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Oxaliplatin is an antineoplastic agent frequently used in the treatment of gastrointestinal tumors. However, it causes dose-limiting sensorimotor neuropathy, referred to as oxaliplatin-induced peripheral neuropathy (OIPN), for which there is no effective treatment. Here, we report that the elevation of neutrophil extracellular traps (NET) is a pathologic change common to both cancer patients treated with oxaliplatin and a murine model of OIPN. Mechanistically, we found that NETs trigger NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and the subsequent release of IL18 by macrophages, resulting in mechanical hyperalgesia. In NLRP3-deficient mice, the mechanical hyperalgesia characteristic of OIPN in our model was reduced. In addition, in the murine model, treatment with the IL18 decoy receptor IL18BP prevented the development of OIPN. We further showed that eicosapentaenoic acid (EPA) reduced NET formation by suppressing the LPS–TLR4–JNK pathway and thereby abolished NLRP3 inflammasome activation and the subsequent secretion of IL18, which markedly prevented oxaliplatin-induced mechanical hyperalgesia in mice. These results identify a role for NET-triggered NLRP3 activation and IL18 release in the development of OIPN and suggest that utilizing IL18BP and EPA could be effective treatments for OIPN.

Supplementary Data from NET-Triggered NLRP3 Activation and IL18 Release Drive Oxaliplatin-Induced Peripheral Neuropathy

Supplementary Figure from NET-Triggered NLRP3 Activation and IL18 Release Drive Oxaliplatin-Induced Peripheral Neuropathy

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High-throughput sequencing of amplicons has been widely used to precisely and efficiently identify species compositions and analyze community structures, greatly promoting biological studies involving large amounts of complex samples, especially those involving environmental and pathogen-monitoring ones. However, commercial library preparation kits for amplicon sequencing, which generally require multiple steps, including adapter ligation and indexing, are expensive and time-consuming, especially for applications at a large scale. Here, to overcome this technical hurdle, we present a one-step PCR amplicon library construction (OSPALC) protocol for amplicon library preparations in the lab along with a QIIME2-based amplicon analysis pipeline. High-quality reads have been generated by this approach to reliably identify species compositions of mock bacterial communities and environmental samples. With this protocol, the amplicon library construction is completed through one regular PCR with long primers, and the total cost per DNA/cDNA sample decreases to just 1/15 of the typical cost via service providers. Empirically tested primers to construct OSPALC libraries for 16S rDNA V4 regions are demonstrated as a case study. Criteria to design primers targeting at any regions of prokaryotic and eukaryotic genomes are also suggested. In principle, OSPALC can be conveniently used in amplicon library constructions of any target gene of both prokaryotes and eukaryotes at the DNA or RNA levels, and will facilitate research in numerous fields.

Oxaliplatin is an antineoplastic agent frequently used in the treatment of gastrointestinal tumors. However, it causes dose-limiting sensorimotor neuropathy, referred to as oxaliplatin-induced peripheral neuropathy (OIPN), for which there is no effective treatment. Here, we report that the elevation of neutrophil extracellular traps (NET) is a pathologic change common to both cancer patients treated with oxaliplatin and a murine model of OIPN. Mechanistically, we found that NETs trigger NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and the subsequent release of IL18 by macrophages, resulting in mechanical hyperalgesia. In NLRP3-deficient mice, the mechanical hyperalgesia characteristic of OIPN in our model was reduced. In addition, in the murine model, treatment with the IL18 decoy receptor IL18BP prevented the development of OIPN. We further showed that eicosapentaenoic acid (EPA) reduced NET formation by suppressing the LPS–TLR4–JNK pathway and thereby abolished NLRP3 inflammasome activation and the subsequent secretion of IL18, which markedly prevented oxaliplatin-induced mechanical hyperalgesia in mice. These results identify a role for NET-triggered NLRP3 activation and IL18 release in the development of OIPN and suggest that utilizing IL18BP and EPA could be effective treatments for OIPN.

The progression of hepatic fibrosis can lead to cirrhosis and hepatic failure, but the development of antifibrotic drugs have faced the challenges of poor effectiveness and targeted specificity. Herein, a theranostic strategy was carried to encapsulate a natural medicine (Quercetin, QR) into hepatitis B core (HBc) protein nanocages (NCs) for imaging and targeted treatment of hepatic fibrosis. It was noted that nanoparticles (RGD-HBc/QR) with surface-displayed RGD targeting ligand exhibit a rather high selectivity toward activated HSCs via the binding affinity with integrin αvβ3, and an efficient inhibition of proliferation and activation of hepatic stellate cells (HSCs) in vitro and in vivo. Once encapsulated in quercetin-gadolinium complex and/or labeled with the NIR fluorescent probes (Cy5.5), the resulting nanoparticles (RGD-HBc/QGd) show great potential as NIR fluorescent and magnetic resonance imaging contrast agents for hepatic fibrosis in vivo. Therefore, the multifunctional integrin-targeted nanoparticles could selectively deliver QR to the activated HSCs, and may provide an effective antifibrotic theranostic strategy.

Ultrafine single-chain tadpole polymers (SCTPs), containing an intrachain crosslinked globule and a pH-sensitive linear polymer chain, have been synthesized. Self-assembly of these polymers depends on the linear block length and the pH, at which the polymer is assembled. Although the SCTPs themselves exhibit a size that is consistent with a single-chain species, the self-assembled SCTPs were found to be substantially larger. Since the transition between these two structures is reversibly dependent on pH, we explored the possibility of utilizing these assemblies to achieve deep tissue penetration in tumors. Our results indicate that there is indeed a pH-dependent deep tissue penetration in ex vivo tumor multicellular spheroids. Moreover, the multi-tadpole assemblies (MTAs) can stably encapsulate hydrophobic molecules, which have been used to encapsulate paclitaxel (PTX). These PTX/MTAs show excellent therapeutic efficacy and biosafety in 4 T1 xenograft mouse models. The innovative multi-compartment aggregates are able to fulfill structure-related function transitions with the variation of microenvironment, which has potential to extremely enrich the design of sophisticated biological agents.

Photodynamic therapy and adipose browning induction are two promising approaches to reverse obesity. The former strategy acts rapidly and locally, whereas the latter has a more gradual and widespread effect. Despite their complementarity, they have rarely been combined and imaged non-invasively in vivo. Here we introduce an adipose-targeting hepatitis B core protein complex that contains a traceable photosensitizer (ZnPcS4 (zinc phthalocyanine tetrasulfonate)) and a browning agent (rosiglitazone) that allows simultaneous photodynamic and browning treatments, with photoacoustic molecular imaging. After intravenous injection in obese mice, the complex binds specifically to white adipose tissues, especially those rich in blood supply, and drives adipose reduction thanks to the synergy of ZnPcS4 photodynamics and rosiglitazone browning. Using photoacoustic molecular imaging, we could monitor the changes induced by the treatment, which included complex activity, lipid catabolism and angiogenesis. Our findings demonstrate the anti-obesity potential of our feedback-based synergic regimen orchestrated by the targeted hepatitis B core complex.

Cyanobacteria, also known as bule-green algae, are capable of photosynthesis and have a fixed carbon and nitrogen effect. The virus that specifically infects cyanobacteria is called the cyanophage. Cyanophages play a key role in building microbial communities. However, only a small number of cyanophages have been reported so far. In this study, a novel Synechococcus cyanophage S-H68 was isolated from the Bohai Sea of China. Transmission electron microscope observations showed that S-H68 has an icosahedral head, 66 ± 1 nm in diameter, and a tail with a length of 107 ± 1 nm, and should be grouped into the family Siphoviridae. To better understand the genetic diversity of this cyanophage, the complete genome was characterized. It consists of 79,639 –bp –length double-stranded DNA with a GC content of 59.8% and is predicted to have 117 open reading frames (ORFs) with an average length of 655 nucleotides. Using the BLASTN tool in the NCBI database for genome comparison, there was no significant similarity between S-H68 and other known cyanophages. So the present study added a new Siphoviridae cyanophage to the marine phage dataset.

A novel Alteromonas phage JH01, with the host strain identified to be Alteromonas marina SW-47(T), was isolated from the Qingdao coast during the summer of 2017. Transmission electron microscopy analysis showed that phage JH01 can be categorized into the Siphoviridae family, with an icosahedral head of 62 ± 5 nm and a long contractile tail of 254 ± 10 nm. The bioinformatic analysis shows that this phage consists of a linear, double-stranded 46,500 bp DNA molecule with a GC content of 44.39%, and 58 ORFs with no tRNA genes. The ORFs are classified into four groups, including phage packaging, phage structure, DNA replication and regulation, and hypothetical protein. The phylogenetic tree, constructed using neighbor-joining analysis, shows that phage JH01 has altitudinal homology with some Vibrio and Pseudoalteromonas phage B8b. Comparative analysis reveals the high similarity between phage JH01 and phage B8b. Additionally, our study of phage JH01 provides useful information for further research on the interaction between Alteromonas phages and their hosts.

A novel marine Alteromonas gracilis siphovirus, phage PB15, was isolated from the surface water of the Yellow Sea in August 2015. It has a head diameter of 58 ± 5 nm head and a contractile tail approximately 105 ± 10 nm in length, and overall the morphology suggests that PB15 belongs to the family Siphoviridae. PB15 phage is stable at over the temperature range 0-60oC. The best MOI of these phage was 0.1 and infectivity decreased above 60oC. The results suggest that phage is stable at pH value ranging between 3.0 and 11.0. Chloroform test shows that PB15 is not a lipid-containing phage. A one-step growth curve with a strain of A. gracilis gave a latent period of 16 minutes and rise period of 24 minutes and burst size of 60 PFU/cell. Genomic analysis of PB15 reveals a genome size of 37,333bp with 45.52% G+C content, and 61 ORFs. ORF sequences accounted for 30.36% of the genome sequence. There is no obvious similarity between PB15 and other known phages by genomic comparison using the BLASTN tool in the NCBI database.