.86 ± 1.03%. Liposomes alleviate the influence of QU on normal A549 cell growth. Enhanced fluorescence intensity was observed in A549 cells treated with coumarin 6-labeled and collagenase-modified nanoliposomes (C6-CLP) after 4 h of incubation on the collagen matrix, confirming that collagenase-loaded liposomes could penetrate the collagen barrier and cells internalized more hydrophobic drug. The mean fluorescence intensity (MFI) of the C6-CLP group was 2.88 times that of the C6-labeled nanoliposomes (C6-LP). Moreover, QU-CLP significantly (**P < 0.01) inhibited the proliferation of A549 cells stimulated by TGF-β1. QU-CLP has excellent potential for delivering QU with enhanced bioavailability, high cellular uptake efficiency, and improved therapeutic efficacy in IPF.