Sepsis is recognized as a life-threatening organ dysfunctional disease that is caused by dysregulated host responses to infection. Up to now, sepsis still remains a dominant cause of multiple organ dysfunction syndrome (MODS) and death among severe condition patients. Pyroptosis, originally named after the Greek words “pyro” and “ptosis” in 2001, has been defined as a specific programmed cell death characterized by release of inflammatory cytokines. During sepsis, pyroptosis is required for defense against bacterial infection because appropriate pyroptosis can minimize tissue damage. Even so, pyroptosis when overactivated can result in septic shock, MODS, or increased risk of secondary infection. Proteolytic cleavage of gasdermin D (GSDMD) by caspase-1, caspase-4, caspase-5, and caspase-11 is an essential step for the execution of pyroptosis in activated innate immune cells and endothelial cells stimulated by cytosolic lipopolysaccharide (LPS). Cleaved GSDMD also triggers NACHT, LRR, and PYD domain-containing protein (NLRP) 3-mediated activation of caspase-1 via an intrinsic pathway, while the precise mechanism underlying GSDMD-induced NLRP 3 activation remains unclear. Hence, this study provides an overview of the recent advances in the molecular mechanisms underlying pyroptosis in sepsis.

Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo−/− mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25− T cells, as well as the organ functions, were determined. Administration of parenteral Vit C per se markedly improved the outcome of sepsis and sepsis-induced MODS of WT and Gulo−/− mice. The negative immunoregulation of Tregs was inhibited, mainly including inhibiting the expression of forkhead helix transcription factor- (Foxp-) 3, cytotoxic T lymphocyte associated antigen- (CTLA-) 4, membrane associated transforming growth factor-β (TGF-βm+), and the secretion of inhibitory cytokines [including TGF-β and interleukin- (IL-) 10], as well as CD4+ T cells-mediated cellular immunosuppression which was improved by parenteral Vit C in WT and Gulo−/− septic mice. These results suggested that parenteral Vit C has the ability to improve the outcome of sepsis and sepsis-induced MODS and is associated with improvement in cellular immunosuppression.

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Background Radio-resistance is an obstacle to the treatment of human nasopharyngeal carcinoma (NPC). However, how microRNAs (miRNA) are involved in this process remains unclear. In the present study we explored the role and possible molecular mechanism of miR-29a-3p, formerly known as tumor suppressors, in radio-sensitivity of NPC cells. Material/Methods A radio-resistant sub-cell line, CNE-2R, was established to detect the expression of miR-29a/b/c-3p using qRT-PCR. CCK-8 assay, colony formation assay, and single-cell gel electrophoresis (SCGE) assay were carried out to analyze the radio-sensitivity of NPC cells. qRT-PCR, luciferase reporter, and Western blot experiments were performed to validate the targeting of COL1A1 by miR-29a. Short interference RNAs (siRNAs) were used to investigate whether COL1A1 mediates the radio-sensitizer role of miR-29a. Expression of miR-29a and COL1A1 in radio-resistant NPC tissues was finally determined. Results miR-29a was decreased in the radio-resistant CNE-2R cells. Following a time-course irradiation (IR) exposure, miR-29a exhibited a time-dependent decrease. Cellular experiments confirmed that miR-29a induced radio-sensitivity of CNE-2R cells via suppressing cell viability and enhancing cell apoptosis after IR. We confirmed that COL1A1 is a direct target of miR-29a and can exert radio-resistance effects in NPC cells. We also found that knockdown of COL1A1 inhibits NPC cell viability and sensitivity to IR. Finally, we observed a downregulation of miR-29a in radio-resistant NPC tissues and its decrease was associated with upregulation of COL1A1. Conclusions miR-29a is a critical determinant of NPC radio-response for NPC patients, and its induction provides a promising therapeutic choice to elevate NPC radio-sensitivity.

Background:This work aimed to screen key biomarkers related to sepsis progression by bioinformatics analyses. Material/Methods:The microarray datasets of blood and neutrophils from patients with sepsis or septic shock were downloaded from Gene Expression Omnibus database. Then, differentially expressed genes (DEGs) from 4 groups (sepsis versus normal blood samples; septic shock versus normal blood samples; sepsis neutrophils versus normal controls and septic shock neutrophils versus controls) were respectively identified followed by functional analyses. Subsequently, protein-protein network was constructed, and key functional sub-modules were extracted. Finally, receiver operating characteristic analysis was conducted to evaluate diagnostic values of key genes. Results:There were 2082 DEGs between blood samples of sepsis patients and controls, 2079 DEGs between blood samples of septic shock patients and healthy individuals, 6590 DEGs between neutrophils from sepsis and controls, and 1056 DEGs between neutrophils from septic shock patients and normal controls. Functional analysis showed that numerous DEGs were significantly enriched in ribosome-related pathway, cell cycle, and neutrophil activation involved in immune response. In addition, TRIM25 and MYC acted as hub genes in protein-protein interaction (PPI) analyses of DEGs from microarray datasets of blood samples. Moreover, MYC (AUC=0.912) and TRIM25 (AUC=0.843) had great diagnostic values for discriminating septic shock blood samples and normal controls. RNF4 was a hub gene from PPI analyses based on datasets from neutrophils and RNF4 (AUC=0.909) was capable of distinguishing neutrophil samples from septic shock samples and controls. Conclusions:Our findings identified several key genes and pathways related to sepsis development.

Expression of programmed cell death receptor ligand 1 (PD-L1) has been shown to be up-regulated in some gastric cancer patients and to correlate with the density of tumour infiltrating lymphocytes (TILs). However, conflicting results have been reported regarding TILs and the expression of PD-L1 as a prognostic marker for gastric cancer. We investigated the correlation of PD-L1 and TILs expression with clinicpathological characteristics in 105 well characterized gastric cancer patients. PD-L1 expression and CD3+ and CD8+ TILs were evaluated by fluorescent multiplex immunohistochemistry (mIHC) analysis. PD-L1 positive staining on tumour cells was observed in 35% cases and 48% cases showed PD-L1 expression on immune cells. Up-regulated PD-L1 expression on tumour cells and immune cells was associated with high density of pre-existing tumour infiltrating CD3+ and CD8+. In additional, more than 70% tumor infiltrating CD3+ cells were CD3+CD8+ cells. More than 60% PD-L1+ immune cells were PD-L1+CD3+CD8+ cells. PD-L1 expression in tumour cells was associated with poor prognosis and high density CD3+ and CD8+ TILs indicated improved overall survival in gastric cancer patients. Increased PD-L1 expression with low density CD3+ and CD8+ TILs had the shortest overall survival. In accordingly, PD-L1 absence with high density CD3+ and CD8+ TILs indicated the best prognosis. Combination of PD-L1 with pre-existing TILs may be more precise than PD-L1 alone for predicting survival in gastric cancer.

In recent years, neutrophil gelatinase-associated lipocalin (NGAL) has been considered to be a key molecule in different cancer types and its carcinogenesis may be related to the NGAL/MMP-9 complex. However, its expression pattern and role in nasopharyngeal carcinoma (NPC) has rarely been reported. In the current study, 158 tumor tissues from NPC patients were collected and immunohistochemistry was performed to determine the NGAL protein expression, to investigate the correlation between its expression and clinical and pathological parameters using Chi square analysis. Furthermore, by over-expressing NGAL in NPC cell lines, biological alteration of NPC cells with respect to cell proliferation, migration and invasion was analyzed. Results suggested that high expression of NGAL predicts better prognosis and longer survival. Overexpression of NGAL significantly reduced the proliferation and migration of NPC cells, and induced the apoptosis by activating caspase 3, 8 and 9, and blocking epithelial-mesenchymal transition by inhibiting mothers against decapentaplegic homolog 2/3 phosphorylation.

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