Shark is a cartilaginous fish that produces new antigen receptor (IgNAR) antibodies. This antibody is identified with a similar human heavy chain but dissimilar sequences. The variable domain (VNAR) of IgNAR is stable and small in size, these features are desirable for drug discovery. Previous study results revealed the effectiveness of VNAR as a single molecule or a combination molecule to treat diseases both in vivo and in vitro with promising clinical applications. We showed the first evidence of IgNAR alternative splicing from spotted bamboo shark (Chiloscyllium plagiosum), broadening our understanding of the IgNARs characteristics. In this review, we summarize the discoveries on IgNAR with a focus on its advantages for therapeutic development based on its peculiar biochemistry and molecular structure. Proper applications of IgNAR will provide a novel avenue to understand its special presence in cartilaginous fishes as well as designing a number of drugs for undefeated diseases.

New aplysiatoxin derivative (oscillatoxin E) exhibiting potent blocking activity against potassium channel Kv1.5 is consistent with molecular docking analysis.

The Wnt/β-catenin signaling pathway plays pivotal roles in axis formation during embryogenesis and in adult tissue homeostasis. Glutathione peroxidase 4 (GPX4) is a selenoenzyme and participates in the reduction of peroxides. Its synthesis depends on the availability of the element selenium. However, the roles of GPX4 in vertebrate embryonic development and underlying mechanisms are largely unknown. Here, we show that maternal loss of zebrafish gpx4b promotes embryonic dorsal organizer formation, whereas overexpression of gpx4b inhibits the development of the dorsal organizer. Depletion of human GPX4 and zebrafish gpx4b (GPX4/ gpx4b) increases, while GPX4/gpx4b overexpression decreases, Wnt/β-catenin signaling in vivo and in vitro. Functional and epistatic studies showed that GPX4 functions at the Tcf/Lef level, independently of selenocysteine activation. Mechanistically, GPX4 interacts with Tcf/Lefs and inhibits Wnt activity by preventing the binding of Tcf/Lefs to the promoters of Wnt target genes, resulting in inhibitory action in the presence of Wnt/β-catenin signaling. Our findings unravel GPX4 as a suppressor of Wnt/β-catenin signals, suggesting a possible relationship between the Wnt/β-catenin pathway and selenium via the association of Tcf/Lef family proteins with GPX4.

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Whitespotted bamboo shark (Chiloscyllium plagiosum), a member of the cartilaginous fish family, has an extremely large liver and demonstrates a strong regeneration ability and immune regulation. Circular RNAs (circRNAs) is an important class of non-coding RNAs. Increasing evidences suggest that circRNAs are a kind of potential regulators. Recently, researchers have isolated and identified different circRNAs from various species, while few reports were on the circRNAs of C. plagiosum. In this study, we have identified a total of 4,558 circRNAs in the liver of C. plagiosum. This finding suggests that circRNAs are not evenly distributed in the chromosomes and follow the GT-AG rule during cyclization. Alternative back-splicing might exist in shark circRNAs as shown by the authenticity identification of predicted circRNAs. The binding strength of circRNAs (<2,000 bp) and the detected miRNAs in shark liver were simultaneously analyzed to construct an mRNA–miRNA–circRNA network for the Glutathione S-transferase P1 gene, and the circRNA authenticity was simultaneously verified. Our data provide not only novel insights into the rich existence of circRNAs in marine animals, but also a basis for characterizing functions of identified circRNAs in the liver homeostasis of C. plagiosum.

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Background: TEA domain transcription factor 4 (TEAD4) is a member of the transcriptional enhancer factor (TEF) family of transcription factors, which is studied to be linked to the tumorigenesis and progression of various forms of cancers, including lung adenocarcinoma (LUAD). However, the specific function of this gene in the progression of LUAD remains to be explored.Method: A total of 19 genes related to the Hippo pathway were analyzed to identify the significant genes involved in LUAD progression. The TCGA-LUAD data (n = 585) from public databases were mined, and the differentially expressed genes (DEGs) in patients with the differential level of TEAD4 were identified. The univariate Cox regression, zero LASSO regression coefficients, and multivariate Cox regression were performed to identify the independent prognostic signatures. The immune microenvironment estimation in the two subgroups, including immune cell infiltration, HLA family genes, and immune checkpoint genes, was assessed. The Gene Set Enrichment Analysis (GSEA) and GO were conducted to analyze the functional enrichment of DEGs between the two risk groups. The potential drugs for the high-risk subtypes were forecasted via the mode of action (moa) module of the connectivity map (CMap) database.Results:TEAD4 was found to be significantly correlated with poor prognosis in LUAD-patients. A total of 102 DEGs in TEAD4-high vs. TEAD4-low groups were identified. Among these DEGs, four genes (CPS1, ANLN, RHOV, and KRT6A) were identified as the independent prognostic signature to conduct the Cox risk model. The immune microenvironment estimation indicated a strong relationship between the high TEAD4 expression and immunotherapeutic resistance. The GSEA and GO showed that pathways, including cell cycle regulation, were enriched in the high-risk group, while immune response-related and metabolism biological processes were enriched in the low-risk group. Several small molecular perturbagens targeting CFTR or PLA2G1B, by the mode of action (moa) modules of the glucocorticoid receptor agonist, cyclooxygenase inhibitor, and NFkB pathway inhibitor, were predicted to be suited for the high-risk subtypes based on the high TEAD4 expression.Conclusion: The current study revealed TEAD4 is an immune regulation–related predictor of prognosis and a novel therapeutic target for LUAD.

Background Although the understanding of resistance to oxaliplatin (OXA) chemotherapy in colorectal cancer (CRC) has been sought for many years, drug tolerance remains a major challenge for cancer therapy. Revealing the molecular mechanism of OXA resistance could help to explain the poor prognosis of patients. Methods Gene expression omnibus (GEO) database was searched, GSE83129, which contains RNA profiling in metastatic CRC patients treated first‐line with OXA, was chosen for the following analysis. Differential expressed genes (DEGs) between the adenocarcinoma and adjacent_normal team, respectively, in the OXA responders and no‐responders were analyzed. The Gene Ontology (GO) and hub genes in the protein–protein interaction (PPI) network were used for the molecular mechanism of OXA resistance. Tumor‐related databases were used for the clinical relevance of the structural maintenance of chromosomes 5 ( SMC5 ) in CRC. The in vitro assays were used to detect the molecular function of SMC5 in CRC cells. Quantitative real‐time PCR (qRT‐PCR) and western blot were used to detect the expression of the structural maintenance of chromosomes 5/6 (SMC5/6) complex components upon OXA and raltitrexed (RTX) treatment. CCK‐8 was used to detect the cell viability of cells with different treatment. Results SMC5 was downregulated in CRC tissues of OXA no‐response patients. Lower expression of SMC5 was correlated with a poor prognosis in CRC patients, improved this gene expression, inhibited the CRC cell growth and invasion in vitro. Furthermore, SMC5 was downregulated upon OXA treatment in CRC cells, while RTX would reverse its expression, and the combination of these two drugs restored the SMC5 level to the normal situation. Finally, RTX treatment enhanced the OXA cytotoxicity. Conclusion SMC5 is a tumor suppressor, that low expression of this gene is benefit for the development of CRC. Combination treatment with RTX and OXA may be more suitable for those OXA no‐responders with lower SMC5 .