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Glutaminyl cyclase (QC) is responsible for converting the N-terminal glutaminyl and glutamyl of the proteins into pyroglutamate (pE) through cyclization. It has been confirmed that QC catalyzes the formation of neurotoxic pE-modified Aβ in the brain of AD patients. But the effects of upregulated QC in diverse diseases have not been much clear until recently. Here, RNA sequencing was applied to identify differentially expressed genes (DEGs) in PC12 cells with QC overexpressing or knockdown. A total of 697 DEGs were identified in QC overexpressing cells while only 77 in QC knockdown cells. Multiple bioinformatic approaches revealed that the DEGs in QC overexpressing group were enriched in endoplasmic reticulum stress (ERS) related signaling pathways. The gene expression patterns of 23 DEGs were confirmed by RT-qPCR, in which the genes related to ERS showed the highest consistency. We also revealed the protein levels of GRP78, PERK, CHOP, and PARP-1, and caspase family was significantly upregulated by overexpressing QC. Moreover, overexpressing QC significantly increased apoptosis of PC12 cells in a time dependent manner. However, no significant alteration was observed in QC knockdown cells. Therefore, our study indicated that upregulated QC could induce ERS and apoptosis, which consequently trigger diseases by catalyzing the generation of pE-modified mediators. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a complex and refractory malignant tumor, ranking the third cause of cancer-related deaths worldwide. Lenvatinib is currently employed to treat advanced, unresectable HCC as a first-line drug. The purpose of this study was to explore the pharmacological mechanisms of lenvatinib acting on HCC through the analysis of differential expressed genes based on network pharmacology. The target genes of lenvatinib were collected from PubChem, SwissTargetPrediction, PharmMapper, and BATMAN-TCM online public databases. In addition, related gene targets for HCC were obtained using NCBI Gene Expression Omnibus (NCBI-GEO) database. Afterward, the protein-protein interaction (PPI) network was established to visualize and understand the interaction relationships of overlapping gene targets from both lenvatinib and HCC. Furthermore, according to the data obtained, Gene Ontology (GO) analysis indicated that these intersectant genes were mainly enriched in response to xenobiotic stimulus, gland development, ion channel complex, membrane raft, and steroid binding. Besides, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that the therapeutic effects of lenvatinib on HCC probably involved bile secretion, MAPK signaling pathway, cGMP-PKG signaling pathway, PI3K-Akt signaling pathway, and Ras signaling pathway. Moreover, a total of six key differential genes, namely, ALB, CCND1, ESR1, AR, CCNA2, and AURKA, were identified as most significant targets associated with lenvatinib treating HCC and further verified by molecular docking, which demonstrated that lenvatinib had a strong binding efficiency with these six key gene-encoded proteins. Taken together, this study systematically provided new insights for researchers to determine the intervention mechanisms of lenvatinib in HCC therapy. [ABSTRACT FROM AUTHOR]

Adiponectin (ADPN) is related to fatty acid synthesis and oxidation in mammals. In chickens, the lipid metabolism, structure and sequence of ADPN are different from that in mammals. The aim of this study was to determine the role of ADPN in broilers lipid metabolism by investigating the temporal and spatial expression profiles of ADPN and its receptors, as well as their response to feed restriction. The results showed that the abdominal fat has the highest expression level, followed by the duodenum, glandular stomach, heart, hypothalamus, liver, and skeletal muscle. Broilers have high energy mobilization during their early stage of growth, in which the fat demand in the liver and muscles is high, thus the expression of ADPN and its receptor are also increased. To study the effects of feed restriction on ADPN and lipid metabolism, broilers were fasted for 12 h and refeed for 2 h. The results showed that fasting decreased the concentration of triglyceride (TG) (P < 0.05) and total cholesterol (TCHO) (P < 0.05) in plasma. The mRNA expression of ADPN in the liver (P < 0.05), breast (P < 0.05) and thigh (P < 0.05), and the mRNA expression of ADPNR1 in the liver (P < 0.05) and duodenum (P < 0.05) were significantly increased in the Fasted group. All above phenomena were recovered after refeeding, suggesting that feed restriction may promote the utilization of fatty acids in active metabolism tissues through ADPN, to guarantee the energy homeostasis of the body. However, the AMP-activated protein kinase (AMPK) signaling pathway and hepatic lipid metabolism were not necessary to cause the above changes under this experimental condition. [ABSTRACT FROM AUTHOR]