Robust reactive oxygen species modulator hitchhiking yeast microcapsules for colitis alleviation by trilogically intestinal microenvironment renovation.

Ulcerative colitis (UC) is characterized by chronic inflammatory processes of the intestinal tract of unknown origin. Current treatments lack understanding on how to effectively alleviate oxidative stress, relieve inflammation, as well as modulate gut microbiota for maintaining intestinal homeostasis synchronously. In this study, a novel drug delivery system based on a metal polyphenol network (MPN) was constructed via metal coordination between epigallocatechin gallate (EGCG) and Fe3+. Curcumin (Cur), an active polyphenolic compound, with distinguished anti-inflammatory activity was assembled and encapsulated into MPN to generate Cur-MPN. The obtained Cur-MPN could serve as a robust reactive oxygen species modulator by efficiently scavenging superoxide radical (O2•-) as well as hydroxyl radical (·OH). By hitchhiking yeast microcapsule (YM), Cur-MPN was then encapsulated into YM to obtain CM@YM. Our findings demonstrated that CM@YM was able to protect Cur-MPN to withstand the harsh gastrointestinal environment and enhance the targeting and retention abilities of the inflamed colon. When administered orally, CM@YM could alleviate DSS-induced colitis with protective and therapeutic effects by scavenging ROS, reducing pro-inflammatory cytokines, and regulating the polarization of macrophages to M1, thus restoring barrier function and maintaining intestinal homeostasis. Importantly, CM@YM also modulated the gut microbiome to a favorable state by improving bacterial diversity and transforming the compositional structure to an anti-inflammatory phenotype as well as increasing the content of short-chain fatty acids (SCFA) (such as acetic acid, propionic acid, and butyric acid). Collectively, with excellent biocompatibility, our findings indicate that synergistically regulating intestinal microenvironment will be a promising approach for UC.

Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Prebiotics-Encapsulated Probiotic Spores Regulate Gut Microbiota and Suppress Colon Cancer.

While microbial-based therapy has been considered as an effective strategy for treating diseases such as colon cancer, its safety remains the biggest challenge. Here, probiotics and prebiotics, which possess ideal biocompatibility and are extensively used as additives in food and pharmaceutical products, are combined to construct a safe microbiota-modulating material. Through the host-guest chemistry between commercial Clostridium butyricum and chemically modified prebiotic dextran, prebiotics-encapsulated probiotic spores (spores-dex) are prepared. It is found that spores-dex can specifically enrich in colon cancers after oral administration. In the lesion, dextran is fermented by C. butyricum, and thereby produces anti-cancer short-chain fatty acids (SCFAs). Additionally, spores-dex regulate the gut microbiota, augment the abundance of SCFA-producing bacteria (e.g., Eubacterium and Roseburia), and markedly increase the overall richness of microbiota. In subcutaneous and orthotopic tumor models, drug-loaded spores-dex inhibit tumor growth up to 89% and 65%, respectively. Importantly, no obvious adverse effect is found. The work sheds light on the possibility of using a highly safe strategy to regulate gut microbiota, and provides a promising avenue for treating various gastrointestinal diseases.

Enzyme-Driven Membrane-Targeted Chimeric Peptide for Enhanced Tumor Photodynamic Immunotherapy.

Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide, PpIX-C6-PEG8-KKKKKKSKTKC-OMe (PCPK), was designed for PM-targeted photodynamic therapy (PM-PDT) and enhanced immunotherapy via tumor cell PM damage and fast release of damage-associated molecular patterns (DAMPs). The PM targeting ability of PCPK originates from the cellular K-Ras signaling, which occurs exclusively to drive the corresponding proteins to PM by PFTase. With the conjugation of the photosensitizer protoporphyrin IX (PpIX), PCPK could generate cytotoxic reactive oxygen species to deactivate membrane-associated proteins, initiate lipid peroxidation, and destroy PM with an extremely low concentration (1 µM) under light irradiation. The specific PM damage further induced the fast release of DAMPs (high-mobility group box 1 and ATP), resulting in antitumor immune responses stronger than those of conventional cytoplasm-localized PDT. This immune-stimulating PM-PDT strategy also exhibited the inhibition effect for distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy.

A comparison study between wide-range and high-sensitivity C-reactive protein assays (Roche Cobas c702) for low C-reactive protein concentration in patients with cardiovascular risk.

BACKGROUND: Low concentration C-reactive protein (CRP) has favorable prognostic significance in patients with cardiovascular risks. METHODS: We compared the wr-CRP method with the hs-CRP method both on Roche Cobas c702 analyzer for the determination of low CRP concentration (<20 mg/L) including 200 patients treated in Cardiology Department in Beijing Tsinghua Changgung Hospital (Beijing, China) from December 2018 to March 2019. RESULTS: The two methods were highly correlated (Spearman's rho = 0.995). Deming regression was used to fit the regression analysis model, giving a slope of 1.058 with an intercept of 0.008. The median method difference (wr-CRP - hr-CRP) was 0.120 mg/L (95% CI, 0.086-0.200 mg/L), and the median percent differences were 7.34% (95% CI, 4.27%-8.47%). The percent bias between both methods at the given cutoff CRP values of 1, 3, and 10 mg/L evaluated by Deming regression was 6.60%, 6.07%, and 5.88%, respectively, all of which were less than the acceptable standard (12.50%). The percentage of sample results concordant by both methods for the risk stratification was 96.0% (kappa = 0.937, P < 0.001). CONCLUSIONS: Roche wr-CRP and hs-CRP assays are highly concordant in determining low concentration CRP. Wr-CRP may be used as an alternative to hs-CRP assay on Roche Cobas c702 analyzer to assess the cardiovascular risk, considering its convenience and lower costs.

Artificial Super Neutrophils for Inflammation Targeting and HClO Generation against Tumors and Infections.

Neutrophils are powerful effector leukocytes that play an important role in innate immune systems for opposing tumor progression and ameliorating pathogen infections. Inspired by their distinct functions against tumors and infections, the artificial "super neutrophils" are proposed with excellent inflammation targeting and hypochlorous acid (HClO) generation characteristics for targeting and eliminating malignant tumor cells and pathogens. The "super neutrophils" are fabricated by embedding glucose oxidase (GOx) and chloroperoxidase (CPO) into zeolitic imidazolate framework-8 (ZIF-8) for HClO generation via enzymatic cascades, and then encapsulating them with the neutrophil membrane (NM) for inflammation targeting. In vitro and in vivo results indicate that these artificial "super neutrophils" can generate seven times higher reactive HClO than the natural neutrophils for eradicating tumors and infections. The "super neutrophils" demonstrated here with easy fabrication and good neutrophil-mimicking property exhibit great potential for biomedical applications.

O2 Economizer for Inhibiting Cell Respiration To Combat the Hypoxia Obstacle in Tumor Treatments.

Hypoxia, a ubiquitously aberrant phenomenon implicated in tumor growth, causes severe tumor resistance to therapeutic interventions. Instead of the currently prevalent solution through intratumoral oxygen supply, we put forward an "O2-economizer" concept by inhibiting the O2 consumption of cell respiration to spare endogenous O2 and overcome the hypoxia barrier. A nitric oxide (NO) donor responsible for respiration inhibition and a photosensitizer for photodynamic therapy (PDT) are co-loaded into poly(d,l-lactide- co-glycolide) nanovesicles to provide a PDT-specific O2 economizer. Once accumulating in tumors and subsequently responding to the locally reductive environment, the carried NO donor undergoes breakdown to produce NO for inhibiting cellular respiration, allowing more O2 in tumor cells to support the profound enhancement of PDT. Depending on the biochemical reallocation of cellular oxygen resource, this O2-economizer concept offers a way to address the important issue of hypoxia-induced tumor resistance to therapeutic interventions, including but not limited to PDT.

A two-photon excited O2-evolving nanocomposite for efficient photodynamic therapy against hypoxic tumor.

This paper reported on a two-photon excited nanocomposite FCRH to overcome tumor hypoxia for enhanced photodynamic therapy (PDT). Through modified by ruthenium (Ⅱ) complex (Ru(bpy)32+) and hyperbranched conjugated copolymer with poly (ethylene glycol) arms (HOP), the water-splitting mediated O2 generation can be triggered via two-photon irradiation from iron-doped carbon nitride (Fe-C3N4) for the first time. While exposured to two-photon laser, Ru(bpy)32+ was activated to generate singlet oxygen (1O2) and Fe-C3N4 was triggered to split water for oxygen supply in the mean time. Owing to the injection of photoinduced electrons from excited Ru(bpy)32+ to Fe-C3N4, O2 generation by Fe-C3N4 was significantly accelerated. After accumulation of the nanocomposite by enhanced permeability and retention (EPR) effect, FCRH was demonstrated to alleviate the tumorous hypoxia and consequently enhance the antitumor efficacy of PDT. Furthermore, tumor metabolism evaluations explained the capability of the nanocomposite in reducing intratumoral hypoxia. Our results provide a new diagram for ameliorating the hypoxic tumor microenvironment and accelerating 1O2 generation under two-photon excitation, which will find great potential for spatiotemporally controlled tumor treatment in vivo.

Self-assembly of core-satellite gold nanoparticles for colorimetric detection of copper ions.

Molecule-coated nanoparticles are hybrid materials which can be engineered with novel properties. The molecular coating of metal nanoparticles can provide chemical functionality, enabling assembly of the nanoparticles that are important for applications, such as biosensing devices. Herein, we report a new self-assembly of core-satellite gold nanoparticles linked by a simple amino acid l-Cysteine for biosensing of Cu(2+). The plasmonic properties of core-satellite nano-assemblies were investigated, a new red shifted absorbance peak from about 600 to 800 nm was found, with specific wavelength depending on ratios with assembly of large and small gold nanoparticles. The spectral features obtained using surface-enhanced Raman spectroscopy (SERS) provided strong evidence for the assembly of the Cu(2+) ions to the L-Cysteine molecules leading to the successful formation of the core-satellite Cu(l-Cysteine) complex on the gold surfaces. In addition, a linear relationship between the concentration of mediating Cu(2+) and absorbance of self-assembled gold nanoparticles (GNPs) at 680 nm was obtained. These results strongly address the potential strategy for applying the functionalized GNPs as novel biosensing tools in trace detections of certain metal ions.

Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway.

AIM: The Wnt signaling pathway plays a pivotal role in cellular developmental processes and human carcinogenesis. The aim of this study was to investigate the effects of quercetin on the growth of the colon carcinoma cell line and the regulation effect of quercetin on the Wnt/beta-catenin signaling pathway. METHODS: MTT assay was used to determine the reduction of cell viability of quercetin on SW480 cells and clone 26 cells. The apoptotic rate and cell-cycle analysis after treatment with quercetin was determined by flow cytometry. Effects of quercetin on mRNA expression of cyclin D(1) and survivin were detected by semiquantitative RT-PCR. After treatment with quercetin, the protein expression of cyclin D(1) and survivin in SW480 cells was analyzed by Western blot analysis. We built a Wnt/beta-catenin signaling pathway reporter gene model. The regulation effect of quercetin on the Wnt/beta-catenin signaling transcription was investigated by using this reporter gene model. RESULTS: Quercetin reduced cell viability in a dose- and time-dependent manner in SW480 and clone 26 cells. The percentages of SW480 cells and clone 26 cells at G(2)/M phase were increased significantly after treatment with 40 approximately 80 micromol/L quercetin for 48 hours. Quercetin induced the apoptosis of SW480 cells in a dose-dependent manner at the concentration of 20, 40, 60, anf 80 micromol/L. However, quercetin only induced the apoptosis of clone 26 cells at the concentration of 80 micromol/L. Quercetin downregulated transcriptional activity of beta-catenin/Tcf in SW480 cells transiently transfected with the TCF-4 reporter gene. Within 24 hours of treatment, a 160-mumol/L concentration of quercetin reduced beta-catenin/Tcf transcriptional activity by about 18-fold. Cyclin D(1) and the survivin gene were downregulated markedly by quercetin in a dose-dependent manner at both the transcription and protein expression levels. CONCLUSION: The results indicate that the molecular mechanism underlying the antitumor effect of quercetin in SW480 colon cancer cells is related to the inhibition of expression of cyclin D(1) and survivin as well as the Wnt/beta-catenin signaling pathway. Therefore, the Wnt/beta-catenin signaling pathway could be qualified as one of the promising targets for innovative treatment strategies of colorectal cancer.