Identification of an endoplasmic reticulum stress-related prognostic risk model with excellent prognostic and clinical value in oral squamous cell carcinoma.

BACKGROUND: Recently, endoplasmic reticulum stress related gene (ERS) markers have performed very well in predicting the prognosis of tumor patients. METHODS: The differentially expressed genes in Oral squamous cell carcinoma (OSCC) were obtained from TCGA and GTEx database. Three prognosis-related and differentially expressed ERSs were screened out by Least Absolute Selection and Shrinkage Operator (Lasso) regression to construct a prognostic risk model. Receiver Operating Characteristic Curve (ROC), riskplots and survival curves were used to verify the model's accuracy in predicting prognosis. Multi-omics analysis of immune infiltration, gene mutation, and stem cell characteristics were performed to explore the possible mechanism of OSCC. Finally, we discussed the model's clinical application value from the perspective of drug sensitivity. RESULTS: Three genes used in the model (IBSP, RDM1, RBP4) were identified as prognostic risk factors. Bioinformatics analysis, tissue and cell experiments have fully verified the abnormal expression of these three genes in OSCC. Multiple validation methods and internal and external datasets confirmed the model's excellent performance in predicting and discriminating prognosis. Cox regression analysis identified risk score as an independent predictor of prognosis. Multi-omics analysis found strong correlations between risk scores and immune cells, cell stemness index, and tumor mutational burden (TMB). It was also observed that the risk score was closely related to the half maximal inhibitory concentration of docetaxel, gefitinib and erlotinib. The excellent performance of the nomogram has been verified by various means. CONCLUSION: A prognostic model with high clinical application value was constructed. Immune cells, cellular stemness, and TMB may be involved in the progression of OSCC.

Efficient tumor synergistic chemoimmunotherapy by self-augmented ROS-responsive immunomodulatory polymeric nanodrug.

Immunotherapy has emerged as a promising therapeutic strategy for cancer therapy. However, the therapeutic efficacy has been distracted due to poor immunogenicity and immunosuppressive tumor microenvironment. In this study, a self-augmented reactive oxygen species (ROS) responsive nanocarrier with immunogenic inducer paclitaxel (PTX) and indoleamine 2,3-dixoygenase 1 (IDO1) blocker 1-methyl-D, L-tryptophan (1-MT) co-entrapment was developed for tumor rejection. The carrier was composed of poly (ethylene glycol) (PEG) as hydrophilic segments, enzyme cleavable 1-MT ester and ROS-sensitive peroxalate conjugation as hydrophobic blocks. The copolymer could self-assemble into prodrug-based nanoparticles with PTX, realizing a positive feedback loop of ROS-accelerated PTX release and PTX induced ROS generation. Our nanoparticles presented efficient immunogenic cell death (ICD) which provoked antitumor immune responses with high effector T cells infiltration. Meanwhile immunosuppressive tumor microenvironment was simultaneously modulated with reduced regulatory T cells (Tregs) and M2-tumor associated macrophages (M2-TAMs) infiltration mediated by IDO inhibition. The combination of PTX and 1-MT achieved significant primary tumor regression and reduction of lung metastasis in 4T1 tumor bearing mice. Therefore, the above results demonstrated co-delivery of immunogenic inducer and IDO inhibitor using the ROS amplifying nanoplatform with potent potential for tumor chemoimmunotherapy.

African swine fever virus MGF505-7R protein interacted with IRF7and TBK1 to inhibit type I interferon production.

African swine fever virus (ASFV) employs diverse strategies to confront or evade host type I interferon (IFN-I)-induced antiviral responses. Moreover, the mechanisms of this process are largely unknown. Here, we assessed 27 ASFV proteins to determine whether any of them suppressed the cGAS-STING pathway to facilitate immune evasion. Using dual-luciferase assays, we found that ASFV MGF505-7R suppressed the activity of the IFN-ß and ISRE promoters and the expression of IFN-I and ISGs. MGF505-7R interacted with IRF7 and TBK1, degrading IRF7 by autophagy, cysteine, and proteasome pathways and TBK1 by the proteasome pathway. Moreover, TBK1 and IRF3 were phosphorylated by cGAS-STING stimulation. Finally, small interfering RNA (siRNA)-based silencing of MGF505-7R enhanced IFN-I antiviral activity. Taken together, these results preliminarily clarified the immune escape mechanism of ASFV MGF505-7R, which provides a potential target for developing antiviral agents.

SP1-Mediated Upregulation of circFAM126A Promotes Proliferation and Epithelial-Mesenchymal Transition of Oral Squamous Cell Carcinoma via Regulation of RAB41.

BACKGROUND: Accumulating evidence indicates that circular RNAs have major roles in the progression of human cancers. Nevertheless, the molecular mechanism and effects of circFAM126A in oral squamous cell carcinoma (OSCC) remain unclear. METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect expression levels of circFAM126A in OSCC tumor tissues and cell lines; the effects of circFAM126A small hairpin RNA (shRNA) on the proliferation, migration, and invasion of OSCC cells were detected by MTT, colony formation, and transwell assays; xenograft mouse models were used to determine the effects of circFAM126A shRNA on the growth of OSCC tumors in vivo; the expression of miR-186 and RAB41 in OSCC tissues and cells was examined by qRT-PCR; the targeting relationship between circFAM126A and miR-186 was verified by dual-luciferase reporter and RNA pull-down assays; and the relationship between miR-186 and RAB41 was explored. RESULTS: The expression of circFAM126A was significantly upregulated in OSCC tissues and cells. The transcription factor SP1 transcriptionally activated circFAM126A. However, knockdown of circFAM126A markedly suppressed the proliferation, migration, and invasion of OSCC cells in vitro and inhibited tumor growth and distant metastasis in vivo. Moreover, circFAM126A increased the expression of RAB41 and promoted its mRNA stability via binding to miR-186 and RNA-binding protein FUS. Overexpression of RAB41 antagonized the effects of circFAM126A knockdown and induced an aggressive phenotype of OSCC cells. CONCLUSION: SP1 transcriptionally activated circFAM126A modulated the growth, epithelial-mesenchymal transition (EMT) of OSCC cells via targeting the miR-186/FUS/RAB41 axis, suggesting that circFAM126A is a potential biomarker for the treatment of OSCC.

African swine fever virus MGF360-11L negatively regulates cGAS-STING-mediated inhibition of type I interferon production.

The type I interferon (IFN-I) signaling pathway is an important part of the innate immune response and plays a vital role in controlling and eliminating pathogens. African swine fever virus (ASFV) encodes various proteins to evade the host's natural immunity. However, the molecular mechanism by which the ASFV-encoded proteins inhibit interferon production remains poorly understood. In the present study, ASFV MGF360-11L inhibited cGAS, STING, TBK1, IKKε, IRF7 and IRF3-5D mediated activation of the IFN-ß and ISRE promoters, accompanied by decreases in IFN-ß, ISG15 and ISG56 mRNA expression. ASFV MGF360-11L interacted with TBK1 and IRF7, degrading TBK1 and IRF7 through the cysteine, ubiquitin-proteasome and autophagy pathways. Moreover, ASFV MGF360-11L also inhibited the phosphorylation of TBK1 and IRF3 stimulated by cGAS-STING overexpression. Truncation mutation analysis revealed that aa 167-353 of ASFV MGF360-11L could inhibit cGAS-STING-mediated activation of the IFN-ß and ISRE promoters. Finally, the results indicated that ASFV MGF360-11L plays a significant role in inhibiting IL-1ß, IL-6 and IFN-ß production in PAM cells (PAMs) infected with ASFV. In short, these results demonstrated that ASFV MGF360-11L was involved in regulating IFN-I expression by negatively regulating the cGAS signaling pathway. In summary, this study preliminarily clarified the molecular mechanism by which the ASFV MGF360-11L protein antagonizes IFN-I-mediated antiviral activity, which will help to provide new strategies for the treatment and prevention of ASF.

A Ferroptosis-Related Prognostic Signature Based on Antitumor Immunity and Tumor Protein p53 Mutation Exploration for Guiding Treatment in Patients With Head and Neck Squamous Cell Carcinoma.

Background: Due to the lack of accurate guidance of biomarkers, the treatment of head and neck squamous cell carcinoma (HNSCC) has not been ideal. Ferroptosis plays an important role in tumor suppression and treatment of patients. However, tumor protein p53 (TP53) mutation may promote tumor progression through ferroptosis. Therefore, it is particularly important to mine prognostic-related differentially expressed ferroptosis-related genes (PR-DE-FRGs) in HNSCC to construct a prognostic model for accurately guiding clinical treatment. Methods: First, the HNSCC data obtained from The Cancer Genome Atlas (TCGA) was used to identify PR-DE-FRGs for screening candidate genes to construct a prognostic model. We not only used a variety of methods to verify the accuracy of the model for predicting prognosis but also explored the role of ferroptosis in the development of HNSCC from the perspective of the immune microenvironment and mutation. Finally, we explored the correlation between the prognostic model and clinical treatment and drew a high-precision nomogram to predict the prognosis. Results: Seventeen of the 29 PR-DE-FRGs were selected to construct a prognostic model with good predictive performance. Patients in the low-risk group were found to have a greater number of CD8 + T cells, follicular helper T cells, regulatory T cells, mast cells, T-cell costimulations, and type II interferon responses. A higher tumor mutation burden (TMB) was observed in the low-risk group and was associated with a better prognosis. A higher risk score was found in the TP53 mutation group and was associated with a worse prognosis. The risk score is closely related to the expression of immune checkpoint inhibitors (ICIs)-related genes such as PD-L1 and the IC50 of six chemotherapeutic drugs. The nomogram we constructed performs well in predicting prognosis. Conclusion: Ferroptosis may participate in the progression of HNSCC through the immune microenvironment and TP53 mutation. The model we built can be used as an effective predictor of immunotherapy and chemotherapy effects and prognosis of HNSCC patients.

MicroRNA and circRNA Expression Analysis in a Zbtb1 Gene Knockout Monoclonal EL4 Cell Line.

Zinc finger and BTB domain containing 1(Zbtb1) is a transcriptional suppressor protein, and a member of the mammalian Zbtb gene family. Previous studies have shown that Zbtb1 is essential for T-cell development. However, the role of Zbtb1 in T-cell lymphoma is undetermined. In this study, an EL4 cell line with Zbtb1 deletion was constructed using the CRISPR-Cas9 technique. The expression profiles of microRNA and circRNA produced by the control and gene deletion groups were determined by RNA-seq. In general, 24 differentially expressed microRNA and 16 differentially expressed circRNA were found between normal group and gene deletion group. Through further analysis of differentially expressed genes, GO term histogram and KEGG scatter plot were drawn, and three pairs of miRNA and circRNA regulatory relationships were found. This study describes the differentially expressed microRNA and circRNA in normal and Zbtb1-deficient EL4 cell lines, thus providing potential targets for drug development and clinical treatment of T-cell lymphoma.

Quercetin nanoformulations: a promising strategy for tumor therapy.

Phytochemicals as dietary constituents are being widely explored for the prevention and treatment of various diseases. Quercetin, a major constituent of various dietary products, has attracted extensive interest due to its anti-proliferative capability, reversal of multidrug resistance, autophagy promotion and tumor microenvironment modulation on different cancer types. Although quercetin has shown potent medical value, its application as an antitumor drug is limited. Problems like poor solubility, bioavailability and stability, short half-life and weak tumor-targeting biodistribution make quercetin an unreliable candidate for cancer therapy. Nanoparticle based platforms have shown a number of advantages in delivering a hydrophobic drug like quercetin to diseased tissues. Quercetin nanoparticles have demonstrated high encapsulation efficiency, stability, sustained release, prolonged circulation time, improved accumulation at tumor sites and therapeutic efficiency. Moreover, a combination of quercetin with other diagnostic or therapeutic agents in one nanocarrier has achieved enhancements in detecting or treating tumors. In this review, we have tried to summarize the pharmacological activities of quercetin with regard to tumor cells and microenvironments in vitro and in vivo. Furthermore, various nanoformulations have been highlighted for quercetin delivery for cancer treatment. These results suggest that quercetin nanoparticles may be a promising antitumor therapeutic agent.

Stimuli-responsive nanoparticles based on poly acrylic derivatives for tumor therapy.

Serve side effects caused by discriminate damage of chemotherapeutic drugs to normal cell and cancer cells remain a main obstacle in clinic. Hence, continuous efforts have been made to find ways to effectively enhance drug delivery and reduce side effects. Recent decades have witnessed impressive progresses in fighting against cancer, with improved understanding of tumor microenvironment and rapid development in nanoscale drug delivery system (DDS). Nanocarriers based on biocompatible materials provide possibilities to improve antitumor efficiency and minimize off-target effects. Among all kinds of biocompatible materials applied in DDS, polymeric acrylic derivatives such as poly(acrylamide), poly(acrylic acid), poly(N-isopropylacrylamide) present inherent biocompatibility and stimuli-responsivity, and relatively easy to be functionalized. Furthermore, nanocarrier based on polymeric acrylic derivatives have demonstrated high drug encapsulation, improved uptake efficiency, prolonged circulation time and satisfactory therapeutic outcome in tumor. In this review, we aim to discuss recent progress in design and development of stimulus-responsive poly acrylic polymer based nanocarriers for tumor targeting drug delivery.

Targeting macrophages using nanoparticles: a potential therapeutic strategy for atherosclerosis.

Atherosclerosis is one of the leading causes of vascular diseases, with high morbidity and mortality worldwide. Macrophages play a critical role in the development and local inflammatory responses of atherosclerosis, contributing to plaque rupture and thrombosis. Considering their central roles, macrophages have gained considerable attention as a therapeutic target to attenuate atherosclerotic progression and stabilize existing plaques. Nanoparticle-based delivery systems further provide possibilities to selectively and effectively deliver therapeutic agents into intraplaque macrophages. Although challenges are numerous and clinical application is still distant, the design and development of macrophage-targeting nanoparticles will generate new knowledge and experiences to improve therapeutic outcomes and minimize toxicity. Hence, the review aims to discuss various strategies for macrophage modulation and the development and evaluation of macrophage targeting nanomedicines for anti-atherosclerosis.