Mesoporous Silicon Nanoparticles with Liver-Targeting and pH-Response-Release Function Are Used for Targeted Drug Delivery in Liver Cancer Treatment.

This article aims to develop an aspirin-loaded double-modified nano-delivery system for the treatment of hepatocellular carcinoma. In this paper, mesoporous silica nanoparticles (MSN) were prepared by the "one-pot two-phase layering method", and polydopamine (PDA) was formed by the self-polymerization of dopamine as a pH-sensitive coating. Gal-modified PDA-modified nanoparticles (Gal-PDA-MSN) were synthesized by linking galactosamine (Gal) with actively targeted galactosamine (Gal) to PDA-coated MSN by a Michael addition reaction. The size, particle size distribution, surface morphology, BET surface area, mesoporous size, and pore volume of the prepared nanoparticles were characterized, and their drug load and drug release behavior in vitro were investigated. Gal-PDA-MSN is pH sensitive and targeted. MSN@Asp is different from the release curves of PDA-MSN@Asp and Gal-PDA-MSN@Asp, the drug release of PDA-MSN@Asp and Gal-PDA-MSN@Asp accelerates with increasing acidity. In vitro experiments showed that the toxicity and inhibitory effects of the three nanodrugs on human liver cancer HepG2 cells were higher than those of free Asp. This drug delivery system facilitates controlled release and targeted therapy.

Mechanism of action of the bile acid receptor TGR5 in obesity.

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.

Maternal exposure to polystyrene nanoplastics causes defective retinal development and function in progeny mice by disturbing metabolic profiles.

Microplastics (MPs) and nanoplastics (NPs) are widely spreading in our living environment, accumulating in the human body and potentially threating human health. The retina, which is a terminally differentiated extension of the central nervous system, is essential for the visual system. However, the effects and molecular mechanisms of MPs/NPs on retina development and function are still unclear. Here, we investigated the effects and modes of action of polystyrene NPs (PS-NPs) on the retina using mice as a mammalian model species. Maternal PS-NP exposure (100 nm) at an environmentally realistic concentration of 10 mg L-1 (or 2.07 *1010 particles mL-1) via drinking water from the first day of pregnancy till the end of lactation (21 days after birth) caused defective neural retinal development in the neonatal mice, by depositing in the retinal tissue and reducing the number of retinal ganglion cells and bipolar cells. Exposure to PS-NPs retarded retinal vascular development, while abnormal electroretinogram (ERG) responses and an increased level of oxidative stress were also observed in the retina of the progeny mice after maternal PS-NP exposure. Metabolomics showed significant dysregulation of amino acids that are pivotal to neuron retinal function, such as glutamate, aspartate, alanine, glycine, serine, threonine, taurine, and serotonin. Transcriptomics identified significantly dysregulated genes, which were enriched in processes of angiogenesis, visual system development and lens development. Regulatory analysis showed that Fos gene mediated pathways could be a potential key target for PS-NP exposure in retinal development and function. Our study revealed that maternal exposure to PS-NPs generated detrimental effects on retinal development and function in progeny mice, offering new insights into the visual toxicity of PS-NPs.

Determination of phosphate in food based on molybdenum yellow derivatization coupled with resonance Rayleigh scattering method.

This paper proposed a rapid, selective and sensitive molybdenum yellow derivatization coupled with Resonance Rayleigh scattering (MYD-RRS) method for detection of phosphate. Under the acidic condition, phosphate can be selectively transformed to Keggin type of phosphomolybdic acid (PMA, i.e., PMo12O403-) through molybdenum yellow derivatization reaction prior to RRS detection. The PMA can further react with cationic methyl violet (MV) to form larger PMA-MV ion association complexes, generating significant RRS signal. The concentration of phosphate was linearly related to the RRS signal in the range of 8-200 ng/mL, with the determining coefficient (R2) of 0.9973 and the detection limit of 4 ng/mL. The analytical procedure can be completed within 10 min and the RRS signal intensity can remain stable more than 4 h. The method showed good stability toward temperature and time, and good anti-interference capability. The method was applied to the determination of phosphate in real food samples with the recovery of 85-117% and RSD of 1-5.2%. With the advantages of rapidness, high sensitivity and good selectivity, the MYD-RRS method exhibits great potential to the determination of phosphate in food. It also provides an instructive strategy for detection of analytes with weak RRS signal.

Serum amyloid A aggravates endotoxin-induced ocular inflammation through the regulation of retinal microglial activation.

Serum amyloid A (SAA) are major acute-phase response proteins which actively participate in many inflammatory diseases. This study was designed to explore the function of SAA in acute ocular inflammation and the underlying mechanism. We found that SAA3 was upregulated in endotoxin-induced uveitis (EIU) mouse model, and it was primarily expressed in microglia. Recombinant SAA protein augmented intraocular inflammation in EIU, while the inhibition of Saa3 by siRNA effectively alleviated the inflammatory responses and rescued the retina from EIU-induced structural and functional damage. Further study showed that the recombinant SAA protein activated microglia, causing characteristic morphological changes and driving them further to pro-inflammatory status. The downregulation of Saa3 halted the amoeboid change of microglia, reduced the secretion of pro-inflammatory factors, and increased the expression of tissue-reparative genes. SAA3 also regulated the autophagic activity of microglial cells. Finally, we showed that the above effect of SAA on microglial cells was at least partially mediated through the expression and signaling of Toll-like receptor 4 (TLR4). Collectively, our study suggested that microglial cell-expressed SAA could be a potential target in treating acute ocular inflammation.

Inhibition of Wnt activity improves peri-implantation development of somatic cell nuclear transfer embryos.

Somatic cell nuclear transfer (SCNT) can reprogram differentiated somatic cells into totipotency. Although pre-implantation development of SCNT embryos has greatly improved, most SCNT blastocysts are still arrested at the peri-implantation stage, and the underlying mechanism remains elusive. Here, we develop a 3D in vitro culture system for SCNT peri-implantation embryos and discover that persistent Wnt signals block the naïve-to-primed pluripotency transition of epiblasts with aberrant H3K27me3 occupancy, which in turn leads to defects in epiblast transformation events and subsequent implantation failure. Strikingly, manipulating Wnt signals can attenuate the pluripotency transition and H3K27me3 deposition defects in epiblasts and achieve up to a 9-fold increase in cloning efficiency. Finally, single-cell RNA-seq analysis reveals that Wnt inhibition markedly enhances the lineage developmental trajectories of SCNT blastocysts during peri-implantation development. Overall, these findings reveal diminished potentials of SCNT blastocysts for lineage specification and validate a critical peri-implantation barrier for SCNT embryos.

Research Progress of Design Drugs and Composite Biomaterials in Bone Tissue Engineering.

Bone, like most organs, has the ability to heal naturally and can be repaired slowly when it is slightly injured. However, in the case of bone defects caused by diseases or large shocks, surgical intervention and treatment of bone substitutes are needed, and drugs are actively matched to promote osteogenesis or prevent infection. Oral administration or injection for systemic therapy is a common way of administration in clinic, although it is not suitable for the long treatment cycle of bone tissue, and the drugs cannot exert the greatest effect or even produce toxic and side effects. In order to solve this problem, the structure or carrier simulating natural bone tissue is constructed to control the loading or release of the preparation with osteogenic potential, thus accelerating the repair of bone defect. Bioactive materials provide potential advantages for bone tissue regeneration, such as physical support, cell coverage and growth factors. In this review, we discuss the application of bone scaffolds with different structural characteristics made of polymers, ceramics and other composite materials in bone regeneration engineering and drug release, and look forward to its prospect.

Toxicity evaluation of silica nanoparticles for delivery applications.

Silica nanoparticles (SiNPs) are being explored as nanocarriers for therapeutics delivery, which can address a number of intrinsic drawbacks of therapeutics. To translate laboratory innovation into clinical application, their potential toxicity has been of great concern. This review attempts to comprehensively summarize the existing literature on the toxicity assessment of SiNPs. The current data suggest that the composition of SiNPs, their physicochemical properties, their administration route, their frequency and duration of administration, and the sex of animal models are related to their tissue and blood toxicity, immunotoxicity, and genotoxicity. However, the correlation between in vitro and in vivo toxicity has not been well established, mainly because both the in vitro and the in vivo-dosed quantities are unrealistic. This article also discusses important factors to consider in the toxicology of SiNPs and current approaches to reducing their toxicity. The aim is to give readers a better understanding of the toxicology of silica nanoparticles and to help identify key gaps in knowledge and techniques.

TREM2 deficiency in microglia accelerates photoreceptor cell death and immune cell infiltration following retinal detachment.

Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2-/-) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2-/- mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2-/- retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2-/- mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.

A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR).

Nonalcoholic fatty liver disease (NAFLD) is primarily caused by abnormal lipid metabolism and the accumulation of triglycerides in the liver. NAFLD is also associated with hepatic steatosis and nutritional and energy imbalances and is a chronic liver disease associated with a number of factors. Nuclear receptors play a key role in balancing energy and nutrient metabolism, and the peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR) regulate lipid metabolism genes, controlling hepatocyte lipid utilization and regulating bile acid (BA) synthesis and transport. They play an important role in lipid metabolism and BA homeostasis. At present, PPARα and FXR are the most promising targets for the treatment of NAFLD among nuclear receptors. This review focuses on the crosstalk mechanisms and transcriptional regulation of PPARα and FXR in the pathogenesis of NAFLD and summarizes PPARα and FXR drugs in clinical trials, laying a theoretical foundation for the targeted treatment of NAFLD and the development of novel therapeutic strategies.

The Ameliorative Effect of COST on Diet-Induced Lipid Metabolism Disorders by Regulating Intestinal Microbiota.

BACKGROUND: Chitosan oligosaccharides, with an average molecular weight ≤ 1000 Da (COST), is a natural marine product that has the potential to improve intestinal microflora and resist lipid metabolism disorders. METHODS: First, by establishing a mice model of lipid metabolism disorder induced by a high fat and high sugar diet, it is proven that COST can reduce lipid metabolism disorder, which may play a role in regulating intestinal microorganisms. Then, the key role of COST in the treatment of intestinal microorganisms is further confirmed through the method of COST-treated feces and fecal bacteria transplantation. CONCLUSIONS: intestinal microbiota plays a key role in COST inhibition of lipid metabolism disorder induced by a high fat and high sugar diet. In particular, COST may play a central regulatory role in microbiota, including Bacteroides, Akkermansia, and Desulfovibrio. Taken together, our work suggests that COST may improve the composition of gut microbes, increase the abundance of beneficial bacteria, improve lipid metabolism disorders, and inhibit the development of metabolic disorders.

GOS Ameliorates Nonalcoholic Fatty Liver Disease Induced by High Fat and High Sugar Diet through Lipid Metabolism and Intestinal Microbes.

The treatment of nonalcoholic fatty liver disease (NAFLD) remains very challenging. This study investigated the therapeutic effect of galactose oligosaccharide (GOS), an important prebiotic, on NAFLD through in vivo and in vitro experiments and preliminarily explored the mechanism by which GOS improves liver lipid metabolism and inflammation through liver and intestinal microbiological analysis. The results of mouse liver lipidomics showed that GOS could promote body thermogenesis in mice with high-fat and high-sugar diet (HFHSD)-induced NAFLD, regulate lipolysis in liver fat cells, and accelerate glycine and cholesterol metabolism. GOS dose-dependently reduced the contents of total cholesterol (TC) and triglyceride (TG) in cells and reduced the accumulation of lipid droplets in cells. GOS also reduced the Firmicutes/Bacteroidetes ratio and altered the composition of the intestinal microbiota in mice fed a HFHSD. GOS can improve liver lipid metabolism and intestinal structure of NAFLD. These results provide a theoretical and experimental basis supporting the use of GOS as a health food with anti-NAFLD functions.

The Therapeutic Effect of SCFA-Mediated Regulation of the Intestinal Environment on Obesity.

Intestinal environment disorder is a potential pathological mechanism of obesity. There is increasing evidence that disorders in the homeostasis of the intestinal environment can affect various metabolic organs, such as fat and liver, and lead to metabolic diseases. However, there are few therapeutic approaches for obesity targeting the intestinal environment. In this review, on the one hand, we discuss how intestinal microbial metabolites SCFA regulate intestinal function to improve obesity and the possible mechanisms and pathways related to obesity-related pathological processes (depending on SCFA-related receptors such as GPCRs, MCT and SMCT, and through epigenetic processes). On the other hand, we discuss dietary management strategies to enrich SCFA-producing bacteria and target specific SCFA-producing bacteria and whether fecal bacteria transplantation therapy to restore the composition of the gut microbiota to regulate SCFA can help prevent or improve obesity. Finally, we believe that it will be of great significance to establish a working model of gut- SCFA- metabolic disease development in the future for the improvement this human health concern.

Marine Chitooligosaccharide Alters Intestinal Flora Structure and Regulates Hepatic Inflammatory Response to Influence Nonalcoholic Fatty Liver Disease.

In this study, C57BL/6 mice were given an HFHSD diet for 8 weeks to induce hepatic steatosis and then given COSM solution orally for 12 weeks. The study found that the HFHSD diet resulted in steatosis and insulin resistance in mice. The formation of NAFLD induced by HFHSD diet was related to the imbalance of intestinal flora. However, after COSM intervention, the abundance of beneficial bacteria increased significantly, while the abundance of harmful bacteria decreased significantly. The HFHSD diet also induced changes in intestinal bacterial metabolites, and the content of short-chain fatty acids in cecal contents after COSM intervention was significantly higher than that in the model group. In addition, COSM not only improved LPS levels and barrier dysfunction in the ileum and colon but upregulated protein levels of ZO-1, occludin, and claudin in the colon and downregulated the liver LPS/TLR4/NF-κB inflammatory pathway. We concluded that the treatment of marine chitooligosaccharide COSM could improve the intestinal microflora structure of the fatty liver and activate an inflammatory signaling pathway, thus alleviating the intrahepatic lipid accumulation induced by HFHSD.

Biodegradation and Prospect of Polysaccharide from Crustaceans.

Marine crustacean waste has not been fully utilized and is a rich source of chitin. Enzymatic degradation has attracted the wide attention of researchers due to its unique biocatalytic ability to protect the environment. Chitosan (CTS) and its derivative chitosan oligosaccharides (COSs) with various biological activities can be obtained by the enzymatic degradation of chitin. Many studies have shown that chitosan and its derivatives, chitosan oligosaccharides (COSs), have beneficial properties, including lipid-lowering, anti-inflammatory and antitumor activities, and have important application value in the medical treatment field, the food industry and agriculture. In this review, we describe the classification, biochemical characteristics and catalytic mechanisms of the major degrading enzymes: chitinases, chitin deacetylases (CDAs) and chitosanases. We also introduced the technology for enzymatic design and modification and proposed the current problems and development trends of enzymatic degradation of chitin polysaccharides. The discussion on the characteristics and catalytic mechanism of chitosan-degrading enzymes will help to develop new types of hydrolases by various biotechnology methods and promote their application in chitosan.

A resonance Rayleigh scattering method for sensitive detection of chitosan based on supramolecular complex and mechanism study.

A convenient and sensitive resonance Rayleigh scattering (RRS) method for the detection of chitosan (CTS) has been developed via forming Cu-Zn supramolecular complex by complexation reaction, hydrophobic force and electrostatic attraction. The microstructure of the complex was characterized by FT-IR, zeta potential, scanning electron microscope (SEM), UV-vis and RRS. Furthermore, the interaction mechanism among Cu(II), Zn(II), CTS and sodium dodecyl benzene sulfonate (SDBS) was studied. The results revealed that CTS and Cu(II) or Zn(II) formed a supramolecular complex with RRS enhancement in weak acid condition. In the presence of SDBS, the RRS intensity of CTS-Cu(II)-SDBS or CTS-Zn(II)-SDBS was significantly higher than that of the binary system without SDBS at the same CTS concentration. The RRS intensity of CTS-Cu(II)-Zn(II)-SDBS was higher than that of CTS-Cu(II)-SDBS and CTS-Zn(II)-SDBS. The RRS intensity increased linearly with the increase of CTS concentration made it possible to determine CTS quantitatively. In the range extending from 0.10 to 5.00 µg/mL, the equation of linear regression was ΔI=1848.8c-138.3 with a correlation coefficient 0.9996, and the detection limit was estimated to be 37.96 ng/mL. The study was successfully applied for the determination of CTS in health food samples, suggesting its great potential toward CTS analysis.

The Microstructure, Antibacterial and Antitumor Activities of Chitosan Oligosaccharides and Derivatives.

Chitosan obtained from abundant marine resources has been proven to have a variety of biological activities. However, due to its poor water solubility, chitosan application is limited, and the degradation products of chitosan oligosaccharides are better than chitosan regarding performance. Chitosan oligosaccharides have two kinds of active groups, amino and hydroxyl groups, which can form a variety of derivatives, and the properties of these derivatives can be further improved. In this review, the key structures of chitosan oligosaccharides and recent studies on chitosan oligosaccharide derivatives, including their synthesis methods, are described. Finally, the antimicrobial and antitumor applications of chitosan oligosaccharides and their derivatives are discussed.

One-pot facile synthesis of enzyme-encapsulated Zn/Co-infinite coordination polymer nanospheres as a biocatalytic cascade platform for colorimetric monitoring of bacteria viability.

A rapid method for colorimetric monitoring of bacterial viability is described. The colorimetric method was carried out based on glucose oxidase-encapsulated Zn/Co-infinite coordination polymer (Zn/Co-ICP@GOx), which was prepared in aqueous solution free of toxic organic solvents at room temperature. The Zn/Co-ICP@GOx was confirmed to be a robust sphere structure with an average diameter of 147.53 ± 20.40 nm. It integrated the catalytic activity of natural enzyme (GOx) and mimetic peroxidase (Co (П)) all in one, efficiently acting as a biocatalytic cascade platform for glucose catalytic reaction. Exhibiting good multi-enzyme catalytic activity, stability, and selectivity, Zn/Co-ICP@GOx can be used for colorimetric glucose detection. The linear range was 0.01-1.0 mmol/L, and the limit of detection (LOD) was 0.005 mmol/L. As the glucose metabolism is a common expression of bacteria, the remaining glucose can indirectly represent the bacterial viability. Hence, a Zn/Co-ICP@GOx-based colorimetric method was developed for monitoring of bacterial viability. The color was intuitively observed with the naked eye, and the bacterial viability was accurately quantified by measurement of the absorbance at 510 nm. The method was applied to determination of bacterial viability in water and milk samples with recoveries of 99.0-103% and RSD of 0.43-7.5%. The method was rapid (less than 40 min) and applicable to different bacterial species irrespective of Gram-positive and Gram-negative bacteria, providing a universal and promising strategy for real-time monitoring of bacterial viability.

Pharmacological Inhibition of Core Regulatory Circuitry Liquid-liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma.

Liquid-liquid phase-separated (LLPS) transcriptional factor assemblies at super-enhancers (SEs) provide a conceptual framework for underlying transcriptional control in mammal cells. However, the mechanistic understanding of LLPS in aberrant transcription driven by dysregulation of SEs in human malignancies is still elusive. By integrating SE profiling and core regulatory circuitry (CRC) calling algorithm, the CRC of metastatic and chemo-resistant osteosarcoma is delineated. CRC components, HOXB8 and FOSL1, produce dense and dynamic phase-separated droplets in vitro and liquid-like puncta in cell nuclei. Disruption of CRC phase separation decreases the chromatin accessibility in SE regions and inhibits the release of RNA polymerase II from the promoter of SE-driven genes. Importantly, absence of CRC key component causes a reduction in osteosarcoma tumor growth and metastasis. Moreover, it is shown that CRC condensates can be specifically attenuated by the H3K27 demethylase inhibitor, GSK-J4. Pharmacological inhibition of the CRC phase separation results in metastasis suppression and re-sensitivity to chemotherapy drugs in patient-derived xenograft model. Taken together, this study reveals a previously unknown mechanism that CRC factors formed LLPS condensates, and provides a phase separation-based pharmacological strategy to target undruggable CRC components for the treatment of metastatic and chemo-resistant osteosarcoma.

A resonance Rayleigh scattering and fluorescence quenching dual-channel sensor for sensitive detection of chitosan based on Eosin Y.

The sensitive chitosan (CTS) detection methods based on the resonance Rayleigh scattering (RRS) quenching method and fluorescence quenching of Eosin Y were put forward. In the HAC-NaAC buffer solution, Eosin Y interacted with Triton X-100 to generate the binary complex which served as the RRS spectral probe. When CTS was interacted with the binary complex, the RRS intensity decreased with the increase of CTS. At the same time, the fluorescence intensity of Eosin Y decreased in the presence of Triton X-100, and the fluorescence intensity of "Eosin Y+Triton X-100" system further decreased when CTS was added. So it was further proved that there was a forming complex in "Eosin Y+Triton X100+CTS" system. The interaction was characterized by zeta potential, RRS, fluorescence spectrum, and UV-Vis spectroscopy. Under optimal conditions, there was a good linear relationship between the RRS decreased intensity (ΔI) and the concentration of CTS in the range of 0.05-1.30 µg/mL, with a regression equation of ΔI = 1325c + 73.66 and correlation coefficient (R2) of 0.9907. The detection limit was 0.0777 µg/mL. Likewise, the linear range of the fluorescence quenching was 0.03-1.30 µg/mL; the regression equation was ΔF = 1926c + 294.0 with R2 = 0.9800 under fluorescence quenching. The detection limit was 0.0601 µg/mL. Therefore, the dual-channel sensor for the determination of CTS was applied to the health products, and the results were satisfactory. The t test result showed that there was no statistical difference between the two methods.