Salivary metabolites are promising noninvasive biomarkers of drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse events of medication use, and its incidence is increasing. However, early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests. AIM: To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools. METHODS: Saliva samples from 31 DILI patients and 35 healthy controls (HCs) were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry. Subsequent analyses, including partial least squares-discriminant analysis modeling, t tests and weighted metabolite coexpression network analysis (WMCNA), were conducted to identify key differentially expressed metabolites (DEMs) and metabolite sets. Furthermore, we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction. The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves. RESULTS: We found 247 differentially expressed salivary metabolites between the DILI group and the HC group. Using WMCNA, we identified a set of 8 DEMs closely related to liver injury for further prediction testing. Interestingly, the distinct separation of DILI patients and HCs was achieved with five metabolites, namely, 12-hydroxydodecanoic acid, 3-hydroxydecanoic acid, tetradecanedioic acid, hypoxanthine, and inosine (area under the curve: 0.733-1). CONCLUSION: Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients. Our study may provide a potentially feasible and noninvasive diagnostic method for DILI, but further validation is needed.

Doxorubicin-loaded polypyrrole nanovesicles for suppressing tumor metastasis through combining photothermotherapy and lymphatic system-targeted chemotherapy.

The lymphatic system provides a main route for the dissemination of most malignancies, which was related to high mortality in cancer patients. Traditional intravenous chemotherapy is of limited effectiveness on lymphatic metastasis due to the difficulty in accessing the lymphatic system. Herein, a novel lymphatic-targeting nanoplatform is prepared by loading doxorubicin (DOX) into sub-50 nm polypyrrole nanovesicles (PPy NVs). The PPy NVs possessed hollow spherical morphologies and a negative surface charge, leading to high drug loading capacity. These vesicles can also convert near-infrared (NIR) light into heat and thus can be used for tumor thermal ablation. DOX loaded PPy NVs (PPy@DOX NVs) along with NIR illumination are highly effective against 4T1 breast cancer cells in vitro. More importantly, following subcutaneous (SC) injection, a direct lymphatic migration of PPy@DOX NVs is confirmed through fluorescence observation of the isolated draining nodes. The acidic conditions in metastatic nodes might subsequently trigger the release of the encapsulated DOX NVs based on their pH-sensitive release profile. In a mouse model bearing 4T1 breast cancer, lymphatic metastases, as well as lung metastases, are significantly inhibited by nanocarrier-mediated trans-lymphatic drug delivery in combination with photothermal ablation. In conclusion, this platform holds great potential in impeding tumor growth and metastasis.

Lymph node-targeted immune-activation mediated by imiquimod-loaded mesoporous polydopamine based-nanocarriers.

Toll-like receptor (TLR) agonists are the potent stimulants of innate immune system and hold promises as an adjuvant for anticancer immunotherapy. Unfortunately, most of them are limited by a prompt dissemination, and thus caused "wasted inflammation". Hence, how to restrict their action radius into lymphoid tissues is of great relevance to enhance their efficacy and concomitantly alleviates the side effects. Here, imiquimod (R837), a TLR 7 agonist, was loaded into mesoporous polydopamine (MPDA) nanocarriers with high efficiency. Moreover, its surface was modified by polyvinyl pyrrolidone (PVP) to enhance their lymphatic drainage ability. These nano-adjuvants have obvious advantages in promoting dendritic cell (DC) maturation in comparison to free R837. Moreover, their transportation and retention ability in proximal lymph nodes (LNs) were also confirmed, by which lymphatic drug exposure can be maximized to a great extent. Consequently, effective DC activation and CD8+ T cell responses were observed as expected by R837 released in draining LNs. This effect was further enhanced by the presence of endogenous tumor antigens from apoptosis debris induced by MPDA-based photothermal effect, and thus led to the growth inhibition of subcutaneous B16 melanomas. The results demonstrated the great potency against melanoma of the designed PVP-MPDA@R837 nano-adjuvants by combining photothermal conversion property of MPDA with lymphatic-focused immune-activation.

Novel bacterial cellulose membrane biosynthesized by a new and highly efficient producer Komagataeibacter rhaeticus TJPU03.

Bacterial cellulose(BC) is a kind of extracellular polymer synthesized by bacteria and it has very wide applications in many fields. However, the application of BC in a large commercial scale can still not be fulfilled due to the low yield and demanding for BC membranes with very different properties. To this end, a new BC-producer Komagataeibacter rhaeticus TJPU03 was isolated from rotten orange peel, which produced 8.28 ± 0.27 g/L(dry weight) in standard HS medium at the 10th day. The membrane is easier to be purified by one-step alkaline treatment and the produced BC(K-BC) membranes possess homogeneous, looser and more porous three-dimensional network composed by thinner cellulose fibrils. However, the wet K-BC possesses stronger mechanical properties and exhibits lower toxicity and higher cytocompatibility to mammalian cell. Owing to the more porous and homogeneous network, K-BC possesses high loading capacity of cell and protein drugs. Also, it exhibits sustained-controlled release ability for proteinaceous drug. The high yield of this strain and the special characteristics of K-BC predict this strain to be a very promising BC-producer and broad applications of K-BC in the fields of wound healing, scaffolds of tissue engineering, tissue repair and regeneration.

Ultrasensitive multi-analyte electrochemical immunoassay based on GNR-modified heated screen-printed carbon electrodes and PS@PDA-metal labels for rapid detection of MMP-9 and IL-6.

An ultrasensitive electrochemical immunoassay was developed for rapid detection of interleukin-6 (IL-6) and matrix metallopeptidase-9 (MMP-9); the method utilized PS@PDA-metal nanocomposites based on graphene nanoribbon (GNR)-modified heated screen-printed carbon electrode (HSPCE). Because of the good hydrophilicity and low toxicity, GNRs were used to immobilize antibodies (Ab) and amplify the electrochemical signal. PS@PDA-metal was used to label antibodies and generate a strong electrochemical signal in acetic buffer. A sandwich strategy was adopted to achieve simultaneous detection of MMP-9 and IL-6 based on HSPCE without cross-talk between adjacent electrodes in the range of 10(-5) to 10(3) ng mL(-1) with detection limits of 5 fg mL(-1) and 0.1 pg mL(-1) (S/N=3), respectively. The proposed method showed wide detection range, low detection limit, acceptable stability and good reproducibility. Satisfactory results were also obtained in the practical samples, thus showing this is a promising technique for simultaneous clinical detection of biocomponent proteins.

Bioactive plasma-polymerized bipolar films for enhanced endothelial cell mobility.

A facile approach to a highly bio-active interface material is reported. XPS reveals that polar entities exist at the interface between PPAam and PPAac nanolayers. They induce strong dipolar orientation polarizability and cause the redistribution of charges, which results in a remarkable increase of polar surface energy and hydrophilicity of the multistack bipolar films. In particular bipolar films with amine groups on their outermost surface show strongly enhanced cellular mobility. The attachment, adhesion, proliferation, migration, and coverage of ECs are significantly enhanced on such films. They are therefore promising as vascular implant materials, and could have applications as coating materials for tissue engineering.