LINC00926 promotes progression of renal cell carcinoma via regulating miR-30a-5p/SOX4 axis and activating IFNγ-JAK2-STAT1 pathway.

The role of long non-coding RNA (lncRNA) in the progression of renal cell carcinoma (RCC) remains further study. Whether lncRNA may be used to predict the immunotherapy efficacy of RCC is less studied. In this study, LINC00926 was found to be mainly located in cytoplasm by FISH and RNA nuclear-cytoplasmic fractionation. Downregulation of LINC00926 in RCC cell lines inhibited the progression and metastasis of RCC cells. RNA pull-down assay and dual-luciferase reporter assay demonstrated that LINC00926 functioned as miR-30a-5p sponge to facilitate SOX4 expression. LINC00926 overexpression in BALB/c mice enhanced PD-L1 surface expression and resulted in immune escape. Mechanistic investigations showed that LINC00926 competitively bound to Lyn, leading to the inhibition of CBL-mediated ubiquitination and degradation, and stabilized Lyn, contributing to the activation of IFNγ-JAK2-STAT1 signaling pathway. Moreover, LINC00926, together with PD-L1 or PD-1 expression, may predict the overall survival in RCC patients. Therefore, LINC00926 has the potential to be a novel therapeutic target and a biomarker to predict ICB immunotherapy response in RCC.

Potential pathways and genes expressed in Chrysanthemum in response to early fusarium oxysporum infection.

BACKGROUND: Chrysanthemum Fusarium wilt is a common fungal disease caused by Fusarium oxysporum, which causes continuous cropping obstacles and huge losses to the chrysanthemum industry. The defense mechanism of chrysanthemum against F. oxysporum remains unclear, especially during the early stages of the disease. Therefore, in the present study, we analyzed chrysanthemum 'Jinba' samples inoculated with F. oxysporum at 0, 3, and 72 h using RNA-seq. RESULTS: The results revealed that 7985 differentially expressed genes (DEGs) were co-expressed at 3 and 72 h after F. oxysporum infection. We analyzed the identified DEGs using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology. The DEGs were primarily enriched in "Plant pathogen interaction", "MAPK signaling pathway", "Starch and sucrose metabolism", and "Biosynthesis of secondary metabolites". Genes related to the synthesis of secondary metabolites were upregulated in chrysanthemum early during the inoculation period. Furthermore, peroxidase, polyphenol oxidase, and phenylalanine ammonia-lyase enzymes were consistently produced to accumulate large amounts of phenolic compounds to resist F. oxysporum infection. Additionally, genes related to the proline metabolic pathway were upregulated, and proline levels accumulated within 72 h, regulating osmotic balance in chrysanthemum. Notably, the soluble sugar content in chrysanthemum decreased early during the inoculation period; we speculate that this is a self-protective mechanism of chrysanthemums for inhibiting fungal reproduction by reducing the sugar content in vivo. In the meantime, we screened for transcription factors that respond to F. oxysporum at an early stage and analyzed the relationship between WRKY and DEGs in the "Plant-pathogen interaction" pathway. We screened a key WRKY as a research target for subsequent experiments. CONCLUSION: This study revealed the relevant physiological responses and gene expression changes in chrysanthemum in response to F. oxysporum infection, and provided a relevant candidate gene pool for subsequent studies on chrysanthemum Fusarium wilt.

Single-component lipid nanoparticles for engineering SOCS1 gene-silenced dendritic cells to boost tumor immunotherapy.

Dendritic cells (DCs) that can prime antitumor responses show great potential in tumor immunotherapy, whereas the unsatisfactory effect which can be ascribed in part to the high expression of inhibitory cytokines, such as the suppressor of cytokine signaling 1 (SOCS1), restricts their application. Thus, silencing these genes in DCs is essential for DC-based therapy. However, safe and effective delivery of siRNA to DCs still faces challenges. Herein, we designed single-component lipid nanoparticles comprising a solely cationic lipid (OA2) for introducing siRNA into mouse DCs in order to inhibit the immunosuppressive gene and boost the effector responses of DC-based therapy. Compared to other multi-component lipid nanoparticles, single-component lipid nanoparticles are theoretically easy-to-control and detective, which is beneficial for future translation. We showed that the application of OA2 lipid nanoparticles significantly downregulated the expression of SOCS1 in DCs over 50%, compared with the commercial lipofectine2000. Besides, the treatment of OA2 lipid nanoparticles had no influence on the antigen capture of DCs. Thus, we fabricated a SOCS1-downregulated DC vaccine pulsed with Ova antigen and demonstrated that the antigen presentation and pro-inflammatory factor secretion ability of DCs were improved due to the SOCS1 downregulation, leading to an ameliorated immunosuppressive tumor microenvironment and finally exhibiting potent tumor prevention and suppression in B16-Ova tumor-bearing mice. Single-component lipid nanoparticles, which provide an available vector platform for siRNA delivery to primary DCs, appear to be a potent tool to engineer DCs and in turn boost DC-based tumor immunotherapy.

Design, Synthesis and Biological Evaluation of Anti-tuberculosis Agents based on Bedaquiline Structure.

BACKGROUND: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial ATP synthase. However, studies have found that bedaquiline has serious side effects due to high lipophilicity. Recently, the complete structure of ATP synthase was first reported in the Journal of Science. OBJECTIVE: The study aimed to design, synthesise and carry out biological evaluation of antituberculosis agents based on the structure of bedaquiline. METHODS: The mode of action of bedaquiline and ATP synthase was determined by molecular docking, and a series of low lipophilic bedaquiline derivatives were synthesized. The inhibitory activities of bedaquiline derivatives towards Mycobacterium phlei 1180 and Mycobacterium tuberculosis H37Rv were evaluated in vitro. A docking study was carried out to elucidate the structureactivity relationship of the obtained compounds. The predicted ADMET properties of the synthesized compounds were also analyzed. RESULTS: The compounds 5c3, 6a1, and 6d3 showed good inhibitory activities (MIC=15.62 ug.mL-1). At the same time, the compounds 5c3, 6a1, and 6d3 also showed good drug-like properties through molecular docking and ADMET properties prediction. CONCLUSION: The results of in vitro anti-tuberculosis activity assays, docking studies and ADMET predictions indicate that the synthesized compounds have potential antifungal activity, with compounds 6a1 being further optimized and developed as lead compounds.