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Eccentric contraction (EC) is known to elicit inflammation and damage in skeletal muscle. Proinflammatory cytokine TNF-alpha plays an important role in this pathogenesis, but the time course of its response to EC and the regulatory mechanisms involved are not clear. The purpose of the study is twofold: 1) to investigate the gene expression of TNF-alpha in rat muscle during and after an acute bout of downhill running and the associated oxidoreductive (redox) changes; and 2) to examine whether EC activates muscle ubiquitin-proteolytic pathway resulting in necrosis and oxidative damage. Female Sprague-Dawley rats (age 3 mo) were randomly divided into five groups (n = 6) that ran on treadmill at 25 m/min at -10% grade for 1 h (group 1) or 2 h (group 2) and were killed immediately; ran for 2 h and killed at 6 h after exercise (group 3), ran for 2 h and killed at 24 h after exercise (group 4); and killed at rest as controls (group 5). TNF-alpha mRNA and protein content showed progressive increases in the deep portion of vastus lateralis (DVL) and gastrocnemius muscles during and after EC. These changes were accompanied by a progressive decrease of mitochondrial aconitase activity and NF-kappaB activation. After 2 h of exercise, elevated levels of serum TNF-alpha, endotoxin, creatine kinase, and lipid peroxidation marker were evident and persisted through 24 h postexercise. At 24 h, there were marked increases in H(2)O(2) concentration, myleoperoxidase activity, and endotoxin level, along with nuclear accumulation of p65, in both muscles. mRNA level of ubiquitin-conjugating enzymes (E(2))-14k was progressively upregulated during exercise and recovery, whereas the expression of the Toll-like receptor 4 (TLR4) in DVL was downregulated in both muscles. We conclude that prolonged EC induces TNF-alpha expression possibly due to NF-kappaB activation stimulated by increased reactive oxygen species generation and endotoxin release. These inflammatory and prooxidative responses may underlie the processes of muscle proteolysis and oxidative damage.

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LEPTIN (LEP) is a circulating hormone released primarily from white adipocytes and is crucial for regulating satiety and energy homeostasis in humans and animals. Using the CRISPR technology, we created a set of Lep mutant rats that carry either null mutations or a deletion of the 14th Ile (LEP∆I14) in the mature LEP protein. We examined the potential off-target sites (OTS) by whole-genome high-throughput sequencing and/or Sanger-sequencing analysis and found no OTS in mutant rats. Mature LEP∆I14 is incessantly produced and released to blood at a much elevated level due to the feedback loop. Structure modeling of binding conformation between mutant LEP∆I14 and LEPTIN receptor (LEPR) suggests that the conformation of LEP∆I14 impairs its binding with LEPR, consistent with its inability to activate STAT3-binding element in the luciferase reporter assay. Phenotypic study demonstrated that Lep∆I14 rats recapitulate phenotypes of Lep-null mutant rats including obesity, hyperinsulinemia, hepatic steatosis, nephropathy, and infertility. Compared to the existing ob/ob mouse models, this Lep∆I14/∆I14 rat strain provides a robust tool for further dissecting the roles of LEP in the diabetes related kidney disease and reproduction problem, beyond its well established function in regulating energy homeostasis.

AT-rich interaction domain 5A (ARID5A) is a member of the ARID family with a function that has been linked to autoimmune as well as inflammatory diseases. Some ARID family members are involved in the initiation and progression of human cancers. However, the function of ARID5A in glioma remains unknown. In this study, ARID5A expression levels were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Subsequently, the relationship between ARID5A expression and the clinical characteristics of glioma patients was evaluated using the Chinese Glioma Genome Atlas (CGGA) database and The Cancer Genome Atlas (TCGA) database. The prognostic value of ARID5A in glioma was estimated by Kaplan-Meier analysis and the receiver operating characteristic (ROC) curve analysis. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) were performed for functional prediction. The Tumor Immune Estimation Resource (TIMER) database was used to analyze the relationship between ARID5A and immune cell infiltration in glioma. Our results demonstrate that the expression of ARID5A was upregulated in glioma compared with that in nontumor brain tissues. High expression of ARID5A is associated with poor prognosis in glioma. We found that the expression of ARID5A was significantly upregulated with an increase in tumor malignancy. GO analysis revealed that co-expression genes of ARID5A are significantly involved in some important functions in glioma, and GSEA showed that multiple cancer-associated and immune-associated signaling pathways are enriched in the high ARID5A expression group. TIMER database indicated that ARID5A is correlated with tumor-infiltrating immune cells in glioma. Collectively, these findings indicate that ARID5A may be a potential prognostic biomarker and is correlated with immune infiltration in glioma.

Glioma is a relatively low aggressive brain tumor. Although the median survival time of patients for lower-grade glioma (LGG) was longer than that of patients for glioblastoma, the overall survival was still short. Therefore, it is urgent to find out more effective molecular prognostic markers. The role of the Fam20 kinase family in different tumors was an emerging research field. However, the biological function of Fam20C and its prognostic value in brain tumors have rarely been reported. This study aimed to evaluate the value of Fam20C as a potential prognostic marker for LGG. A total of 761 LGG samples (our cohort, TCGA and CGGA) were included to investigate the expression and role of Fam20C in LGG. We found that Fam20C was drastically overexpressed in LGG and was positively associated with its clinical progression. Kaplan-Meier analysis and a Cox regression model were employed to evaluate its prognostic value, and Fam20C was found as an independent risk factor in LGG patients. Gene set enrichment analysis also revealed the potential signaling pathways associated with Fam20C gene expression in LGG; these pathways were mainly enriched in extracellular matrix receptor interactions, cell adhesion, cell apoptosis, NOTCH signaling, cell cycle, etc. In summary, our findings provide insights for understanding the potential role of Fam20C and its application as a new prognostic biomarker for LGG.

Inflammation is an important biological process for eliciting immune responses against physiological and pathological stimuli. Inflammation must be efficiently regulated to ensure homeostasis in the body. Nuclear factor-kappa B (NF-κB) signaling is crucial for inflammatory and immune responses. Aberrant activation of NF-κB signaling leads to development of numerous human diseases. In this study, we investigated the function of chromosome 7 open reading frame 41 (C7ORF41) in NF-κB signaling during inflammation. C7ORF41 was upregulated in cells stimulated with tumor necrosis factor-alpha or lipopolysaccharide. Moreover, overexpression of C7ORF41 inhibited the activation of NF-κB and decreased the expression of its downstream target genes. Notably, small hairpin RNA-mediated depletion of C7ORF41 increased the levels of downstream genes and enabled the activation of NF-κB. In conclusion, C7ORF41 negatively regulated inflammation via NF-κB signaling and p65 phosphorylation in vitro. These findings may help to diagnose and prognosticate inflammatory conditions and may help develop new strategies for the management of inflammation-related diseases.

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