Comprehensive analysis of KCTD family genes associated with hypoxic microenvironment and immune infiltration in lung adenocarcinoma.

To obtain novel insights into the tumor biology and therapeutic targets of LUAD, we performed a comprehensive analysis of the KCTD family genes. The expression patterns and clinical significance of the KCTD family were identified through multiple bioinformatics mining. Moreover, the molecular functions and potential mechanisms of differentially expressed KCTDs were evaluated using TIMER 2.0, cBioPortal, GeneMANIA, LinkedOmics and GSEA. The results indicated that the mRNA and protein expression levels of KCTD9, KCTD10, KCTD12, KCTD15 and KCTD16 were significantly decreased in LUAD, while those of KCTD5 were significantly increased. High KCTD5 expression was significantly associated with advanced tumor stage, lymph node metastasis, TP53 mutation and poor prognosis. In addition, KCTD5 was positively correlated with CD8 + T cell, neutrophil, macrophage and dendritic cell infiltration. Additionally, KCTDs demonstrate promising prospects in the diagnosis of LUAD. Importantly, high KCTD5 expression was enriched in signaling pathways associated with the malignant progression of tumors, including the inflammatory response, the IL6/JAK/STAT3 signaling pathway, EMT and hypoxia. Further association analysis showed that KCTD5 was positively correlated with hypoxia-related genes such as HIF1. Overall, KCTDs can be used as molecular targets for the treatment of LUAD, as well as effective molecular biomarkers for diagnosis and prognosis prediction.

Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors.

AXL is a member of the TAM (TYRO3, AXL, MER) subfamily of receptor tyrosine kinases. It is upregulated in a variety of cancers and its overexpression is associated with poor disease prognosis and acquired drug resistance. Utilizing a fragment-based lead discovery approach, a new indazole-based AXL inhibitor was obtained. The indazole fragment hit 11, identified through a high concentration biochemical screen, was expeditiously improved to fragment 24 by screening our in-house expanded library of fragments (ELF) collection. Subsequent fragment optimization guided by docking studies provided potent inhibitor 54 with moderate exposure levels in mice. X-ray crystal structure of analog 50 complexed with the I650M mutated kinase domain of Mer revealed the key binding interactions for the scaffold. The good potency coupled with reasonable kinase selectivity, moderate in vivo exposure levels, and availability of structural information for the series makes it a suitable starting point for further optimization efforts.

A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors.

The COVID-19 pandemic caused by SARS-CoV-2 has created an unprecedented global health emergency. As of July 2021, only three antiviral therapies have been approved by the FDA for treating infected patients, highlighting the urgent need for more antiviral drugs. The SARS-CoV-2 3CL protease (3CLpro) is deemed an attractive drug target due to its essential role in viral polyprotein processing and pathogenesis. Indeed, a number of peptidomimetic 3CLpro inhibitors armed with electrophilic warheads have been reported by various research groups that can potentially be developed for treating COVID-19. However, it is currently impossible to compare their relative potencies due to the different assays employed. To solve this, we conducted a head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay to compare and identify potent inhibitors for development. Inhibitor design and the suitability of various warheads are also discussed.

Comparative Evaluation of the Chemical Composition, Antioxidant and Antimicrobial Activities of the Volatile Oils of Hawk Tea from Six Botanical Origins.

In this study, volatile oils of six Hawk tea varieties were studied for their chemical composition, antioxidant and antimicrobial activities to screen the most suitable botanical origins of Hawk tea. A total of 72 components were separated and identified from the six oils. The major constituents of the volatile oils were: α-pinene, camphene, limonene, 1,8-cineole, linalool, cis-nerolidol, and germacrene B. Moreover, the volatile oils were evaluated for antioxidant potential and antimicrobial activities. The results showed that all volatile oils exhibited acceptable antioxidant and antimicrobial activities, which suggested that these volatile oils may serve as natural alternatives to synthetic antioxidants and preservatives to be applied in food and pharmaceutical industries. Principal component analysis results denoted that some major compounds may be closely related to the antioxidant and antimicrobial activities. It also showed that the volatile oils from Litsea coreana var. lanuginosa and Litsea pungens Hemsl. were characterized by positive values of first two principal components, indicating higher active chemical compounds and antioxidant and antimicrobial activities compared with other species. Thus, they were temporarily considered as good sources of Hawk tea.

[Study on Brand Discrimination of Differential Oil Using Near-Infrared Spectroscopy with Different Resolutions].

The performance and influence of near-infrared spectroscopy with different resolutions for brand discrimination of differential oil was studied. Spectral data with resolutions of 4, 8, 16 and 32 cm(-1) were collected, and 10522.28-4443.425 cm(-1) spectra were analyzed after the removal of the absolute noises. The principal component analysis (PCA) of the spectral data at different resolutions indicated that the brands of differential oil could be discriminated. Patial least squares-discriminant analysis (PLS-DA) and support vector machine (SVM) models were built based on the full spectra with different resolutions. The discrimination results showed that all models obtained similar and good performances with the classification rate over 90%, and the best results were obtained when the model was built based on the full spectra with the resolution of 8 cm(-1). Successive projections algorithm was applied to select effective wavenumbers, and different effective wavenumbers were selected for the spectra with different resolutions. PLS-DA and SVM models based on the selected effective wavenumbers both obtained good results. Their results were similar to the models established based on full spectra. The results indicated that spectral resolution had little effect on the discrimination results, and spectral resolution effected the selection of effective wavenumbers, and spectral resolution should be taken into consideration for the selection of effective wavenumbers in practical applications. In all, near-infrared spectroscopy with different resolutions and the corresponding selected effective wavenumbers could be used for discrimination of differential oil brands.