Anaerobic cyanides oxidation with bimetallic modulation of biological toxicity and activity for nitrite reduction.

Cyanide is a typical toxic reducing agent prevailing in wastewater with a well-defined chemical mechanism, whereas its exploitation as an electron donor by microorganisms is currently understudied. Given that conventional denitrification requires additional electron donors, the cyanide and nitrogen can be eliminated simultaneously if the reducing HCN/CN- and its complexes are used as inorganic electron donors. Hence, this paper proposes anaerobic cyanides oxidation for nitrite reduction, whereby the biological toxicity and activity of cyanides are modulated by bimetallics. Performance tests illustrated that low toxicity equivalents of iron-copper composite cyanides provided higher denitrification loads with the release of cyanide ions and electrons from the complex structure by the bimetal. Both isotopic labeling and Density Functional Theory (DFT) demonstrated that CN--N supplied electrons for nitrite reduction. The superposition of chemical processes reduces the biotoxicity and enhances the biological activity of cyanides in the CN-/Fe3+/Cu2+/NO2- coexistence system, including complex detoxification of CN- by Fe3+, CN- release by Cu2+ from [Fe(CN)6]3-, and NO release by nitrite substitution of -CN groups. Cyanide is the smallest structural unit of C/N-containing compounds and serves as a probe to extend the electron-donating principle of anaerobic cyanides oxidation to more electron-donor microbial utilization.

Establishment and validation of a novel lysosome-related gene signature for predicting prognosis and immune landscape in hepatocellular carcinoma.

BACKGROUND: Recent studies have shown that lysosomes not only provide energy for tumor cell growth, but also participate in the occurrence and development of malignant tumors by regulating various ways of tumor cell death. However, the role of lysosome associated genes (LSAGs) in hepatocellular carcinoma (HCC) remains unclear. METHODS: Transcriptome data and clinical data of HCC were downloaded from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. We identified differential expression of LSAGs by comparing tumor tissue with normal liver tissue. Subsequently, we used univariate COX analysis and least absolute shrinkage and selection operator (LASSO) COX regression to construct the prognostic feature of LSAGs. Kaplan-Meier survival curve and receiver operating characteristic curve were used to evaluate the predictive ability of LSAGs feature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for functional enrichment analysis of risk differential genes. The relationship between LSAGs score and tumor microenvironment and chemotherapy drug sensitivity was analyzed. Finally, the cellular communication of tumor cells with high and low expression of model LSAGs was explored. RESULTS: We identified sixteen prognostic associated LSAGs, four of which were selected to construct prognostic feature of LSAGs. Patients in the low LSAGs group had a better prognosis than those in the high LSAGs group. GO and KEGG analyses showed that risk differential genes were enriched in leukocyte migration, cytokine-cytokine receptor interaction and PI3K-Akt signaling pathway. The group with low LSAGs score had lower immune score. Patients in the high LSAGs group were more sensitive to drugs for chemotherapy. In addition, tumor cells with high expression of model LSAGs showed stronger association with immune cells through the interleukin-2 (IL2), fibroblast growth factor (FGF), adiponectin, and bone morphogenetic proteins (BMP) signaling pathways. CONCLUSION: We established a LSAGs signature that had the ability to predict clinical prognosis and immune landscape, proposing potential therapeutic targets for HCC.

Prognostic Prediction Value and Biological Functions of Non-Apoptotic Regulated Cell Death Genes in Lung Adenocarcinoma.

Objective To explore the potential biological functions and prognostic prediction values of non-apoptotic regulated cell death genes (NARCDs) in lung adenocarcinoma.Methods Transcriptome data of lung adenocarcinoma were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. We identified differentially expressed NARCDs between lung adenocarcinoma tissues and normal tissues with R software. NARCDs signature was constructed with univariate Cox regression analysis and the least absolute shrinkage and selection operator Cox regression. The prognostic predictive capacity of NARCDs signature was assessed by Kaplan-Meier survival curve, receiver operating characteristic curve, and univariate and multivariate Cox regression analyses. Functional enrichment of NARCDs signature was analyzed with gene set variation analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes. In addition, differences in tumor mutational burden, tumor microenvironment, tumor immune dysfunction and exclusion score, and chemotherapeutic drug sensitivity were analyzed between the high and low NARCDs score groups. Finally, a protein-protein interaction network of NARCDs and immune-related genes was constructed by STRING and Cytoscape software. Results We identified 34 differentially expressed NARCDs associated with the prognosis, of which 16 genes (ATIC, AURKA, CA9, ITGB4, DDIT4, CDK5R1, CAV1, RRM2, GAPDH, SRXN1, NLRC4, GLS2, ADRB2, CX3CL1, GDF15, and ADRA1A) were selected to construct a NARCDs signature. NARCDs signature was identified as an independent prognostic factor (P < 0.001). Functional analysis showed that there were significant differences in mismatch repair, p53 signaling pathway, and cell cycle between the high NARCDs score group and low NARCDs score group (all P < 0.05). The NARCDs low score group had lower tumor mutational burden, higher immune score, higher tumor immune dysfunction and exclusion score, and lower drug sensitivity (all P < 0.05). In addition, the 10 hub genes (CXCL5, TLR4, JUN, IL6, CCL2, CXCL2, ILA, IFNG, IL33, and GAPDH) in protein-protein interaction network of NARCDs and immune-related genes were all immune-related genes. Conclusion The NARCDs prognostic signature based on the above 16 genes is an independent prognostic factor, which can effectively predict the clinical prognosis of patients of lung adenocarcinoma and provide help for clinical treatment.

The mechanism and progress of ferroptosis in pancreatic cancer.

Pancreatic cancer is one of the deadliest cancers in the world, causing hundreds of thousands of deaths worldwide annually. Because of late diagnosis, rapid metastasis and drug resistance to chemotherapy, pancreatic cancer has a poor prognosis. Although the treatment of pancreatic cancer has made tremendous progress, the options for effective treatment are still limited, and new treatment methods are in crying needs to improve prognosis in clinic. Ferroptosis is an iron-dependent non-apoptotic cell death mode, which is mediated by lipid peroxidation and iron accumulation. Ferroptosis plays a momentous role in regulating different cancers in recent years, such as breast cancer, hepatocellular carcinoma, lung cancer and pancreatic cancer. In this present review, we elaborate on the regulatory mechanisms and signaling pathways of ferroptosis in pancreatic cancer, with the intention of delivering directions and new ideas for the treatment of pancreatic cancer.

C-X-C Motif Chemokine 10 Contributes to the Development of Neuropathic Pain by Increasing the Permeability of the Blood-Spinal Cord Barrier.

Neuropathic pain is among the most debilitating forms of chronic pain. Studies have suggested that chronic pain pathogenesis involves neuroimmune interactions and blood-spinal cord barrier (BSCB) disruption. However, the underlying mechanisms are poorly understood. We modeled neuropathic pain in rats by inducing chronic constriction injury (CCI) of the sciatic nerve and analyzed the effects on C-X-C motif chemokine 10 (CXCL10)/CXCR3 activation, BSCB permeability, and immune cell migration from the circulation into the spinal cord. We detected CXCR3 expression in spinal neurons and observed that CCI induced CXCL10/CXCR3 activation, BSCB disruption, and mechanical hyperalgesia. CCI-induced BSCB disruption enabled circulating T cells to migrate into the spinal parenchyma. Intrathecal administration of an anti-CXCL10 antibody not only attenuated CCI-induced hyperalgesia, but also reduced BSCB permeability, suggesting that CXCL10 acts as a key regulator of BSCB integrity. Moreover, T cell migration may play a critical role in the neuroimmune interactions involved in the pathogenesis of CCI-induced neuropathic pain. Our results highlight CXCL10 as a new potential drug target for the treatment of nerve injury-induced neuropathic pain.

Analgesic Effect of Methane Rich Saline in a Rat Model of Chronic Inflammatory Pain.

How oxidative stress contributes to neuro-inflammation and chronic pain is documented, and methane is reported to protect against ischemia-reperfusion injury in the nervous system via anti-inflammatory and antioxidant properties. We studied whether methane in the form of methane rich saline (MS) has analgesic effects in a monoarthritis (MA) rat model of chronic inflammatory pain. Single and repeated injections of MS (i.p.) reduced MA-induced mechanical allodynia and multiple methane treatments blocked activation of glial cells, decreased IL-1ß and TNF-α production and MMP-2 activity, and upregulated IL-10 expression in the spinal cord on day 10 post-MA. Furthermore, MS reduced infiltrating T cells and expression of IFN-γ and suppressed MA-induced oxidative stress (MDA and 8-OHDG), and increased superoxide dismutase and catalase activity. Thus, MS may offer anti-inflammatory and antioxidant effects to reduce chronic inflammatory pain.

Bidirectional modulation between infiltrating CD3+ T-lymphocytes and astrocytes in the spinal cord drives the development of allodynia in monoarthritic rats.

Increasing evidence suggests that T cells and glia participate in the process of neuropathic pain. However, little is known about the involvement of T cells or the interaction between glia and T cells at the molecular level. Here we investigated the phenotype of T cell infiltration into the spinal cord in inflammatory pain and explored potential crosstalk between glia and T cells. The establishment of monoarthritis produced T cell infiltration and astrocyte activation, exhibiting similar kinetics in the spinal cord. T-cell-deficient (Rag1-/-) mice significantly attenuated MA-induced mechanical allodynia and GFAP upregulation. Double immunofluorescence staining showed that CD3 mainly colocalized with interferon-gamma (IFN-γ). Western blot and flow cytometry showed that multiple intrathecal administrations of astrocytic inhibitor fluorocitrate decreased IFN-γ-production without decreasing T cell number in the spinal cord. Spinal IFN-γ blockade reduced MA-induced mechanical allodynia and astroglial activation. In contrast, treatment with rIFN-γ directly elicited persistent mechanical allodynia and upregulation of GFAP and pJNK1/2 in naïve rats. Furthermore, rIFN-γ upregulated the phosphorylation of NF-κB p65 in cultured astrocytes vitro and spinal dorsal horn vivo. The results suggest that Th1 cells and astrocytes maintain inflammatory pain and imply that there may be a positive feedback loop between these cells via IFN-γ.