The standard care of glioblastoma multiforme (GBM), which is surgery followed by temozolomide concurrent radiotherapy (RT/TMZ), confers limited survival benefit for patients. 1 Additionally, current animal models do not faithfully recapitulate human GBM features, impeding animal-to-human translation. 2 Here, we developed and characterized a novel orthotopic murine GBM model, in which we tested the efficacy of the RT/TMZ supplemented with mannose (RT/TMZ/Man). Following the optimized protocol illustrated in Figure 1A, we established a stable subcutaneous-intracranial G422-GBM syngeneic mouse model system. Subcutaneous injection of 1 × 10 6 fresh G422 cells led to 100% tumor formation, and the tumors reaching 1 cm 3 on day 7-9 postimplantation (p.i.) were used for further experiments (Figure 1B). Microinjection of 1 × 10 3-1 × 10 5 G422 cells in mouse striatum caused 100% lethality within 30 days (Figure 1C) and 5 × 10 4 cells, which led to mouse death within 14-23 days (Figure S1A), were selected for establishing the orthotopic model. We then determined the pathology and molecular characters of G422-tumors. The brain slices showed rapid G422-tumor development during day 7-15 p.i. (Figure S1B). The G422tumors were GFAP + Vimentin + CD3 − and infiltrated into distant brain areas (Figure 1D-G) on day 5 p.i. They were IDH1/2 WT chromosome1/19 Intact TERT-promoter WT with ATRX Mutant and Trp53 Mutant (Figure 1H), determined by the whole genome sequencing, and thus belonged to the triple-negative (TN) primary GBM subtype. 3 Our model was therefore named the G422 TN-GBM. Next, we determined the therapeutic responses of the orthotopic G422 TN-GBM to conventional surgery, radiotherapy, temozolomide, and the therapies of combining these two or three. Surgery alone, performed on day 7 p.i., effectively removed the tumor and slightly extended the median survival of the G422-mice (Figure 2A-C and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Introduction: The present investigation determined the protective effect of myricitrin against sepsis-associated encephalopathy in rats. Material and methods: Sepsis was induced by cecal ligation and puncture (CLP); rats were treated with 30 or 100 mg/kg of myricitrin for 5 days prior to the induction of CLP. The effect of myricitrin was observed by determining the neurological function using the open field test and step-down inhibitory avoidance test. Cerebral oedema and the levels of inflammatory and oxidative stress mediators were determined in brain tissues. Moreover, the expression levels of Bcl-2, Bax, IκB-α, nuclear factor κB (NF-κB), caspase-3 and NLRP3 were estimated in brain tissues by Western blotting and the mRNA expression of NF-κB, caspase-3 and NLRP3 in brain tissues was estimated by realtime polymerase chain reaction. An immunofluorescence assay was performed to estimate inflammasome activity. Results: The results suggest that treatment with myricitrin protects neuronal function in rats with CLP-induced sepsis. Decreases in inflammation and oxidative stress mediators were observed in the brain tissues of the myricitrin-treated group compared to the CLP group. Moreover, treatment with myricitrin ameliorated the altered Bcl-2, Bax, IκB-α, NF-κB, caspase-3 and NLRP3 protein and mRNA expression levels in the brain tissues of septic rats. Conclusions: The data reveal that myricitrin ameliorated neuroinflammation and improved memory in rats with CLP-induced sepsis by regulating the NLRP3/Bax/Bcl signalling pathway.

Background: Emerging evidence has indicated that interleukin-8 (IL-8) gene-251A/T polymorphism may affect individual susceptibility to sepsis. However, the results of published studies are inconclusive. The aim of this meta-analysis was to elucidate the association between this polymorphism and the risk and mortality of sepsis. Methods: Relevant publications were searched from PubMed, EmBase, and Web of Science databases up to January 31, 2021, with studies only in English. The reference lists of the retrieved studies were investigated as well. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to figure out the relationship between IL-8-251 A/T polymorphisms and the risk and mortality of sepsis. All of the data were analyzed with Stata 16.0. Results: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. Conclusion: This meta-analysis will summarize the relationship between IL-8-251 A/T polymorphism and the risk and mortality of sepsis.

Background The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Methods Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Results Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen. Conclusion Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.