Oncolytic Newcastle disease virus carrying the IL24 gene exerts antitumor effects by inhibiting tumor growth and vascular sprouting.

The second-leading cause of death, cancer, poses a significant threat to human life. Innovations in cancer therapies are crucial due to limitations in traditional approaches. Newcastle disease virus (NDV), a nonpathogenic oncolytic virus, exhibits multifunctional anticancer properties by selectively infecting, replicating, and eliminating tumor cells. To enhance NDV's antitumor activity, four oncolytic NDV viruses were developed, incorporating IL24 and/or GM-CSF genes at different gene loci using reverse genetics. In vitro experiments revealed that oncolytic NDV virus augmented the antitumor efficacy of the parental virus rClone30, inhibiting tumor cell proliferation, inducing tumor cell fusion, and promoting apoptosis. Moreover, NDV carrying the IL24 gene inhibited microvessel formation in CAM experiments. Evaluation in a mouse model of liver cancer confirmed the therapeutic efficacy of oncolytic NDV viral therapy. Tumors in mice treated with oncolytic NDV virus significantly decreased in size, accompanied by tumor cell detachment and apoptosis evident in pathological sections. Furthermore, oncolytic NDV virus enhanced T cell and dendritic cell production and substantially improved the survival rate of mice with hepatocellular carcinoma, with rClone30-IL24(P/M) demonstrating significant therapeutic effects. This study establishes a basis for utilizing oncolytic NDV virus as an antitumor agent in clinical practice.

Ze-Qi-Tang formula inhibits MDSCs glycolysis through the down-regulation of p21/Hif1α/Glut1 signal in psoriatic-like mice.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease that affects the quality of life and mental health of approximately 150 million people worldwide. Ze-Qi-Tang (ZQT) is a classic compound used in China for lung disease; however, its mechanism of action in psoriasis remains unclear. This study aimed to investigate the therapeutic effect of the ZQT formula on psoriasis and explore the underlying molecular mechanisms. METHODS: Peripheral blood samples were collected from patients with psoriasis and healthy individuals. Flow cytometry was used to detect changes in the proportions of myeloid-derived suppressor cells (MDSCs) and other immune cells. Psoriasis was induced in mice by the daily application of imiquimod. ZQT was administered separately or in combination with anti-Gr1 antibody to deplete MDSC. The glycolysis levels of the MDSCs were detected using a Seahorse analyzer. The p21/Hif1α/Glut1 pathway was identified and validated by mRNA sequence, RT-qPCR, WB, IF, and the application of p21 inhibitor UC2288. RESULTS: The number of MDSCs was significantly increased in patients with psoriasis, with the increased expression of p21, Hif1α, and Glut1 in MDSCs. ZQT significantly alleviated psoriasis-like skin lesions in mice. ZQT formula significantly reduced the number of MDSCs in psoriatic-like mice and enhanced their suppressive capacity for T cells. The efficacy of ZQT in alleviating psoriatic dermatitis is compromised by MDSC depletion. ZQT decreased the expressions of p21, Hif1α, and Glut1-induced glycolysis in MDSCs, thereby inhibiting Th17 cell differentiation. CONCLUSION: These suggest that ZQT alleviates IMQ-induced psoriatic dermatitis, by inhibiting p21/Hif1α/Glut1-induced glycolysis in MDSCs.

Fibroblast growth factor 21 mitigates lupus nephritis progression via the FGF21/Irgm 1/NLRP3 inflammasome pathway.

As an endocrine cytokine, fibroblast growth factor 21 (FGF21) exhibits anti-inflammatory properties. With the development of lupus nephritis (LN), which is tightly related to pathogenic factors, including inflammation and immune cell dysregulation, we explored the impact of Fibroblast Growth Factor 21 (FGF21) as well as its underlying mechanism. We induced an in vivo LN model using pristane in both wild-type C57BL/6 and FGF21 knockout (FGF21-/-) mice. LN serum obtained from 32-week-old wild-type LN mice was used to stimulate RAW264.7 and human renal tubular epithelial (HK-2) cells to mimic an in vitro LN model. Moreover, our findings revealed that FGF21-/- mice showed more severe kidney injury compared to wild-type mice, as evidenced by increased levels of renal function markers, inflammatory factors, and fibrosis markers. Notably, exogenous administration of FGF21 to wild-type LN mice markedly mitigated these adverse effects. Additionally, we used tandem mass tag (TMT)-based quantitative proteomics to detect differentially expressed proteins following FGF21 treatment. Results indicated that 121 differentially expressed proteins influenced by FGF21 were involved in biological processes such as immune response and complement activation. Significantly upregulated protein Irgm 1, coupled with modulated inflammatory response, appeared to contribute to the beneficial effects of FGF21. Furthermore, Western blot analysis demonstrated that FGF21 upregulated Irgm 1 while inhibiting nucleotide-binding oligomerization domain-like receptors family pyrin domain including 3 (NLRP3) inflammasome expression. Silencing Irgm 1, in turn, reversed FGF21's inhibitory effect on NLRP3 inflammasome. In summary, FGF21 can potentially alleviate pristane-induced lupus nephritis in mice, possibly through the FGF21/Irgm 1/NLRP3 inflammasome pathway.

Fibroblast growth factor 21 attenuates the progression of hyperuricemic nephropathy through inhibiting inflammation, fibrosis and oxidative stress.

Elevated levels of circulating fibroblast growth factor 21 (FGF21) have been reported in patients with hyperuricemia. However, the effect of FGF21 in hyperuricemic nephropathy (HN) remains unexplored. Here, we investigated the effect and mechanism of action of FGF21 on HN. HN model was induced with adenine and potassium oxysalt in wild-type C57BL/6 mice and FGF21-/- mice. For in vitro studies, human renal tubular epithelial (HK-2) cells were exposed to uric acid with/without FGF21 or ß-Klotho-siRNA. Here, we reported aggravated renal dysfunction and structural damage in the FGF21-/- mice compared to the wild-type mice. These were evident in the upsurge of inflammatory factors IL-1ß, TNF-α, IL-6, and IL-18; fibrotic markers Collagen I and α-SMA; and oxidation products ROS and MDA. However, exogenous administration of FGF21 to wild-type HN mice significantly reversed these negative effects. In terms of mechanism, FGF21 significantly inhibited NF-κB/NLRP3 and TGF-ß1/Smad3 pathways and promoted nuclear translocation of Nrf2 both in vivo and in vitro. Furthermore, the silencing of ß-Klotho was marked by the attenuation of the improved effect of FGF21 on cell damage. In conclusion, our studies revealed that exogenous FGF21 treatment significantly improved HN, which was achieved by the inhibition of inflammation, fibrosis, and oxidative stress.

Development and evaluation of a recombinant VP2 neutralizing epitope antigen vaccine candidate for infectious bursal disease virus.

Infectious bursal disease (IBD) is one of the most economically important infectious diseases. Currently, vaccination is the most effective method to prevent IBD. Medium-virulence vaccines can damage the bursa of Fabricius and result in immunosuppression. Therefore, it is essential to develop a safe and effective vaccine against infectious bursal disease virus (IBDV). In this study, the five neutralizing epitopes of the IBDV VP2 protein were confirmed by neutralizing single chain variable fragment antibodies. Then, the neutralizing epitopes antigen (NEA) protein was constructed with five neutralizing epitopes and expressed by pET-27b. Furthermore, the immune effect and protective immunity of the NEA protein with the following adjuvants were evaluated in specific-pathogen-free chickens: oil emulsion adjuvant (OEA), double emulsion adjuvant (DEA), granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvant and complete Freund's adjuvant (CFA). The experimental results demonstrated that chickens immunized with NEA vaccines elicited stronger humoral and/or cellular immune responses and inflammatory responses than those in the NEA protein group. Chickens were protected in OEA, CFA and GM-CSF adjuvant groups, which were challenged with virulent IBDV BC6/85. Furthermore, IBDV RNA was not measured, and there appeared to be little apoptosis in the bursa of Fabricius based on TUNEL histology and the expression of Bax and Bcl-2 in the OEA, CFA and GM-CSF adjuvant groups. Based on the experimental results, the advantages and disadvantages of adjuvants and industrial production methods, GM-CSF was found to be the optimal adjuvant. Therefore, NEA with GM-CSF adjuvant is a promising vaccine candidate against IBDV, and it provides a framework for developing other vaccines against infectious viral diseases.