Self-Assembly of Organelle-Localized Neuropeptides Triggers Intrinsic Apoptosis Against Breast Cancer.

Biosynthesis has become a diverse toolbox for the development of bioactive molecules and materials, particularly for enzyme-induced modification and assembly of peptides. However, intracellular spatiotemporal regulation of artificial biomolecular aggregates based on neuropeptide remains challenging. Here, an enzyme responsive precursor (Y1 L-KGRR-FF-IR) is developed based on the neuropeptide Y Y1 receptor ligand, which self-assembles into nanoscale assemblies in the lysosomes and subsequently has an appreciable destructive effect on the mitochondria and cytoskeleton, resulting in breast cancer cell apoptosis. More importantly, in vivo studies reveal that Y1 L-KGRR-FF-IR has a good therapeutic effect, reduces breast cancer tumor volume and generates excellent tracer efficacy in lung metastasis models. This study provides a novel strategy for stepwise targeting and precise regulation of tumor growth inhibition through functional neuropeptide Y-based artificial aggregates for intracellular spatiotemporal regulation.

Transformable Neuropeptide Prodrug with Tumor Microenvironment Responsiveness for Tumor Growth and Metastasis Inhibition of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has the worst prognosis among all breast cancer subtypes due to lack of specific target sites and effective treatments. Herein, a transformable prodrug (DOX-P18) based on neuropeptide Y analogue with tumor microenvironment responsiveness is developed for TNBC treatment. The prodrug DOX-P18 can achieve reversible morphological transformation between monomers and nanoparticles through the manipulation of protonation degree in different environments. It can self-assemble into nanoparticles to enhance the circulation stability and drug delivery efficiency in the physiological environment while transforming from nanoparticles to monomers and being endocytosed into the breast cancer cells in the acidic tumor microenvironment. Further, the DOX-P18 can precisely be enriched in the mitochondria, and efficiently activated by matrix metalloproteinases. Then, the cytotoxic fragment (DOX-P3) can subsequently be diffused into the nucleus, generating a sustained cell toxicity effect. In the meanwhile, the hydrolysate residue P15 can assemble into nanofibers to construct nest-like barriers for the metastasis inhibition of cancer cells. After intravenous injection, the transformable prodrug DOX-P18 demonstrated superior tumor growth and metastasis suppression with much better biocompatibility and improved biodistribution compared to free DOX. As a novel tumor microenvironment-responsive transformable prodrug with diversified biological functions, DOX-P18 shows great potential in smart chemotherapeutics discovery for TBNC.

Custom-Made Ceria Nanoparticles Show a Neuroprotective Effect by Modulating Phenotypic Polarization of the Microglia.

The neuroprotective effect of ceria nanoparticles in the context of brain disorders has been explained by their antioxidant effect. However, the in-depth mechanism remains unknown. As resident immune cells in the brain, microglia exert a variety of functional reprogramming termed as polarization in response to stress stimuli. Herein, custom-made ceria nanoparticles were developed and found to scavenge multiple reactive oxygen species with extremely high efficiency. These nanoparticles drove microglial polarization from a pro-inflammatory phenotype to an anti-inflammatory phenotype under pathological conditions. Pretreatment of these nanoparticles changed the microglial function from detrimental to protective for the neuronal cells by blocking the pro-inflammatory signaling. This work not only helps to elucidate the mechanism of ceria-nanoparticle-mediated neuroprotection but also provides a new strategy to rebalance the immuno-environment by switching the equilibrium of the phenotypic activation of microglia.

PADI4 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis.

The objective of the study was to investigate the association between peptidylarginine deiminase 4 (PADI4) polymorphism and susceptibility to rheumatoid arthritis (RA). An electronic searching strategy was employed to collect relevant studies on the association between PADI4 polymorphism and susceptibility to RA. The odds ratio (OR) with the 95 % confidence interval (95 % CI) was used to evaluate the RA risk presented by PADI4 polymorphism. Fixed or random effects models were selected based on heterogeneity. Publication bias was assessed using funnel plots, Begg's test, and Egger's test. A total of 27 studies from 21 articles were included. Six gene loci (padi4_94, 104, 92, 90, 89, and 100) were chosen for the meta-analysis. The pooled ORs (95 % CI) for allele 2 versus 1 were 1.08 (1.05-1.12), 1.17 (1.12-1.23), 1.26 (1.18-1.36), 1.17 (1.10-1.24), 1.30 (1.17-1.44), and 1.25 (1.11-1.40), respectively. All six SNPs were significantly associated with RA in Asian populations. Three SNPs (PADI4_104, 90, 89) showed significant associations, while the other three SNPs (PADI4_94, 92, 100) exhibited no associations in the European population. A dose-response relationship between allele 2 of PADI4 and the risk of RA was also identified. In conclusion, this meta-analysis suggests that PADI4 polymorphisms represent a significant risk factor for RA, especially in Asians.

[Study on the correlation between induced abortion and reproductive tract infections].

OBJECTIVE: To explore the correlation between induced abortion and reproductive tract infections (RTIs). METHODS: On the basis of keeping the representation of cities under study, 53 652 fertile women aged 15 - 49 were surveyed by using a stratified-cluster-random sampling. Investigation and gynecological examination were conducted by two steps - firstly converging at the clinics, and then visiting those households for someone who did not show up at the clinics. RESULTS: Among all the 32.0% (n=16 800) women ever having experienced the history of induced abortion, 21.1% (n = 11 090) of them had one, 7.6% (n=3976) women had two, and 4.1% (n=1734) women had at least three events. 59.0% (n=30 959) women among our studied samples had ever had RTI, with 30.9% (n=16 215) of them had only one 20.0% (n=10 494) women had two and 8.1% (n=4250) had three or more RTIs. Data from χ(2) text and ordinal regression analysis revealed that the rural married women who underwent more induced abortions were more likely to suffer from RTIs, especially cervical infection and PID. CONCLUSION: Our study showed that the rates of induced abortion and reproductive tract infections among married women in Anhui province were both high. Women who underwent induced abortions had a higher prevalence rate of reproductive tract infections.

Loneliness among the rural older people in Anhui, China: prevalence and associated factors.

OBJECTIVES: To clarify the prevalence of loneliness and evaluate the impact of social support, family function and socio-demographic factors on loneliness and their correlation among the rural older people in Anhui, China. METHODS: A sample of 5652 older people were surveyed using the UCLA (University of California at Los Angeles)-Loneliness Scale, the FAD (family assessment device), and the SSRS (Social Support Rating Scale). RESULTS: 78.1% of the older people had moderate to severe levels of loneliness. There was a great difference between loneliness level and subjects' age, marital status and income, family size and education level. Social support and family function were negatively associated with loneliness. Multiple regressions indicated that more social support and better family function offered protection against loneliness. CONCLUSIONS: The high rate of loneliness among rural older people in Anhui deserves attention. Family function and social support have played an important role in the development and course of loneliness. The strategy and intervention to alleviate loneliness among rural older people should be designed to enhance family function and social support.