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关键词： MT: Regular Issue   oncolytic virus   vaccinia virus   cytokine   IL-18   DR-18   systemic toxicity   tumor microenvironment   anti-CTLA-4 antibody   immune checkpoint inhibitor   immunotherapy  

摘要： Cytokines are promising for cancer treatment but face challenges like short half-lives, high-dose requirements, and systemic toxicity. Oncolytic viruses provide an ideal platform to overcome these limitations by delivering cytokines directly to tumor sites, enabling high local concentrations within the tumor microenvironment (TME). This study utilized an oncolytic vaccinia virus (oVV) to deliver interleukin-18 (IL-18) and its variants and assessed their antitumor effects across different tumor models. The non-secreted mature IL-18 mutein (nsmDR-18)-expressing oVV demonstrated potent antitumor efficacy with reduced systemic toxicity. It increased the expression of antitumor factors, including IL-2, interferon gamma (IFN-γ), granzyme B, and perforin, while expanding tumor-reactive CD39 + CD103 + CD8 + T cells and reducing severely exhausted PD-1 + TIM-3 + CD8 + T cells, thereby transforming immunologically “cold” tumors into “hot” tumors. However, nsmDR-18-expressing oVV treatment also elevated regulatory T cells (Tregs) and upregulated immune checkpoint molecules (PD-1, PD-L1, and CTLA-4). Combining nsmDR-18-expressing oVV with anti-CTLA-4 antibody significantly improved overall survival and induced systemic, tumor-specific antitumor immunity. These results highlight the potential of nsmDR-18-expressing oVV as a therapeutic strategy, supporting further exploration in clinical trials.

关键词： MT: Regular Issue   oncolytic HSV   cancer therapy   IL-12   IL-15   immune response  

摘要： Oncolytic herpes simplex virus type 1 (HSV-1) directly targets and destroys tumor cells while selectively infecting surrounding tumor tissue and releasing progeny viruses to continue the attack. We engineered the replicative HSV-1 vector, including the oncolytic HSV-1 (oHSV) with deleted inverted repeat and α47 gene, and then the oHSV expressing interleukin-15 (IL-15) gene and the oHSV expressing IL-15 and interleukin-12 (IL-12) gene. We evaluated the titer and growth characteristics of the oHSV-1 in Vero and cancer cell lines. Furthermore, we rigorously assessed the antitumor efficacy of HSV-1 in CT26 and B16-F10 cells, along with murine tumor models. The engineered oHSV-1 demonstrated growth patterns comparable to wild-type HSV-1. The viral titers exhibited consistency within the same tumor cells. Treatment with RG2006 significantly reduced tumor growth and extended survival rates compared to other forms of oHSV-1. Analyses indicated a marked elevation in T cell and NK cell activation in mice receiving RG2006. Our findings unequivocally demonstrate that including IL-15 and IL-12 can significantly enhance antitumor immunity when deploying oncolytic herpes simplex virus. This has substantial practical implications, suggesting that integrating multiple therapeutic genes alongside oncolytic viral therapy and immunotherapy could pave the way for more effective clinical strategies in cancer treatment.

关键词： Breast cancer   Bruceine D   Cancer-associated fibroblasts   IL-6   Tumor angiogenesis  

摘要： Cancer-associated fibroblasts (CAFs) facilitate tumor angiogenesis by secreting cytokines. Bruceine D (BD), a natural quassinoid compound extracted from the Chinese herb Brucea javanica (L.) Merr., has demonstrated potential in inhibiting breast cancer (BC). However, the involvement of CAF-promoted tumor angiogenesis in the antitumor effects of BD remains unclear. This study investigated the effects of BD on CAF-promoted tumor angiogenesis and its underlying mechanisms. In vivo results showed that BD alleviated hypoxia, suppressed CAF activation, and reduced IL-6 secretion in orthotopic BC-bearing mice. These changes led to significant down-regulation of phosphorylation of STAT3, Notch1, and phosphorylation of VEGFR2 expression, ultimately inhibiting tumor angiogenesis and metastasis. Furthermore, BD was demonstrated significantly inhibition of both IL-6 secretion from CAFs and subsequent activation of the STAT3/Notch1/VEGFR2 signaling axis. This effect disrupted CAF-endothelial cell crosstalk, thereby impairing CAF-promoted endothelial cell proliferation, sprouting, invasion, migration, and tube formation. Collectively, these findings identify BD as a promising candidate for inhibiting CAF-driven tumor angiogenesis, offering a novel therapeutic strategy for patients with BC.

关键词： PM2.5   Vc   Thyroid   Ferroptosis   IL-17A signaling pathway  

摘要： Fine particulate matter (PM2.5) is a ubiquitous environmental pollutant that has been demonstrated to affect the thyroid function in women. However, its specific mechanism remains unclear, and protective drugs are deficient. In the present study, we used female rat thyroid models in vivo and rat FRTL5 cell models in vitro to investigate the thyroid toxicity mechanism of PM2.5 and the protective pathway of vitamin C in female rats. PM2.5 exposure caused the production of inflammatory cells in thyroid tissue;transformations of the mitochondrial morphology;increases in the reactive oxygen species (ROS), ferrous ion (Fe2 +), and malondialdehyde (MDA) content in thyroid cells;and decreases in the glutathione peroxidase 4 (GPX4) levels, which resulted in ferroptosis in rat thyroid tissues. In addition, the Interleukin (IL)-17A/IL-17RA/Nuclear factor activator (Act1) signaling pathway was activated by PM2.5. However, vitamin C treatment improved ferroptosis and significantly reduced the expression of the IL-17A, IL-17RA, and ACT1 signaling pathway-related factors. These findings indicate that vitamin C demonstrates protective effects against thyroid injury and ferroptosis, potentially through the inhibition of the IL-17A signaling pathway.

关键词： Schizophrenia   Interleukin-33   Aggression   Cytokine   Alarmin  

摘要： Aggression in schizophrenia (SCZ) poses a serious risk to others and complicates treatment. Inflammation has been confirmed to be associated with aggression in SCZ, but specific biomarkers remain unidentified. This study aimed to measure plasma interleukin-33 (IL-33) levels and explore their association with aggression in SCZ for the first time. The enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of IL-33 in SCZ with aggression (SCZ-Ag, n = 31) and non-aggression (NSCZ-Ag, n = 32), and healthy controls (HCs, n = 26). Aggression was measured using the Modified Overt Aggression Scale (MOAS), and clinical symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). The results showed that the plasma IL-33 levels were elevated in SCZ-Ag compared with NSCZ-Ag and HCs, with no significant difference between NSCZ-Ag and HCs. In the patient group, partial correlation analysis indicated a positive correlation between IL-33 levels and PANSS total scores, positive symptom subscores, and MOAS total scores. Regression analysis showed that a higher likelihood of aggression in SCZ was associated with elevated plasma IL-33 levels (OR = 1.075, 95 % CI: 1.023-1.129). ROC curve analysis showed that IL-33 (AUC = 0.713, 95 % CI: 0.582-0.844) demonstrated moderate performance in distinguishing SCZ-Ag from NSCZ-Ag. These findings suggest that elevated plasma IL-33 levels are a potential risk factor for aggression in patients with SCZ and are implicated in the clinical symptoms of patients. Increased plasma IL-33 levels may serve as a potential marker for aggression in SCZ. These findings require further validation in future studies.

关键词： HuR   NSCLC   SFPQ   circRNAs   ubiquitylation  

摘要： Among lung cancers, non-small-cell lung cancer (NSCLC) is the most common type. Evidence demonstrates that abnormal expression of circular RNAs (circRNAs) is associated with cancer progression through interactions with RNA-binding proteins (RBPs). Therefore, further elucidation of the role of circular RNAs may provide new therapeutic targets for NSCLC patients. This study identified a novel circRNA, circHMGCS1 (hsa_circ_0072387), using circRNA microarrays. Validation and characterization of circHMGCS1 were performed by Sanger sequencing and RNase R treatment. CCK-8 and Transwell assays were used to determine the function of circHMGCS1 in cell proliferation and migration. The interaction between circHMGCS1 and human antigen R (HuR) protein was verified by RNA pull-down and RNA immunoprecipitation (RIP) assays. The effect of HuR on the stability of splicing factor proline- and glutamine-rich (SFPQ) mRNA was verified by dual-luciferase reporter gene assay and actinomycin D treatment. We found that circHMGCS1 was upregulated in NSCLC cells and tissues. Mechanistically, circHMGCS1 binds to HuR, and its high expression stabilizes HuR by inhibiting its ubiquitin-mediated degradation. HuR was shown to mediate the stability of SFPQ mRNA and promote the progression of NSCLC. RNA sequencing analysis indicated that SFPQ may inhibit apoptosis by suppressing tumor necrosis factor (TNF) signaling. This study revealed that circHMGCS1 contributes to NSCLC progression by stabilizing oncogenic HuR and promoting post-transcriptional upregulation of SFPQ, highlighting its potential as a diagnostic and prognostic biomarker for NSCLC.

关键词： Interleukin-6   Molecularly imprinted polymer   Electrochemical sensor   Lipopolysaccharide   Point-of-care  

摘要： Interleukin-6 (IL-6) is a multifunctional cytokine that plays a key role in driving proinflammatory responses in a wide range of acute, chronic, and infectious diseases. Therefore, it is of practical importance to monitor the IL-6 level of individuals in disease diagnosis and healthcare. Currently, there is an urgent need for developing rapid, cost-effective diagnostic and prognostic sensing systems. Herein, we developed a molecularly imprinted polymer (MIP)-based electrochemical sensor for IL-6 detection. The results showed that the MIP sensor demonstrated high sensitivity in the trace of IL-6 concentration, with a limit of detection of 31.3 fM and a wide dynamic range of 100 fg/mL to 1 mu g/mL. Moreover, the MIP sensors are highly selective for IL-6, compared to other inflammatory cytokines (Interleukin-1 beta, transforming growth factor-beta 3, and tumor necrosis factor-alpha) and various interfering biomolecules (glucose, human serum albumin, fibrinogen, and lactic acid). We also confirmed that the MIP sensors maintained robust stability over three weeks without appreciable deterioration. The performance of the MIP sensors was validated using a lipopolysaccharide-induced cellular senescence model, emphasizing its potential as a point-of-care tool for IL-6 monitoring. The results suggest that our MIP-based IL-6 sensor could serve as an effective point-of-care tool in quantifying age-related physiological changes and monitoring low-grade systemic inflammation.

关键词： Chronic stress intensity   Depression severity   Behavior   Cortisol   Inflammatory factors  

摘要： Backgrounds: The etiology of depression involves chronic stress, a recognized determinant of onset and severity. This study adopts a translational approach, utilizing a mouse model and a clinical cohort to explore the relationship between chronic stress, molecular changes, and depression severity. Methods: In the mouse model, mice were exposed to varying frequencies of chronic stressors over several weeks, followed by behavioral assessments to confirm depressive-like behaviors and measurement of serum indicators to analyze their relationship with stress intensity. In the clinical cohort, we recruited 239 participants, including 137 patients with diagnosed depression and 102 healthy controls, and analyzed their plasma profiles for cortisol and inflammatory cytokines. The clinical cohort revealed distinctive plasma profiles, identifying cortisol and IL17 as potential markers. Machine learning models were developed using these markers to distinguish depression severity. Results: The study revealed subtle behavioral-molecular changes in mice subjected to varying chronic stress intensities, confirming dose-response relationships. It identified cortisol and IL-17 as potential biomarkers for distinguishing depression severity and developed machine learning models demonstrating robust diagnostic capabilities. Limitations: There is a substantial disparity in the number of individuals among different groups in the clinical participants. Conclusion: The study establishes a correlation between cortisol, IL-17, and chronic stress intensity, suggesting the latter accelerates depression progression. Cortisol and IL-17 exhibit diagnostic potential, providing insights into depression progression and guiding targeted interventions. This research advances our understanding of stress-induced molecular changes in depression, contributing to the comprehension of the intricate relationship between chronic stress, molecular alterations, and depression severity.

关键词： IL-2   IL-2 receptor alpha   IL-2 receptor beta &   gamma   Inclusion body   Refolding   Assay validation  

摘要： IL-2 is a potent cytokine that promotes multiple immune cells proliferation and activation. Accordingly, IL-2 based immunotherapies are emerging to treat cancers or AIDS by enhancing T cell growth and function. Besides, IL-2 is indispensable in in vitro cultivation of immune cells which is a critical step of CAR-T or CAR-NK immunotherapies. In bulk manufacturing of recombinant IL-2, E. coli expression system has several advantages such as low cost and rapid growth. However, high level protein expression in prokaryotic organisms often results in inactive insoluble aggregates, also known as inclusion bodies. It is crucial and most challenging work to solubilize and refold the protein of interest from inclusion bodies to generate its bioactive form. While multiple spectrum method had been applied to monitor the refolding process, the question of how to measure the refolding efficiency from the perspective of its biological function remained unaddressed. Here we present a receptor-based sandwich ELISA method to evaluate the bioactive product in samples and provide a guidance for manufacturing bioactive rhIL-2 (recombinant human IL-2) with prokaryotic expression system. Compared to traditional antibody-based ELISA method, this novel approach truly measures the presence of functional rhIL-2 and also potentially allows the detection of rhIL-2 variants with modifications like PEGylation as it doesn't rely on the exact amino acid sequence.