Using machine learning methods to analyze the association between urinary polycyclic aromatic hydrocarbons and chronic bowel disorders in American adults.

The etiology of chronic bowel disorders is multifaceted, with environmental exposure to harmful substances potentially playing a significant role in their pathogenesis. However, research on the correlation between polycyclic aromatic hydrocarbons (PAHs) and chronic bowel disorders remains limited. Using data from the National Health and Nutrition Examination Survey (NHANES) conducted in 2009-2010, we investigated the relationship between 9 PAHs and chronic diarrhea and constipation in U.S. adults. We employed unsupervised methods such as clustering and Principal Component Analysis (PCA) to identify participants with similar exposure patterns. Additionally, we used supervised learning techniques, namely weighted quantile sum (WQS) and Bayesian kernel machine (BKMR) regressions, to assess the association between PAHs and the occurrence of chronic diarrhea and chronic constipation. PCA identified three principal components in the unsupervised analysis, explaining 86.5% of the total PAH variability. The first component displayed a mild association with chronic diarrhea, but no correlation with chronic constipation. Participants were divided into three clusters via K-means clustering, based on PAH concentrations. Clusters with higher PAH exposure demonstrated an increased odds ratio for chronic diarrhea, but no meaningful connection with chronic constipation. In the supervised analysis, the WQS regression underscored a positive relationship between the PAH mixture and chronic diarrhea, with three PAHs significantly impacting the mixture effect. The mixture index showed no correlation with chronic constipation. BKMR analysis illustrated a positive trend in the impact of four specific PAHs on chronic diarrhea, given other metabolites were fixed at their 50th percentiles. Our results suggest a clear association between higher PAH exposure and an increased risk of chronic diarrhea, but not chronic constipation. It also underscores the potential role of specific PAHs in contributing to the risk of chronic diarrhea.

Enzymatically synthesised MnO2 nanoparticles for efficient near-infrared photothermal therapy and dual-responsive magnetic resonance imaging.

Manganese dioxide (MnO2) nanoparticles (NPs) are highly attractive for biomedical applications due to their biocompatibility, stimuli-responsive magnetic resonance imaging (MRI) properties and capability to modulate the hypoxic tumour microenvironment (TME). However, conventional MnO2 NPs do not possess photothermal therapy (PTT) functions except for hybrids with other photothermal materials. Herein, we first reveal the extraordinary photothermal conversion efficiency (44%) of enzymatically synthesised MnO2 NPs (Bio-MnO2 NPs), which are distinct from chemically synthesised MnO2 NPs. In addition, the Bio-MnO2 NPs revealed high thermal recycling stability and solubility as well as dual pH- and reduction-responsive MRI enhancement for tumour theragnosis. These NPs were prepared through a facile MnxEFG enzyme-mediated biomineralization process. The MnxEFG complex from Bacillus sp. PL-12 is the only manganese mineralization enzyme that could be heterologously overexpressed in its active form to achieve Bio-MnO2 NPs without a bacterial host. The hexagonal layer symmetry of the Bio-MnO2 NPs is the key feature facilitating the high photothermal conversion efficiency and TME-responsive T1-weighted MRI. Evaluations both in vitro at the cellular level and in vivo in a systematic tumour-bearing mouse xenograft model demonstrated the high photothermal ablation efficacy of the Bio-MnO2 NPs, which achieved complete tumour eradication with high therapeutic biosafety without obvious reoccurrence. Moreover, stimuli-responsive MR enhancement potentially allows imaging-guided precision PTT. With their excellent biocompatibility, mild synthesis conditions and relatively simple composition, Bio-MnO2 NPs hold great translational promise.

Mitochondrion-targeted selenium nanoparticles enhance reactive oxygen species-mediated cell death.

Selenium nanoparticles (SeNPs) can induce reactive oxygen species (ROS)-mediated cell death when accumulated in cancer cells, while rendering anti-oxidation and cancer prevention in healthy tissues at low doses. Although they are promising anticancer agents with fewer side effects, their application is limited by their relative low toxicity to cancer cells. Therefore, we propose a mitochondrion-targeting strategy to improve their cancer cell killing efficiency. Such mitochondrion-targeted SeNPs could efficiently increase ROS production and mitochondrion damage in cancer cells; however, only a slightly increased toxicity to normal cells was observed, indicating a potentially better therapeutic window for anticancer treatments.

Activatable Near-Infrared Probe for Fluorescence Imaging of γ-Glutamyl Transpeptidase in Tumor Cells and In Vivo.

γ-Glutamyl transpeptidase (GGT) is a cell-membrane-bound enzyme that is involved in various physiological and pathological processes and is regarded as a potential biomarker for many malignant tumors, precise detection of which is useful for early cancer diagnosis. Herein, a new GGT-activatable near-infrared (NIR) fluorescence imaging probe (GANP) by linking of a GGT-recognitive substrate γ-glutamate (γ-Glu) and a NIR merocyanine fluorophore (mCy-Cl) with a self-immolative linker p-aminobenzyl alcohol (PABA) is reported. GANP was stable under physiological conditions, but could be efficiently activated by GGT to generate ≈100-fold enhanced fluorescence, enabling high sensitivity (detection limit of ≈3.6 mU L-1 ) and specificity for the real-time imaging of GGT activity as well as rapid evaluation of the inhibition efficacy of GGT inhibitors in living tumor cells. Notably, the deep tissue penetration ability of NIR fluorescence could further allow GANP to image GGT in frozen tumor tissue slices with large penetration depth (>100 µm) and in xenograft tumors in living mice. This GGT activatable NIR fluorescence imaging probe could facilitate the study and diagnosis of other GGT-correlated diseases in vivo.

Dual Stimuli-Responsive Nanoparticles for Controlled Release of Anticancer and Anti-inflammatory Drugs Combination.

Dual stimuli-responsive nanoparticles capable of fine-tuning drug release to augment therapeutic efficacy have become a promising tool for anticancer drug delivery. However, the rational design of these "smart" nanoparticles for a selective delivery and controlled release of multidrug combinations in cancer cells to achieve synergistic effects remain challenging. Here we report the pH/redox dual responsive nanoparticle FA-DOX-Ind-NP (FA=folic acid, DOX=doxorubicin, Ind=indomethacin, NP=nanoparticle) based on the novel tumor targeting and biodegradable poly(ß-amino ester) polymer, and demonstrate its high ability to enter into cancer cells and release a combination of the anticancer drug doxorubicin and the non-steroidal anti-inflammatory drug indomethacin to achieve synergistic chemo-anti-inflammatory effects and overcome multidrug resistance. This study highlights the great potential of tumor targeting and dual stimuli-responsive nanoparticles for an efficient delivery of multidrug combination to improve the cancer therapeutic efficacy.

Redox-Mediated Disassembly to Build Activatable Trimodal Probe for Molecular Imaging of Biothiols.

Activatable multimodal probes that show enhancement of multiplex imaging signals upon interaction with their specific molecular target have become powerful tools for rapid and precise imaging of biological processes. Herein, we report a stimuli-responsive disassembly approach to construct a redox-activatable fluorescence/19F-MRS/1H-MRI triple-functional probe 1. The small molecule probe 1 itself has a high propensity to self-assemble into nanoparticles with quenched fluorescence, attenuated 19F-MRS signal, and high 1H-MRI contrast. Biothiols that are abundant in reducing biological environment were able to cleave the disulfide bond in probe 1 to induce disassembly of the nanoparticles and lead to fluorescence activation (∼70-fold), 19F-MRS signal amplification (∼30-fold) and significant r1 relaxivity reduction (∼68% at 0.5 T). Molecular imaging of reducing environment in live cells and in vivo was realized using probe 1. This approach could facilitate the development of other stimuli-responsive trimodal probes for molecular imaging.

Lysosome-Targeting Fluorogenic Probe for Cathepsin B Imaging in Living Cells.

Cathepsin B (CTB) is a lysosomal protease which has been recognized as a promising biomarker for many malignant tumors, and accurate detection of its activity is important in early diagnosis of cancers and predicting metastasis. Herein, we reported a lysosome-targeting fluorogenic small-molecule probe for fluorescence imaging of lysosomal CTB in living cancer cells by incorporating a CTB-recognitive peptide substrate Cbz-Lys-Lys-p-aminobenzyl alcohol (Cbz-Lys-Lys-PABA) and a lysosome locating group morpholine. We demonstrated that the probe could be efficiently activated by CTB to generate ∼73-fold enhancement in fluorescence under acidic lysosomal environment (pH 4.5-6.0), allowing for high sensitivity and specificity to detect CTB. Fluorescence imaging results showed selective accumulation and fluorescence turn-on in the lysosomes of cancer cells, which were capable of reporting on lysosomal CTB activity in cancer cells and normal tissue cells. This study highlights the potential of using a lysosome-targeting group to design a sensitive and specific fluorogenic probe for fluorescence imaging of lysosomal CTB in living cells.

Preparation and characterization of a novel pH-sensitive Salecan-g-poly(acrylic acid) hydrogel for controlled release of doxorubicin.

Salecan is a novel water-soluble extracellular ß-glucan produced by a salt-tolerant strain Agrobacterium sp. ZX09. Salecan is suitable for the fabrication of hydrogels for biomedical applications due to its excellent physicochemical and biological properties. In this paper, a series of pH-sensitive hydrogels were prepared in aqueous solution by the graft copolymerization of Salecan and acrylic acid (AA) using N,N'-methylene diacrylamide as a crosslinker for controlled drug delivery. The structure and thermal stability of the resulting hydrogels were characterized by FT-IR, XRD and TGA. By SEM analysis, freeze-dried hydrogels displayed an interconnected porous structure with tunable pore size in the range of 23.2-90.3 µm. The swelling behavior of the hydrogels was shown to be highly dependent on the environmental pH, salt type and concentration, as well as the contents of Salecan and BAAm. They are almost unswellable at pH 1.2 and swollen extensively at pH 6.86. Meanwhile, the increase in the content of hydrophilic Salecan could enhance the swelling ratio, whereas the presence of more BAAm reduced the swelling capacity but promoted the water retention to some extent. Rheological tests revealed that storage modulus G' was strongly influenced by the crosslink density of the obtained hydrogel network. Especially, doxorubicin (DOX) as a model anti-cancer drug was very efficiently loaded into the negatively charged hydrogels (up to 69.4 wt%) through electrostatic interactions. More importantly, the release of DOX from this intelligent system exhibited pH-responsive behavior and a sustained release pattern. For SPA2, the cumulative release profile showed a low level of drug release (about 12.3 wt% in 24 h) at pH 7.4, and was significantly accelerated at pH 4.0 (over 40 wt% in 6 h). Cytotoxicity experiments confirmed that all blank hydrogels were non-toxic to A549 cells, while DOX released from the drug-loaded hydrogels remained biologically active and had the capability to kill cancer cells. The preliminary results clearly suggested that the Salecan-g-PAA hydrogels may be promising carriers for controlled drug delivery.

Synthesis and characterization of a novel semi-IPN hydrogel based on Salecan and poly(N,N-dimethylacrylamide-co-2-hydroxyethyl methacrylate).

Salecan is a novel water-soluble, high molecular mass extracellular ß-glucan produced by Agrobacterium sp. ZX09. Salecan has excellent physicochemical and biological properties, making it very suitable for hydrogel preparation. In this study, a series of novel semi-interpenetrating polymer network (semi-IPN) hydrogels containing Salecan and poly(N,N-dimethylacrylamide-co-2-hydroxyethylmethacrylate) (poly(DMAA-co-HEMA)) were synthesized by radical polymerization and semi-IPN technology. Structure and morphology of the hydrogels were characterized by FTIR, XRD, TGA and SEM. The semi-IPNs had a well-interconnected porous structure with tunable pore size ranging from 6 to 41µm. Swelling capability of the hydrogels was improved by introducing the hydrophilic Salecan. Rheological results indicated that the incorporation of poly(DMAA-co-HEMA) into hydrogels enhanced the storage modulus. Compression tests revealed that these semi-IPNs were robust materials with compressive modulus between 13.3 and 90.5kPa, the addition of Salecan increased the fracture strain from 71.1% to 88.8%. Degradation and cytotoxicity tests demonstrated that semi-IPNs were degradable and non-toxic.

Synthesis and characterization of a novel hydrogel: salecan/polyacrylamide semi-IPN hydrogel with a desirable pore structure.

Salecan is a novel water-soluble ß-glucan produced by a salt-tolerant strain Agrobacterium sp. ZX09 which was isolated from a soil sample in our laboratory and the 16S rDNA sequence of this novel strain was deposited in the GenBank database under the accession number GU810841. Salecan has excellent physicochemical properties and can be used in industries such as food and medicine. In this paper, novel semi-interpenetrating polymer network (semi-IPN) hydrogels based on salecan and polyacrylamide (PAAm) were synthesized by radical polymerization/cryopolymerization and semi-IPN techniques. The resulting hydrogels with different salecan/PAAm composition ratios and preparation temperatures were characterized using FTIR, XRD, TGA and SEM measurements. The semi-IPNs exhibited a homogeneous porous architecture with a tunable pore size in a very broad range of 5-150 µm. Furthermore, swelling behaviors of the hydrogels were also studied to investigate the response properties of the hydrogels. The hydrogels obtained at subzero temperature can attain the equilibrium state in water within 260 seconds. Mechanical measurements showed that all semi-IPNs possessed good mechanical properties. In vitro degradation was also studied in PBS solution. Cytotoxicity results suggested that semi-IPN hydrogels were non-toxic to COS-7 cells. A cell culture experiment performed using COS-7 cells revealed their appropriateness for cell adhesion. Together, these results make salecan/PAAm semi-IPNs promising materials for biomedical applications.

[Effect of plumbism on auditory brainstem response of children].

OBJECTIVE: To observe the injury of plumbism to the nerve system in children. METHODS: One hundred children with plumbism which had no masculine body sign of nerve system were divided into two groups. Fifty of them were as controls, while others were treated by calcium. Fifty age and gender matched healthy children were selected as the normal group in order to compare with plumbism group. All of their auditory brainstem response (ABR), pure tone and distortion product otoacoustic emission (DPOAE) were examined. RESULTS: Latency period of wave V of the plumbism groups was longer than that of normal group. The difference between them was significant statistically (t =3.21, P <0.01). The interval between wave I and wave III of plumbism group was longer than that of normal group, but there was no difference between them (former: t = 2.06, P > 0.05; later: t = 1.64, P > 0.05). The interval between wave III and wave V and the interval between wave I and wave V of plumbism group was longer than that of normal group, and their difference was significant statistically (former: t = 7.30, P <0.01; later: t = 3.14, P < 0.01). The interval between wave I and wave III of plumbism group was longer than that of normal group, but there was no difference between them (t = 0.91, P > 0.05). The amplitude of wave I, wave III and wave V of plumbism group was lower than that of normal group, and their difference was significant statistically (I: t =3.20, P < 0.01; III: t=3.31, P < 0.01; V: t=3.41, P < 0.01). The auditory brainstem response, pure tone and DPOAE in all three groups had no obvious change after six months treatment (P >0.05). CONCLUSIONS: Plumbism may have potential clinical injury to nerve system. There has no obvious change of ABR after treatment by calcium. ABR may be a forepart examination to find the injury of plumbism to the nerve system.