Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study.

BACKGROUND: This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. METHODS: Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification. FINDINGS: During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01-1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03-1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10 µg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12-1.79; P = 0.004; I2 = 90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival. INTERPRETATION: Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110. FUNDING: Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).

Engineering an Injectable Electroactive Nanohybrid Hydrogel for Boosting Peripheral Nerve Growth and Myelination in Combination with Electrical Stimulation.

Electrical stimulation (ES) can be used to manipulate recovery after peripheral nerve injuries. Although biomaterial-based strategies have already been implemented to gain momentum for ES and engineer permissive microenvironments for neural regeneration, the development of biomaterials for specific stimuli-responsive modulation of neural cell properties remains a challenge. Herein, we homogeneously incorporate pristine carbon nanotubes into a functional self-assembling peptide to prepare a hybrid hydrogel with good injectability and conductivity. Two-dimensional (on the surface) and three-dimensional (within the hybrid hydrogel) culturing experiments demonstrate that ES promotes axon outgrowth and Schwann cell (SC) migration away from dorsal root ganglia spheres, further revealing that ES-enhanced interactions between SCs and axons result in improved myelination. Thus, our study not only advances the development of tailor-made materials but also provides useful insights into comprehensive approaches for promoting nerve growth and presents a practical strategy of repairing peripheral nerve injuries.

Assembly Pathway Selection of Designer Self-Assembling Peptide and Fabrication of Hierarchical Scaffolds for Neural Regeneration.

The self-assembling peptide (SAP) RADA 16-I has been modified with various functional motifs to improve its performances in biomedical applications. Nevertheless, the assembly mechanisms of designer functional RADA 16-I SAPs (F-SAPs) have not been clearly illustrated. The main problem is the difficulty in preparing a completely molecular aqueous solution of F-SAP. In the current study, we demonstrated that different procedures for preparing the F-SAP solution could result in the formation of different conformations and consequently micro/macroscopic morphologies. F-SAP was molecularly dissolved in an appropriate solvent, such as hexafluoroisopropanol (HFIP), as evidenced by random coil conformation characterized by circular dichroism spectroscopy and morphologies under transmission electron microscopy. The monomers were induced into monolayers when the F-SAP solution in HFIP was adsorbed on mica as observed by atomic force microscopy. However, nanoscaled filaments containing ß-sheets dominated in the F-SAP aqueous solution, in which case water acted as a poor solvent of F-SAP. Furthermore, the results of molecular dynamics simulation implicated that water facilitated F-SAP aggregation, whereas HFIP inhibited it. The ß-sheet assemblies formed in water exhibited a high kinetic stability and did not disassemble rapidly after the addition of HFIP. Our study indicated that selecting the right assembly pathway of F-SAP required for targeted functions, for example, delivery of hydrophobic drugs in aqueous conditions, could be achieved by optimizing the preparation protocol in addition to molecular design. Moreover, hierarchical scaffolds mimicking the natural extracellular matrix could be fabricated by the direct electrospinning of F-SAP molecular solution in HFIP and biodegradable polymer for applications in neural regeneration by promoting neural differentiation, neurite outgrowth, and synapse formation.

The effects of motif net charge and amphiphilicity on the self-assembly of functionally designer RADA16-I peptides.

RADA16-I (Ac-(RADA)4-CONH2) is a widely investigated self-assembling peptide (SAP) in the biomedical field. It can undergo ordered self-assembly to form stable secondary structures, thereby further forming a nanofiber hydrogel. The modification of RADA16-I with functional peptide motifs has become a popular research topic. Researchers aim to exhibit particular biomedical signaling, and subsequently, further expand its applications. However, only a few fundamental reports are available on the influences of the peptide motifs on self-assembly mechanisms of designer functional RADA16-I SAPs. In this study, we designed RGD-modified RADA16-I SAPs with a series of net charges and amphiphilicities. The assembly/reassembly of these functionally designer SAPs was thoroughly studied using Raman spectroscopy, CD spectroscopy, and AFM. The nanofiber morphology and the secondary structure largely depended on the balance between the hydrophobic effects versus like-charge repulsions of the motifs, which should be to the focus in order to achieve a tailored nanostructure. Our study would contribute insight into considerations for sophisticated design of SAPs for biomedical applications.

Self-assembly behaviors of molecular designer functional RADA16-I peptides: influence of motifs, pH, and assembly time.

In the current study, we present three designer self-assembling peptides (SAPs) by appending RADA 16-I with epitopes IKVAV, RGD, and YIGSR, which have different net charges and amphiphilic properties at neutral pH. The self-assembly of the designer SAPs is intensively investigated as a function of pH, canion type, and assembly time. The morphologies of the designer SAPs were studied by atomic force microscope. The secondary structure was investigated by circular dichroism. The dynamic viscoelasticity of designer SAP solutions was examined during titration with different alkaline reagents. Our study indicated that both electrostatic and hydrophilic/hydrophobic interactions of the motifs exhibited influences on the self-assembly, consequentially affecting the fiber morphologies and rheological properties. Moreover, NaOH induced a quicker assembly/reassembly of the designer SAPs than Tris because of its strong ionic strength. Therefore, our study gained comprehensive insight into the self-assembling mechanism as references for developing RADA 16-I-based functional SAPs.

Numerical and analytical solutions for sound propagation and absorption in porous media at high sound pressure levels.

On the basis of the work of Wilson et al. [J. Acoust. Soc. Am. 84, 350-359 (1988)], a more exact numerical approach was constructed for predicting the nonlinear sound propagation and absorption properties of rigid porous media at high sound pressure levels. The numerical solution was validated by the experimental results for sintered fibrous porous steel samples and its predictions were compared with the numerical solution of Wilson et al. An approximate analytical solution was further put forward for the normalized surface acoustic admittance of rigid air-saturated porous materials with infinite thickness, based on the wave perturbation method developed by Lambert and McIntosh [J. Acoust. Soc. Am. 88, 1950-1959 (1990)]. Comparisons were made with the numerical results.

Improving the anti-tumor effect of genistein with a biocompatible superparamagnetic drug delivery system.

The practical application of genistein as a low toxicity chemotherapeutic drug is hindered by many of its in vivo properties. To overcome these obstacles, a new multifunctional drug delivery system is developed, which is based on covalently attaching genistein onto Fe3O4 nanoparticles coated by cross-linked carboxymethylated chitosan (CMCH). The structure of the Fe3O4-CMCH-genistein nano-conjugate was confirmed by transmission electron micrographs (TEM), X-ray diffraction (XRD) and Fourier-transfer infrared (FT-IR) spectroscopy. The nano-conjugate shows good water solubility and superparamagnetic properties with a saturation magnetization of 55.1 emu/g. The effects of free genistein and FeO4-CMCH-genistein nano-conjugate on the proliferation and apoptosis of gastric cancer cell line SGC-7901 were investigated by MTT assay and flow cytometry (FACS). MTT results indicate that the Fe3O4-CMCH-genistein nano-conjugate exhibits a significantly enhanced inhibition effect to the SGC-7901 cancer cells than the free genistein. FACS data suggests that the inhibition on cell proliferation of the nano-conjugate is related with an induced apoptosis process. This drug delivery system is promising for future multifunctional chemotherapeutic application that combines drug release and magnetic hyperthermia therapy.