Bioinformatics analysis of CUL2/4A/9 and its function in head and neck squamous cell carcinoma

Introduction: Several previous studies have shown that differential expression of cullin (CUL) family proteins may be involved in mediation of the signal transduction pathways associated with cancer. However, the function of CULs is still unclear in head and neck squamous cell carcinoma (HNSCC). Material and methods: We used The Cancer Genome Atlas (TCGA) database, cBioPortal, Metascape, STRING, Cytoscape, Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter, and Tumor Immune System Interaction Database (TISIDB) to access the expression of CULs and the possible correlation with the tumourigenesis, development, prognosis, immunity, and transcriptional level of CULs in HNSCC. Furthermore, real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect messenger ribonucleid acid (mRNA) levels in HNSCC tissues and cell samples. We also explored the cell proliferation and migration separately by CCK8 assay and wound healing assay. Results: The results showed that the expressions of CUL2/4A were upregulated and CUL9 was downregulated in HNSCC patients as compared with normal patients. CUL2/4A/9 were also linked to the clinicopathological features and overall survival of HNSCC in bioinformatics analysis. Moreover, we noticed that CUL2/4A/9 may take part in tumour-specific immune response by modulating the tumour-infiltrating lymphocytes (TILs) and immunomodulators. Lastly, we found that CUL2/4A/9 could promote cellular proliferation and migration. Conclusion: These results suggest that the transcriptional levels of CUL2/4A/9 were upregulated and these genes could affect proliferation and migration of HNSCC cells. Therefore, CUL2/4A/9 could potentially function as novel independent biomarkers in HNSCC patients

Down-regulation of long non-coding RNA ESCCAL_1 inhibits tumor growth of esophageal squamous cell carcinoma in a xenograft mouse model.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignant cancers with high incidence and mortality. Current reliable effective diagnostic and prognostic biomarkers are very limited in clinic. Emerging evidence indicates that dysregulated expression of the long non-coding RNAs (lncRNAs) was examined in various types of cancer including ESCC. ESCC associated lncRNA _1 (ESCCAL_1) was first time identified to be increased expression in ESCC, and therefore named by our research team. However, its potential function in the progression of ESCC remains unclear. In this study, we investigated the effect of ESCCAL_1 knockdown on ESCC tumorigenicity using a xenograft mouse model and explored the underlying molecular mechanism. Here we showed that ESCCAL_1 knockdown significantly inhibited EC9706 cell growth in nude mice. Interestingly, we also found that reduced expression of ESCCAL_1 resulted in distinct alterations of relative phosphorylation level of kinases (p-p38α, p-JNK, p-FAK and p-Src), and significant changes of the expression level of apoptosis-related proteins (p53, BAX, Bcl-2 and Caspase-3). In summary, our results suggest that lncRNA ESCCAL_1 is a potential diagnostic and prognostic target of ESCC

Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1HKO) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1f/f), Ddah1HKO mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy

DDAH1 Protects against Cardiotoxin-Induced Muscle Injury and Regeneration

Nitric oxide (NO) is an important biological signaling molecule affecting muscle regeneration. The activity of NO synthase (NOS) is regulated by dimethylarginine dimethylaminohydrolase 1 (DDAH1) through degradation of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). To investigate the role of DDAH1 in muscle injury and regeneration, muscle-specific Ddah1-knockout mice (Ddah1MKO) and their littermates (Ddah1f/f) were used to examine the progress of cardiotoxin (CTX)-induced muscle injury and subsequent muscle regeneration. After CTX injection, Ddah1MKO mice developed more severe muscle injury than Ddah1f/f mice. Muscle regeneration was also delayed in Ddah1MKO mice on Day 5 after CTX injection. These phenomena were associated with higher serum ADMA and LDH levels as well as a great induction of inflammatory response, oxidative stress and cell apoptosis in the gastrocnemius (GA) muscle of Ddah1MKO mice. In the GA muscle of CTX-treated mice, Ddah1 deficiency decreased the protein expression of M-cadherin, myogenin, Bcl-2, peroxiredoxin 3 (PRDX3) and PRDX5, and increased the protein expression of MyoD, TNFα, Il-6, iNOS and Bax. In summary, our data suggest that DDAH1 exerts a protective role in muscle injury and regeneration

Genetic and Pharmacological Inhibition of GCN2 Ameliorates Hyperglycemia and Insulin Resistance in Type 2 Diabetic Mice

It is well recognized that there is a strong and complex association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We previously demonstrated that genetic knockout or pharmacological inhibition of general control nondepressible kinase 2 (GCN2), a well-known amino acid sensor, alleviated hepatic steatosis and insulin resistance in obese mice. However, whether GCN2 affects the development of T2D remains unclear. After a high-fat diet (HFD) plus low-dose streptozotocin (STZ) treatments, Gcn2−/− mice developed less hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress than wild-type (WT) mice. Inhibition of GCN2 by intraperitoneal injection of 3 mg/kg GCN2iB (a specific inhibitor of GCN2) every other day for 6 weeks also ameliorated hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress in HFD/STZ- and leptin receptor deletion (db/db)-induced T2D mice. Moreover, depletion of hepatic GCN2 in db/db mice by tail vein injection of an AAV8-shGcn2 vector resulted in similar improvement in those metabolic disorders. The protective mechanism of GCN2 inhibition in T2D mice was associated with regulation of the glucose metabolic pathway, repression of lipogenesis genes, and activation of the Nrf2 pathway. Together, our data provide evidence that strategies to inhibit hepatic GCN2 activity may be novel approaches for T2D therapy

Rapid ultrasound-assisted synthesis of controllable Zn/Co-based zeolitic imidazolate framework nanoparticles for heterogeneous catalysis

While metal-organic frameworks (MOFs) exhibit excellent potential in extensive catalytic reactions, predictably synthesizing MOF nanoparticles (NPs) with desired and uniform sizes remains a great challenge. Here, a mild and efficient ultrasound-assisted synthetic method has been developed to prepare ZIF-8, ZIF-67, and Co/ZIF-8 with well-designed particle size and morphology. By adjusting the cobalt content doped into a heterometallic ZIF-8 structure, tunable particle sizes ranging from 35 nm to over 300 nm have been achieved, resulting from the differences in nucleation and growth rates of zinc and cobalt ZIFs. Impressively, this as-obtained bimetallic Zn/Co-ZIF shows hierarchical porous structure with modified physicochemical properties, leading to a change of nitrogen adsorption-desorption characteristics. In addition, when used as a heterogenous catalyst, the bimetallic Co-doped ZIF-8 is demonstrated to have both enhanced catalytic performance for the activation of peroxymonosulfate (PMS) in organic dye degradation compared to pure ZIF-8, as well as superior structural stability, when compared to monometallic ZIF-67. This work provides a novel strategy for the predictable design and controlled fabrication of bimetallic MOF nanostructures with desired structures and compositions.Ministry of Education (MOE)Submitted/Accepted versionThe authors gratefully acknowledge the financial support from the Ministry of Education (MOE) Singapore AcRF Tier 1 grant (2018-T1- 001-077) and the UK Engineering and Physical Sciences Research Council (EP/R01650X/1)

<i>ErmF</i> and <i>ereD</i> Are Responsible for Erythromycin Resistance in <i>Riemerella anatipestifer</i>

<div><p>To investigate the genetic basis of erythromycin resistance in <i>Riemerella anatipestifer</i>, the MIC to erythromycin of 79 <i>R</i>. <i>anatipestifer</i> isolates from China and one typed strain, ATCC11845, were evaluated. The results showed that 43 of 80 (53.8%) of the tested <i>R</i>. <i>anatipestifer</i> strains showed resistance to erythromycin, and 30 of 43 erythromycin-resistant <i>R</i>. <i>anatipestifer</i> strains carried <i>ermF</i> or <i>ermFU</i> with an MIC in the range of 32–2048 μg/ml, while the other 13 strains carrying the <i>ereD</i> gene exhibited an MIC of 4–16 μg/ml. Of 30 <i>ermF</i> + <i>R</i>. <i>anatipestifer</i> strains, 27 (90.0%) carried the <i>ermFU</i> gene which may have been derived from the CTnDOT-like element, while three other strains carried <i>ermF</i> from transposon Tn4351. Moreover, sequence analysis revealed that <i>ermF</i>, <i>ermFU</i>, and <i>ereD</i> were located within the multiresistance region of the <i>R</i>. <i>anatipestifer</i> genome.</p></div

Distribution of <i>R</i>. <i>anatipestifer</i> strains with different MICs for erythromycin.

<p>Distribution of <i>R</i>. <i>anatipestifer</i> strains with different MICs for erythromycin.</p

Clustal W alignment of the upstream sequences from the <i>ermF</i> / <i>ermFU</i> genes from CTnDOT, Tn4351, and different <i>R</i>. <i>anatipestifer</i> strains.

<p>The start codon ATG of <i>ermFU</i>/<i>ermF</i> gene was underlined.</p