A Cyclodextrin-Based pH-Responsive MicroRNA Delivery Platform Targeting Polarization of M1 to M2 Macrophages for Sepsis Therapy.

The mortality rate of sepsis remains high despite improvements in the diagnosis and treatment of sepsis using symptomatic and supportive therapies, such as anti-infection therapy and fluid resuscitation. Nucleic acid-based drugs have therapeutic potential, although their poor stability and low delivery efficiency have hindered their widespread use. Herein, it is confirmed that miR-223 can polarize proinflammation M1 macrophages to anti-inflammation M2 macrophages. A pH-sensitive nano-drug delivery system comprising ß-cyclodextrin-poly(2-(diisopropylamino)ethyl methacrylate)/distearoyl phosphoethanolamine-polyethylene glycol (ß-CD-PDPA/DSPE-PEG) is synthesized and developed to target M1 macrophages and miR-223 is encapsulated into nanoparticles (NPs) for sepsis treatment. NPs/miR-223 demonstrated in vitro pH responsiveness with favorable biosafety, stability, and high delivery efficiency. In vivo studies demonstrate that NPs/miR-223 are preferentially accumulated and retained in the inflammation site, thereby reducing inflammation and improving the survival rate of mice with sepsis while exhibiting ideal biosafety. Mechanically, NPs/miR-223 regulates macrophage polarization by targeting Pknox1 and inhibiting the activation of the NF-κB signaling pathway, thereby achieving an anti-inflammatory effect. Collectively, it is demonstrated that the miRNA delivery vector described here provides a new approach for sepsis treatment and accelerates the advancement of nucleic acid drug therapy.

[Relationship between immune regulation and structure of polysaccharides].

Polysaccharides have significant immunomodulatory activity and have good development value in food and medicine fields. At present, there are many studies on the chemical structure and immune activity of polysaccharides, but the relationship between them of polysaccharides has not been fully explained, which limits the further development and utilization of polysaccharide resources. The immune activity of polysaccharides is closely related to their own structure. This paper systematically summarized the relationship between the relative molecular weight, monosaccharide composition, glycosidic bond types, chemical modification, and advanced conformation of polysaccharides and the immune regulation, aiming to provide references for the profound study of polysaccharide structure-activity relationship and utilization of polysaccharides.

Carrageenan-Based Pickering Emulsion Gels Stabilized by Xanthan Gum/Lysozyme Nanoparticle: Microstructure, Rheological, and Texture Perspective.

In this study, Pickering emulsion gels were prepared by the self-gel method based on kappa carrageenan (kC). The effects of particle stabilizers and polysaccharide concentrations on the microstructure, rheological characteristics, and texture of Pickering emulsion gels stabilized by xanthan gum/lysozyme nanoparticles (XG/Ly NPs) with kC were discussed. The viscoelasticity of Pickering emulsion gels increased significantly with the increase of kC and XG/Ly NPs. The results of temperature sweep showed that the gel formation mainly depended on the kC addition. The XG/Ly NPs addition could accelerate the formation of Pickering emulsion gels and increase its melting temperature (Tmelt), which is helpful to improve the thermal stability of emulsion gels. Cryo-scanning electron microscope (Cryo-SEM) images revealed that Pickering emulsion gel has a porous network structure, and the oil droplets were well wrapped in the pores. The hardness increased significantly with the increase of XG/Ly NPs and kC. In particular, the Pickering emulsion gel hardness was up to 2.9 Newton (N) when the concentration of kC and XG/Ly NPs were 2%. The results showed that self-gelling polysaccharides, such as kC, could construct and regulate the structure and characteristics of Pickering emulsion gel. This study provides theoretical support for potential new applications of emulsion gels as functional colloids and delivery systems in the food industry.

CTSB promotes sepsis-induced acute kidney injury through activating mitochondrial apoptosis pathway.

Background: Acute kidney injury is a common and severe complication of sepsis. Sepsis -induced acute kidney injury(S-AKI) is an independent risk factor for mortality among sepsis patients. However, the mechanisms of S-AKI are complex and poorly understand. Therefore, exploring the underlying mechanisms of S-AKI may lead to the development of therapeutic targets. Method: A model of S-AKI was established in male C57BL/6 mice using cecal ligation and puncture (CLP). The data-independent acquisition (DIA)-mass spectrometry-based proteomics was used to explore the protein expression changes and analyze the key proteomics profile in control and CLP group. The methodology was also used to identify the key proteins and pathways. S-AKI in vitro was established by treating the HK-2 cells with lipopolysaccharide (LPS). Subsequently, the effect and mechanism of Cathepsin B (CTSB) in inducing apoptosis in HK-2 cells were observed and verified. Results: The renal injury scores, serum creatinine, blood urea nitrogen, and kidney injury molecule 1 were higher in septic mice than in non-septic mice. The proteomic analysis identified a total of 449 differentially expressed proteins (DEPs). GO and KEGG analysis showed that DEPs were mostly enriched in lysosomal-related cell structures and pathways. CTSB and MAPK were identified as key proteins in S-AKI. Electron microscopy observed enlarged lysosomes, swelled and ruptured mitochondria, and cytoplasmic vacuolization in CLP group. TUNEL staining and CTSB activity test showed that the apoptosis and CTSB activity were higher in CLP group than in control group. In HK-2 cell injury model, the CTSB activity and mRNA expression were increased in LPS-treated cells. Acridine orange staining showed that LPS caused lysosomal membrane permeabilization (LMP). CA074 as an inhibitor of CTSB could effectively inhibit CTSB activity. CCK8 and Annexin V/PI staining results indicated that CA074 reversed LPS-induced apoptosis of HK-2 cells. The JC-1 and western blot results showed that LPS inhibited mitochondrial membrane potential and activated mitochondrial apoptosis pathway, which could be reversed by CA074. Conclusions: LMP and CTSB contribute to pathogenesis of S-AKI. LPS treatment induced HK-2 cell injury by activating mitochondrial apoptosis pathway. Inhibition of CTSB might be a new therapeutic strategy to alleviate sepsis-induced acute kidney injury.

Depicting the composition of gut microbiota in children with tic disorders: an exploratory study.

BACKGROUND: Symptom improvement in children with tic disorder (TD) following fecal microbiota transplantation led us to investigate the gut microbiota in TD. This exploratory study aims to depict the gut microbial profile in patients with TD and explore the impact of dopamine receptor antagonist (DRA) drugs on the composition and metabolic function of the gut microbiota. METHODS: The gut microbiota were profiled in fecal samples of 49 children with TD and 50 matched healthy controls (HC) using shotgun metagenomic sequencing. A random forest (RF) model was constructed using the gut bacterial species to distinguish TD from HC. Associations between clinical metadata and microbial abundance or function were analyzed using MaAsLin2 and Spearman correlation. RESULTS: The gut microbiota in children with TD was featured by higher abundances of Bacteroides plebeius and Ruminococcus lactaris (a potential pro-inflammatory taxon) and lower abundances of Prevotella stercorea and Streptococcus lutetiensis compared to HC. The constructed RF model accurately distinguished TD from HC based on the gut microbiota profile, resulting in an AUC of 0.884. Significant correlations were observed between tic symptom severity and the abundances of multiple bacterial species and gut microbiota metabolic functions. Multivariate analysis identified an upregulation of 4-aminobutanoate (GABA) degradation in the gut microbiota associated with TD status. The gut microbiota of DRA-treated TD children showed a distinct gut microbiota compared to the treatment-naïve group, represented by an increase in some potential enteric pathogens such as Escherichia coli, a decline in several species including Akkermansia muciniphila, and alterations in various metabolic functions. CONCLUSIONS: Bacterial species promoting inflammatory responses and those modulating neurotransmitters such as GABA may be involved in the pathogenesis of TD. The use of DRA drugs is likely to induce overgrowth of some enteric pathogens and alter the gut microbiota metabolism.

Classification of topological phases in one dimensional interacting non-Hermitian systems and emergent unitarity.

Topological phases in non-Hermitian systems have become fascinating subjects recently. In this paper, we attempt to classify topological phases in 1D interacting non-Hermitian systems. We begin with the non-Hermitian generalization of the Su-Schrieffer-Heeger (SSH) model and discuss its many-body topological Berry phase, which is well defined for all interacting quasi-Hermitian systems (non-Hermitian systems that have real energy spectrum). We then demonstrate that the classification of topological phases for quasi-Hermitian systems is exactly the same as their Hermitian counterparts. Finally, we construct the fixed point partition function for generic 1D interacting non-Hermitian local systems and find that the fixed point partition function still has a one-to-one correspondence to their Hermitian counterparts. Thus, we conclude that the classification of topological phases for generic 1D interacting non-Hermitian systems is still exactly the same as Hermitian systems.

Effect of antibiotic therapy in patients with ulcerative colitis: a meta-analysis of randomized controlled trials.

BACKGROUND: Gut microbiota may play a role in the pathogenesis of ulcerative colitis (UC). Antibiotic therapy for patients with UC has shown conflicting results. OBJECTIVES: To evaluate the effect of antibiotic therapy in treating UC. METHODS: PubMed, EMBASE, Cochrane Library, Wanfang Data, and China National Knowledge Infrastructure (CNKI) databases were searched to identify randomized controlled trials (RCTs) that evaluated antibiotics compared with placebo or no antibiotics in patients with UC. We extracted and pooled the risk ratio (RR). RESULTS: Twelve RCTs were included in this systematic review and meta-analysis, which included 739 patients with active UC. Antibiotic therapy had statistically significant efficacy in inducing remission rate in patients with UC, observed at the end of trials (random-effect RR = 0.77; 95% confidence interval [CI] 0.60 to 0.98, p = .03) or at 12 months after trials (fixed-effect RR = 0.83; 95% CI 0.73 to 0.94, p = .003). CONCLUSIONS: Antibiotic therapy appeared to induce remission more effectively than a placebo or no antibiotic intervention not only in the short-term but also in the long-term for patients with UC. More high-quality clinical trials are needed before clinical recommendations for antibiotic therapy in UC management are made.