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The present study explored the role of gut microbiota and gut-associated metabolism in oral toxicity induced by TiO2 NPs.

BackgroundDue to its excellent physicochemical properties and wide applications in consumer goods, titanium dioxide nanoparticles (TiO2 NPs) have been increasingly exposed to the environment and the public. However, the health effects of oral exposure of TiO2 NPs are still controversial. This study aimed to illustrate the hepatotoxicity induced by TiO2 NPs and the underlying mechanisms. Rats were administered with TiO2 NPs (29 nm) orally at exposure doses of 0, 2, 10, 50 mg/kg daily for 90 days. Changes in the gut microbiota and hepatic metabolomics were analyzed to explore the role of the gut-liver axis in the hepatotoxicity induced by TiO2 NPs.ResultsTiO2 NPs caused slight hepatotoxicity, including clear mitochondrial swelling, after subchronic oral exposure at 50 mg/kg. Liver metabolomics analysis showed that 29 metabolites and two metabolic pathways changed significantly in exposed rats. Glutamate, glutamine, and glutathione were the key metabolites leading the generation of energy-related metabolic disorders and imbalance of oxidation/antioxidation. 16S rDNA sequencing analysis showed that the diversity of gut microbiota in rats increased in a dose-dependent manner. The abundance of Lactobacillus_reuteri increased and the abundance of Romboutsia decreased significantly in feces of TiO2 NPs-exposed rats, leading to changes of metabolic function of gut microbiota. Lipopolysaccharides (LPS) produced by gut microbiota increased significantly, which may be a key factor in the subsequent liver effects.ConclusionsTiO2 NPs could induce slight hepatotoxicity at dose of 50 mg/kg after long-term oral exposure. The indirect pathway of the gut-liver axis, linking liver metabolism and gut microbiota, played an important role in the underlying mechanisms.

MicroRNAs (miRNAs) have emerged as the promising molecular biomarkers for early diagnosis and enhanced understanding of the molecular pathogenesis of cancers as well as certain diseases. Here, a facile, label-free, and amplification-free electrochemical biosensor was developed to detect miRNA by using DNA origami nanostructure-supported DNA probes, with methylene blue (MB) serving as the hybridization redox indicator, for the first time. Specifically, the use of cross-shaped DNA origami nanostructures containing multiple single-stranded DNA probes at preselected locations on each DNA nanostructure could increase the accessibility and the recognition efficiency of the probes (due to the rational controlled density of DNA probes). The successful immobilization of DNA origami probes and their hybridization with targeted miRNA-21 molecules was confirmed by electrochemical impedance spectroscopy and cyclic voltammetry methods. A differential pulse voltammetry technique was employed to record the oxidation peak current of MB before and after target hybridization. The linear detection range of this biosensor was from 0.1 pM to 10.0 nM, with a lower detection limit of 79.8 fM. The selectivity of the miRNA biosensor was also studied by observing the discrimination ability of single-base mismatched sequences. Because of the larger surface area and unprecedented customizability of DNA origami nanostructures, this strategy demonstrated great potential for sensitive, selective, and label-free determination of miRNA for translational biomedical research and clinical applications.

Circular RNAs (circRNAs) have been demonstrated to be involved in various biological processes. Nevertheless, the function of circRNAs in medulloblastoma (MB) is still unknown. The present study aimed to investigate the expression profiles of circRNAs and related mechanisms for regulating the proliferation and growth of tumor cells in MB. The expression profiles of circRNAs were screened from four normal cerebellum and four MB samples using a HiSeq Sequencer. Bioinformatic analysis was employed to predict the interaction between circRNAs and mRNAs in MB. Subsequently, the expression levels of eight differential circRNAs [circ‐SKA3 (hsa_circ_0029696), circ‐DTL (hsa_circ_0000179), circ‐CRTAM, circ‐MAP3K5 (hsa_circ_0006856), circ‐RIMS1‐1 (hsa_circ_0132250), circ‐RIMS1‐2 (hsa_circ_0076967), circ‐FLT3‐1 (hsa_circ_0100165), and circ‐FLT3‐2 (hsa_circ_0100168)] were validated using quantitative reverse transcription−polymerase chain reaction. Moreover, circ‐SKA3 and circ‐DTL were silenced using small interfering RNAs and their host genes were overexpressed to investigate their role in the pathogenesis of MB. A total of 33 circRNAs were found to be differentially expressed in MB tissues (fold change ≥ 2.0, FDR <0.05), of which three were upregulated and 30 were downregulated; six circRNAs were experimentally validated successfully. Upregulated circ‐SKA3 and circ‐DTL promoted the proliferation migration and invasion in vitro by regulating the expression of host genes. This novel study exploited the profiling of circRNAs in MB and demonstrated that circ‐SKA3 and circ‐DTL were crucial in the tumorigenesis and development of MB and might be considered as novel and potential biomarkers for the diagnosis and new targets for the intervention of MB.

Nanomaterials have been extensively utilized in biosensing systems for highly sensitive and selective detection of a variety of biotargets. In this work, a facile, label-free, and ultrasensitive electrochemical DNA biosensor has been developed, based on “urchinlike” carbon nanotube-gold nanoparticle (CNT-AuNP) nanoclusters, for signal amplification. Specifically, electrochemical polymerization of dopamine (DA) was employed to modify a gold electrode for immobilization of DNA probes through the Schiff base reaction. Upon sensing the target nucleic acid, the dual-DNA (reporter and linker) functionalized AuNPs were introduced into the sensing system via DNA hybridization. Afterward, the end-modified single-wall carbon nanotubes with DNA (SWCNT-DNA) were attached to the surface of the AuNPs through linker-DNA hybridization that formed 3D radial nanoclusters, which generated a remarkable electrochemical response. Because of the larger contact surface area and super electronic conductivity of CNT-AuNP clusters, this novel designed 3D radial nanostructure exhibits an ultrasensitive detection of DNA, with a detection limit of 5.2 fM (a linear range of from 0.1 pM to 10 nM), as well as a high selectivity that discriminates single-mismatched DNA from fully matched target DNA under optimal conditions. This biosensor, which combines the synergistic properties of both CNTs and AuNPs, represents a promising signal amplification strategy for achieving a sensitive biosensor for DNA detection and diagnostic applications.

The regulation of human pluripotent stem cell (hPSC) behaviors has been mainly studied through exploration of biochemical factors. However, the current directed differentiation protocols for hPSCs that completely rely on biochemical factors remain suboptimal. It has recently become evident that coexisting biophysical signals in the stem cell microenvironment, including nanotopographic cues, can provide potent regulatory signals to mediate adult stem cell behaviors, including self-renewal and differentiation. Herein, we utilized a recently developed, large-scale nanofabrication technique based on reactive-ion etching (RIE) to generate random nanoscale structures on glass surfaces with high precision and reproducibility. We report here that hPSCs are sensitive to nanotopographic cues and such nanotopographic sensitivity can be leveraged for improving directed neuronal differentiation of hPSCs. We demonstrate early neuroepithelial conversion and motor neuron (MN) progenitor differentiation of hPSCs can be promoted using nanoengineered topographic substrates. We further explore how hPSCs sense the substrate nanotopography and relay this biophysical signal through a regulatory signaling network involving cell adhesion, the actomyosin cytoskeleton, and Hippo/YAP signaling to mediate the neuroepithelial induction of hPSCs. Our study provides an efficient method for large-scale production of MNs from hPSCs, useful for regenerative medicine and cell-based therapies.

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