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The transition metal iron plays a crucial role in living cells. However, high levels of iron are potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungus Candida albicans for colonization in the iron-rich gastrointestinal tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 de-repress the expression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress adaptation of C. albicans to gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism. [ABSTRACT FROM AUTHOR]

This study used transcriptome and epigenetic data to predict the prognosis of immune-related genes (IRGs) Apelin (APLN) in patients with hepatocellular carcinoma (HCC). The TCGA database has gene expression and clinical data for HCC. And DNA methylation 450 k data for HCC was download from the University of California Santa Cruz (UCSC) Xena browser. Performing clinical and prognostic analysis of APLN expression, results show that APLN is highly expressed in tumor samples. And it has an increasing trend with the development of clinical stage and T stage. To explore the prognostic role of APLN, the Immune-related DNA methylation (DNAm) sites associated with APLN analyzed by bioinformatics. Univariate COX screened the methylation sites that are related to both APLN and survival. The risk score related to methylation site signature was determined according to their least absolute shrinkage and selection operator (LASSO) coefficients. Then the patients were divided into high-risk groups and low-risk groups. Significant differences in overall survival (OS) were found in the training cohort. Nomogram shows that APLN or methylation signature can effectively predict the prognosis of HCC patients. In summary, APLN may be a diagnostic and prognostic marker for HCC. [ABSTRACT FROM AUTHOR]

Background and Objectives: To optimize the pretreatment method of colorectal cancer tissue samples for metabolomics research based on solid-phase nuclear magnetic resonance (NMR). Methods and Study Design: The mucosal tissues of colorectal cancer were classified into five groups with a volume of 0.2 cm*0.2 cm*0.2 cm. The pretreatment methods for each group were as follows: I. Preservation with liquid nitrogen alone. Samples were also treated with liquid nitrogen for 10 (II), 20 (III), and 30 min (IV), respectively, immediately after isolation and then transferred to a -80°C refrigerator; V. Only -80°C refrigerator storage. No more than 30 minutes should pass between isolation and pretreatment of tumor samples. The tissue sample testing process was carried out on Bruker AVII-600 NMR Spectrometer. NMR signals were collected and analysed using partial least-squares discrimination analysis (PLS-DA) to explore the effects of different pretreatment methods on the metabolic changes of samples. Results: The levels of pelargonic acid, stearic acid, D-Ribose, heptadecanoic acid, pyruvic acid, succinate, sarcosine, glycine, creatine, and L-lactate in the group I (only liquid nitrogen) were significantly lower than the other groups (p<0.05); the content of glycerophosphocholine in the group I (only liquid nitrogen) was lower than that in the other groups (p=0.055). These indicated that the glucose and choline phospholipid metabolism levels of the liquid nitrogen group were significantly lower than those of the other four groups. Conclusions: Liquid nitrogen storage can stop the metabolic process of glucose and choline phospholipid in colorectal cancer tissue samples in vitro, thus maintaining the metabolic state of tissue samples in vivo as much as possible. [ABSTRACT FROM AUTHOR]

Type I interferons (IFNs) are the first frontline of the host innate immune response against invading pathogens. Herein, we characterized an unknown protein encoded by phospholipase A2 inhibitor and LY6/PLAUR domain-containing (PINLYP) gene that interacted with TBK1 and induced type I IFN in a TBK1- and IRF3-dependent manner. Loss of PINLYP impaired the activation of IRF3 and production of IFN-ß induced by DNA virus, RNA virus, and various Toll-like receptor ligands in multiple cell types. Because PINLYP deficiency in mice engendered an early embryonic lethality in mice, we generated a conditional mouse in which PINLYP was depleted in dendritic cells. Mice lacking PINLYP in dendritic cells were defective in type I IFN induction and more susceptible to lethal virus infection. Thus, PINLYP is a positive regulator of type I IFN innate immunity and important for effective host defense against viral infection. [ABSTRACT FROM AUTHOR]

The 5-year survival of hepatocellular carcinoma (HCC) is difficult due to the high recurrence rate and metastasis. Tumor infiltrating immune cells (TICs) and immune-related genes (IRGs) bring hope to improve survival and treatment of HCC patients. However, there are problems in predicting immune signatures and identifying novel therapeutic targets. In the study, the CIBERSORT algorithm was used to evaluate 22 immune cell infiltration patterns in gene expression omnibus (GEO) and the cancer genome atlas (TCGA) data. Eight immune cells were found to have significant infiltration differences between the tumor and normal groups. The CD8+ T cells immune signature was constructed by least absolute shrinkage and selection operator (LASSO) algorithm. The high infiltration level of CD8+ T cells could significantly improve survival of patients. The weighted gene co-expression network analysis (WGCNA) algorithm identified MMP9 was closely related to the overall survival of HCC patients. K-M survival and tROC analysis confirmed that MMP9 had an excellent prognostic prediction. Cox regression showed that a dual immune signature of CD8+ T cells and MMP9 was independent survival factor in HCC. Therefore, a dual prognostic immune signature could improve the survival of patient and may provide a new strategy for the immunotherapy of HCC. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Agmatine, a cationic polyamine formed by decarboxylation of L-arginine, is an endogenous neuromodulator that plays protective roles in diverse central nervous system(CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, agmatine has been reported to have beneficial effects on depression, anxiety, hypoxic ischemia, Parkinson's disease, and gastric disorder. In this study, we tested the effect of agmatine on the lung inflammation induced by Zymosan (ZYM) challenge in mice. We found that agmatine treatment relieved ZYM-induced acute lung injury, as evidenced by the reduced histological scores, wet/dry weight ratio, and myeloperoxidase activity in the lung tissue. This was accompanied by reduced levels of TNF-α, IL-1β, and IL-6 in lung and bronchoalveolar lavage fluid and decreased iNOS expression in lung. Furthermore, agmatine inhibited the phosphorylation and degradation of IκB and subsequently blocked the activation of nuclear factor (NF)-κB induced by Zymosan. Taken together, our results showed that agmatine treatment inhibited NF-κB signaling in lungs and protected mice against ALI induced by Zymosan, suggesting agmatine may be a potential safe and effective approach for the treatment of ALI. [ABSTRACT FROM AUTHOR]

Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodiae fructus. With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and themoregulative effects. Evodiamine has evolved a superior ability to bind various proteins, so we also argue that it is good starting point for multi-target drugs. This review is primarily addressed to the description of the recent advances in the biological activity studies of evodiamine, with a focus on pharmacological mechanism. The present review also includes the pharmacokinetics and the detailed exploration of target-binding properties of evodiamine in an attempt to provide a direction for further multi-target drug design. [ABSTRACT FROM AUTHOR]

Accurate assessment of the potential binding mode of drugs is crucial to computer-aided drug design paradigms. It has been reported that evodiamine acts as an agonist of the vanilloid receptor Transient receptor potential vanilloid-1 (TRPV1). However, the precise interaction between evodiamine and TRPV1 was still not fully understood. In this perspective, the homology models of TRPV1 were generated using the crystal structure of the voltage-dependent shaker family K+ channel as a template. We then performed docking and molecular dynamics simulation to gain a better understanding of the probable binding modes of evodiamine within the TRPV1 binding pocket. There are no significant interspecies differences in evodiamine binding in rat, human and rabbit TRPV1 models. Pharmacophore modeling further provided confidence for the validity of the docking studies. This study is the first to shed light on the structural determinants required for the interaction between TRPV1 and evodiamine, and gives new suggestions for the rational design of novel TRPV1 ligands [ABSTRACT FROM AUTHOR]