Sulfonated Perylene as Three-in-One STING Agonist for Cancer Chemo-Immunotherapy.

Activation of stimulator of interferon genes (STING) by cyclic dinucleotides (CDNs) has been considered as a powerful immunotherapy strategy. While promising, the clinical translation of CDNs is still overwhelmed by its limited biostability and the resulting systemic immunotoxicity. Being differentiating from current application of exogenous CDNs to address these challenges, we herein developed one perylene STING agonist PDIC-NS, which not only promotes the production of endogenous CDNs but also inhibits its hydrolysis. More significantly, PDIC-NS can well reach lung-selective enrichment, and thus mitigates the systemic immunotoxicity upon intravenous administration. As a result, PDIC-NS had realized remarkable in vivo antitumor activity, and backward verified on STING knock out mice. Overall, this study states that PDIC-NS can function as three-in-one small-molecule STING agonist characterized by promoting the content and biostability of endogenous CDNs as well as possessing good tissue specificity, and hence presents an innovative strategy and platform for tumor chemo-immunotherapy.

Whole-Genome Methylation Sequencing of Large Yellow Croaker (Larimichthys crocea) Liver Under Hypoxia and Acidification Stress.

Large yellow croaker (Larimichthys crocea) is an important aquaculture species in China. This study analysed whole-genome methylation differences in liver tissues of young fish under different hypoxic and acidification conditions. Differentially methylated regions (DMRs) and differentially methylated genes (DMGs) were identified. Gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) enrichment analyses of DMGs were conducted to explore the mechanism of coping with hypoxic acidification. The main methylation type was CG, accounting for > 70% of total methylation, significantly higher than CHG and CHH methylation types. GO enrichment analysis of DMGs revealed strong enrichment of nervous system development, cell periphery, plasma membrane, cell junction organisation, cell junction, signalling receptor activity, molecular sensor activity, cell-linked tissue junction organisation, cell-cell adhesion and nervous system development. KEGG enrichment analysis of DMR-related genes identified cell adhesion molecules, cortisol synthesis and secretion and aldosterone synthesis and secretion as the three key pathways regulating the physiological responses to hypoxia and acidification. Long-term hypoxic and acidification stress affected the immune system, nervous system and stress responses of large yellow croaker. Whole-genome sequencing analysis of exposed tissues was used to investigate changes that occur in L. crocea in response to hypoxic and acidic conditions at the DNA methylation level. The findings contribute to our comprehensive understanding of functional methylation in large yellow croaker and will support future research on the response mechanisms of this species under different environmental pressures.

Perylene-Mediated Electron Leakage in Respiratory Chain to Trigger Endogenous ROS Burst for Hypoxic Cancer Chemo-Immunotherapy.

Perylene derivatives can be stimulated by the hypoxic tumor microenvironment to generate radical anion that is proposed to arouse electron exchange with oxidizing substance, and in turn, realize reactive oxygen species (ROS) burst. Here, three perylene therapeutic agents, PDI-NI, PDIB-NI, and PDIC-NI, are developed and it is found that the minimum lowest unoccupied molecular orbital (LUMO) energy level makes PDIC-NI most easily accept electrons from the oxidative respiratory chain to form lots of anions, and the resultant maximum ROS generation, establishing an unambiguous mechanism for the formation of perylene radical anions in the cell, presents solid evidence for LUMO energy level determining endogenous ROS burst. Stirringly, PDIC-NI-induced ROS generation arouses enhanced mitochondrial oxidative stress and concurrently activates immunogenic cell death (ICD), which not only efficiently kills lung tumor cells but also reprograms immunosuppressive tumor microenvironment, including the cytokine secretion, dendritic cell maturation, as well as cytotoxic T lymphocytes activation, to inhibit the growth of xenografted and metastasis tumor, presenting a proof-of-concept demonstration of perylene that acts as an integrated therapeutic agent to well realize hypoxia-activated chemotherapy with ICD-induced immunotherapy on lung cancer.

Complete mitochondrial genome of the deep pugnose ponyfish Secutor ruconius (Perciformes: Leiognathidae) in the East China Sea.

The complete mitochondrial genome sequence of Secutor ruconius is firstly described in this article. The total length of mitogenome is16,465 bp. It contains 13 protein-coding genes, 22 tRNA genes, and 2 ribosomal RNA genes. The overall base composition of H-strand is 31.58% A, 28.65% C, 25.23% T, and 14.53% G, with an A + T bias of 56.81%. The phylogenetic analysis result showed that the S. ruconius, Zebrasoma flavescens, and Pristipomoides multidens were closely related.

Complete mitochondrial genome of the glowbelly Acropoma japonicum (Perciformes: Acropomatidae) in the East China Sea.

The complete mitochondrial genome sequence of Acropoma japonicum is first described in this article. The total length of mitogenome is16,973 bp. It contains 13 protein-coding genes, 23 tRNA genes, and 2 ribosomal RNA genes. The overall base composition of H-strand is 27.64% A, 29.49% C, 26.84% T, and 16.03% G, with an A＋T bias of 54.48%. The phylogenetic analysis result showed that the A. japonicum and Lutjanus peru had a close relationship.

The ethanol extract of honeysuckle stem modulates the innate immunity of Chinese mitten crab Eriocheir sinensis against Aeromonas hydrophila.

Honeysuckle stem had been used as feed additives to modulate immunity in breeding industry, which was limited in the aquaculture field. In this study, the immunomodulation of honeysuckle stem ethanol extract (designed as HSE) on Chinese mitten crab Eriocheir sinensis was detected. The crabs fed with HSE diets for 30 days had higher level of the total haemocyte count (HTC), lysozyme activity and PO activity (P < 0.05), and had no obvious affect on the phagocytic activity, NO and TNF-α level. When challenged with Aeromonas hydrophila (1.0 × 107 colony-forming units), HSE exhibited weak antibacterial activity against A. hydrophila and increased survival rate of crabs. The decreasing of THC and the increasing of TNF-α concentration, EsCaspase and EsLITAF mRNA expression level were all inhibited significantly by HSE treatment (P < 0.05), when the crabs were challenged by A. hydrophila. Moreover, the following immune parameters of crabs were enhanced by HSE treatment after A. hydrophila infection, including the rising of phagocytosis index and phagocytic rate of haemocyte, the rising of lysozyme, PO, NOS activities and nitric oxide concentration (P < 0.05). Therefore, it was concluded that HSE had great potential to develop into feed additive of crabs, which could enhance the innate immunity of Chinese mitten crabs E. sinensis effectively after A. hydrophila infection.

Characterization of the complete mitochondrial genome of the endangered species Schizothorax integrilabiatus.

Schizothorax integrilabiatus is an endangered fish species found in the Buqun Lake of Qinghai-Tibet Plateau. In this study, we determined the complete mitochondrial genome sequence of the S. integrilabiatus. The circular mitochondrial genome was 16,621 bp in length, containing 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes and a control region (D-loop). The overall base composition is A 30.1%, C 26.9%, G 17.4%, and T 25.6%, with a high A + T content (55.7%). Further, phylogenetic analysis suggested that S. integrilabiatus is closely related to species of S. plagiostomus, and then clustered into a clade with other Schizothoracinae species. This work provides additional molecular information for studying S. integrilabiatus conservation genetics and evolutionary relationships.

Preparation of magnetic glycoprotein-imprinted nanoparticles with dendritic polyethyleneimine as a monomer for the specific recognition of ovalbumin from egg white.

Glycoproteins are crucial in massive physiological events and clinical application. It is necessary to prepare new materials to isolate the specific glycoprotein. New and simple core-shell molecularly imprinted polymers were prepared by surface imprinting. The polymers are synthesized with magnetic nanoparticles as the core, water-soluble dendritic polyethyleneimine as the monomer and the ovalbumin as the template. The prepared imprinted polymers showed thin imprinted shell, biocompatibility and superparamagnetic properties. The resultant materials exhibited fast kinetics, high adsorption capacity, perfect selectivity and reusability. More important, they can absorb the template glycoprotein from the neutral solution and successfully be applied to recognize the ovalbumin from egg white, which means that they can provide an alternate method to isolate glycoprotein from bodily fluids.

Preparation of biocompatible molecularly imprinted shell on superparamagnetic iron oxide nanoparticles for selective depletion of bovine hemoglobin in biological sample.

Bovine hemoglobin (BHb), as one of the high-abundance proteins, could seriously mask and hamper the analysis of low-abundance proteins in serum. To selectively deplete BHb, we design a simple and effective strategy for preparation of biocompatible molecularly imprinted shell on superparamagnetic iron oxide nanoparticles through surface imprinting technique combined with template immobilization strategy. Firstly, template proteins are immobilized on the directly aldehyde-functionalized magnetic nanoparticles through imine bonds. Then, with gelatin as functional monomer, a polymeric network molded around the immobilized template proteins is obtained. Finally, the specific cavities for BHb are fabricated after removing the template proteins. The effects of imprinting conditions were investigated and the optimal imprinting conditions are found to be 40mg of BHb, 150mg of gelatin, and 8h of polymerization time. The resultant materials exhibit good dispersion, high crystallinity, and satisfactory superparamagnetic property with a high saturation magnetization (33.43emug(-1)). The adsorption experiments show that the imprinted nanomaterials have high adsorption capacity of 93.1mgg(-1), fast equilibrium time of 35min, and satisfactory selectivity for target protein. Meanwhile, the obtained polymers could be used without obvious deterioration after six adsorption-desorption cycles. In addition, the resultant polymers are successfully applied in the selective isolation BHb from bovine blood sample, which could provide an alternative solution for the preparatory work of proteomics.