Bioinspired metal-organic framework nanozyme reinforced with thermosensitive hydrogel for regulating inflammatory responses in Parkinson’s disease

Parkinson’s disease(PD)is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury.Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD.However,traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability.Herein,Cu-doping zeolite imidazolate framework-8(ZIF-8)nanozyme is designed to simulate Cu/Zn superoxide dismutase(SOD)by biomimetic mineralization.The nanozyme composite is then integrated into thermosensitive hydrogel(poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid)(PLGA-PEG-PLGA))to form an effective antioxidant system(Cu-ZIF@Hydrogel).The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion,prolonging nanozyme retention time,and modulating antioxidant activity,thus significantly improving the bioavailability of nanozymes.At the cellular and animal levels of PD,we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells.Moreover,the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site.Therefore,the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.

Composition and Functional Capacity of Gut Microbes are Associated with Arterial Stiffness:A Prospective Study

Objective:Arterial stiffness is an important predictor of cardiovascular disease.Microbial diversity in the gut has been shown to be associated inversely with arterial stiffness in Caucasian populations.However,due to the different profiles of the gut microbiota among ethnicities,the relationship between gut-microbiota dysbiosis and the progression of arterial stiffness merits further investigation.This study aimed to investigate the association between the composition and functional capacity of the gut microbiota and the progression of arterial stiffness.Methods:“Shotgun”metagenomics sequencing were undertaken in 96 individuals from a hypertension-associated gut-microbiota study in the Kailuan cohort,who measured brachial-ankle pulse wave velocity(baPWV)and provided fecal samples between September 2014 and February 2015 at Kailuan General Hospital and 11 affiliated hospitals.The different composition and functional capacity of the gut microbiota were compared between individuals without arterial stiffness(normal arterial stiffness group,baPWV<1,400 cm/s,n=27)and participants with arterial stiffness(increased arterial stiffness group,baPWV≥1,400 cm/s,n=69)at baseline.These participants were followed up prospectively for a mean duration of 2.6 years,and 50 underwent a repeat baPWV measurement.Associations between the gut microbiota and severity and progression of arterial stiffness were assessed using MaAsLin2 software after adjustment for age,sex,and mean arterial blood pressure and correction for multiple testing.Gene“catalogs”were aligned to the Kyoto Encyclopedia of Genes and Genomes(KEGG)database to obtain information for potential functional capacities of the gut microbiota.Results:In this study,14 genera and 50 species of bacteria were identified to be abundant in participants with normal arterial stiffness compared with those with increased arterial stiffness.Of 14 genera,the prevalence of beneficial bacteria of the genera Leadbetterella and Cytophaga was correlated inversely with baPWV(P<0.05).Analyses of functional capacity revealed gut-microbial dysfunctions in the synthetic processes of“threonine dehydratase”“hypothetical protein”“mannosyl transferase”and“type-IV secretion-system proteins”in individuals suffering from arterial stiffness.During follow-up,bacteria of the proinflammatory genera Escherichia,Shigella,and Ruegeria were enriched in individuals with increased baPWV.Functional analyses showed that 26 KEGG orthologs of gut microbes were associated with an increase in baPWV and involved in“carbohydrate metabolism”“amino acid metabolism”and“protein families related to genetic information processing.”Conclusions:The composition and functional capacity of the microbial community in the gut of people suffering from arterial stiffness differed from those in individuals not suffering from arterial stiffness.Our data provide a new direction for the causality of the host-gut microbiota in arterial stiffness.

CRISPR-CasRx knock-in mice for RNA degradation

The RNA editing tool CRISPR-CasRx has provided a platform for a range of transcriptome analysis tools and therapeutic approaches with its broad efficacy and high specificity.To enable the application of CasRx in vivo,we established a Credependent CasRx knock-in mouse.Using these mice,we specifically knocked down the expression of Meis1 and Hoxb13 in cardiomyocytes,which induced cardiac regeneration after myocardial infarction.We also knocked down the lnc RNA Mhrt in cardiomyocytes with the CasRx knock-in mice,causing hypertrophic cardiomyopathy.In summary,we generated a Credependent CasRx knock-in mouse that can efficiently knock down coding gene and lnc RNA expression in specific somatic cells.This in vivo CRISPR-CasRx system is promising for gene function research and disease modeling.