Chondroitin sulfate functionalized palmitic acid and cysteine cografted-quaternized chitosan for CD44 and gut microbiota dual-targeted delivery of curcumin.

Curcumin (CUR) has a regulatory effect on the gut microbiota (GM), and its significant anti-inflammatory properties make it a research hotspot for inflammatory bowel disease (IBD) treatment. However, the low bioavailability and poor pharmacokinetic properties of CUR limit its practical application. Herein, CD44 and GM dual-targeted nanoparticles (NPs) loaded with CUR (CUR@Chs-PNC NPs) were derived from a quaternized chitosan and surface functionalization with chondroitin sulfate (Chs). The generated CUR@Chs-PNC NPs had an ideal average particle size (238.9 â€‹nm), a uniform size distribution, and a positive surface charge (+41.93 â€‹mV). Strikingly, the CUR@Chs-PNC NPs had a good sustained-release effect in a simulated gastrointestinal environment and exhibited the full drug release when in a simulated colon environment. Moreover, Chs functionalization endowed the NPs with a notable CD44-targeted drug delivery ability and thereby enhanced the CUR content in the plasma of SD rats. The biodistribution of the CUR@Chs-PNC NPs in vivo indicated that the NPs could prolong the intestinal residence time, thereby promoting the interaction between CUR and GM. Most importantly, in a DSS-induced colitis mouse model, the CUR@Chs-PNC NPs decreased the disease activity index, improved the oxidative stress and inflammation condition, promoted the production of short-chain fatty acids (SCFAs), regulated immune cells, and maintained intestinal microbiome homeostasis. This study demonstrates that CUR@Chs-PNC NPs, which exhibit excellent biocompatibility and biodegradability, on-demand drug release property, and CD44 and GM dual-targeted capacities, have the potential for further application in the treatment of colitis.

Fecal fermentation and high-fat diet-induced obesity mouse model confirmed exopolysaccharide from Weissella cibaria PFY06 can ameliorate obesity by regulating the gut microbiota.

Obesity associated with diet and intestinal dysbiosis is a worldwide public health crisis, and exopolysaccharides (EPS) produced by lactic acid bacteria (LAB) have prebiotic potential to ameliorate obesity. Therefore, the present study obtained LAB with the ability to produce high EPS, examined the structure of EPS, and explained its mechanism of alleviating obesity by in vivo and in vitro models. The results showed that Weissella cibaria PFY06 with a high EPS yield was isolated from strawberry juice, and pure polysaccharide (PFY06-EPS) was purified by Sephadex G-100. The structural characteristics of PFY06-EPS showed that the molecular weight was 8.08 × 106 Da and composed of α-(1,6)-D glucosyl residues. An in vitro simulated human colon fermentation test demonstrated that PFY06-EPS increased the abundance of Prevotella and Bacteroides. Cell tests confirmed that PFY06-EPS after fecal fermentation inhibited fat accumulation by promoting the secretion of endogenous gastrointestinal hormones and insulin and inhibiting the secretion of inflammatory factors. Notably, PFY06-EPS reduced weight gain, fat accumulation, inflammatory reactions and insulin resistance in a high-fat diet-induced obesity mouse model and improved glucolipid metabolism. PFY06-EPS intervention reversed obesity-induced microflora disorders, such as reducing the Firmicutes/Bacteroides ratio and increasing butyrate-producing bacteria (Roseburia and Oscillibacter), and reduced endotoxemia to maintain intestinal barrier integrity. Therefore, in vivo and in vitro models showed that PFY06-EPS had potential as a prebiotic that may play an anti-obesity role by improving the function of the gut microbiota.

Palmitic acid- and cysteine-functionalized nanoparticles overcome mucus and epithelial barrier for oral delivery of drug.

Nanoparticles (NPs) used for oral administration have greatly improved drug bioavailability and therapeutic efficacy. Nevertheless, NPs are limited by biological barriers, such as gastrointestinal degradation, mucus barrier, and epithelial barrier. To solve these problems, we developed the PA-N-2-HACC-Cys NPs loaded with anti-inflammatory hydrophobic drug curcumin (CUR) (CUR@PA-N-2-HACC-Cys NPs) by self-assembled amphiphilic polymer, composed of the N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC), hydrophobic palmitic acid (PA), and cysteine (Cys). After oral administration, the CUR@PA-N-2-HACC-Cys NPs had good stability and sustained release under gastrointestinal conditions, followed by adhering to the intestine to achieve drug mucosal delivery. Additionally, the NPs could penetrate mucus and epithelial barriers to promote cellular uptake. The CUR@PA-N-2-HACC-Cys NPs could open tight junctions between cells for transepithelial transport while striking a balance between mucus interaction and diffusion through mucus. Notably, the CUR@PA-N-2-HACC-Cys NPs improved the oral bioavailability of CUR, which remarkably relieved colitis symptoms and promoted mucosal epithelial repair. Our findings proved that the CUR@PA-N-2-HACC-Cys NPs had excellent biocompatibility, could overcome mucus and epithelial barriers, and had significant application prospects for oral delivery of the hydrophobic drugs.

Evaluation of antioxidation, regulation of glycolipid metabolism and potential as food additives of exopolysaccharide from Sporidiobolus pararoseus PFY-Z1.

At present, there are relatively few studies on the production of exopolysaccharide (EPS) by yeasts. Therefore, exploring the properties of EPS produced by yeast can not only enrich the source of EPS, but also play an important role in its future application in the food field. The aim of this study was to explore the biological activities of EPS (named SPZ) from Sporidiobolus pararoseus PFY-Z1, as well as the dynamic changes in physical and chemical properties that occur during simulated gastrointestinal digestion, and the effects of SPZ on microbial metabolites during fecal fermentation in vitro. The results revealed that SPZ had good water solubility index, water-holding capacity, emulsifying ability, coagulated skim milk, antioxidant properties, hypoglycemic activities, and bile acid-binding abilities. Furthermore, the content of reducing sugars increased from 1.20 ± 0.03 to 3.34 ± 0.11 mg/mL after gastrointestinal digestion, and had little effect on antioxidant activities. Moreover, SPZ could promote the production of short-chain fatty acids during fermentation for 48 h, in particular, propionic acid and n-butyric acid increased to 1.89 ± 0.08 and 0.82 ± 0.04 mmol/L, respectively. Besides this, SPZ could inhibit LPS production. In general, this study can help us to better understand the potential bioactivities, and the changes in bio-activities of compounds after digestion of SPZ.

Curcumin encapsulation in self-assembled nanoparticles based on amphiphilic palmitic acid-grafted-quaternized chitosan with enhanced cytotoxic, antimicrobial and antioxidant properties.

The practical application of curcumin (CUR) is greatly limited due to its instability, high hydrophobicity, low bioavailability, and inability to cross the mucosal barrier of gastrointestinal tract. To overcome these disadvantages, several delivery systems have been explored to formulate CUR for oral administration. Nanoparticles (NPs) can significantly enhance oral absorption, bioavailability and therapeutic efficacy of drug, however, NPs are limited by the gastrointestinal degradation, mucosal and epithelial barriers. A novel amphiphilic quaternary ammonium chitosan (N-2-HACC) based NP delivery carrier was prepared using palmitic acid (PA) to encapsulate CUR. Palmitoyl chitosan (PA-N-2-HACC) was characterized including FT-IR, 1H NMR, TGA, and CAC. The particle size of PA-N-2-HACC NPs and PA-N-2-HACC NPs loaded with CUR (CUR@PA-N-2-HACC NPs) was 231.6 ± 9.24 nm and 264.5 ± 4.31 nm. The encapsulation efficiency and loading capacity of CUR@PA-N-2-HACC NPs was 75.43 ± 1.25 % and 6.81 ± 0.16 %. CUR@PA-N-2-HACC NPs exhibited sustained and controlled release. Compared with the CUR, minimum inhibitory concentration of the CUR@PA-N-2-HACC NPs against Escherichia coli, Staphylococcus aureus and Candida albicans was reduced by 4.2 times, 1.6 times and 4.6 times, respectively. Moreover, the antioxidant activity of CUR@PA-N-2-HACC NPs was dose-dependent and higher than that of free CUR. The PA-N-2-HACC NPs show little toxicity and are a promising delivery system for encapsulating hydrophobic drugs.

The Mucoadhesive Nanoparticle-Based Delivery System in the Development of Mucosal Vaccines.

Mucosal tissue constitutes the largest interface between the body and the external environment, regulating the entry of pathogens, particles, and molecules. Mucosal immunization is the most effective way to trigger a protective mucosal immune response. However, the majority of the currently licensed vaccines are recommended to be administered by intramuscular injection, which has obvious shortcomings, such as high production costs, low patient compliance, and lack of mucosal immune response. Strategies for eliciting mucosal and systemic immune responses are being developed, including appropriate vaccine adjuvant, delivery system, and bacterial or viral vectors. Biodegradable mucoadhesive nanoparticles (NPs) are the most promising candidate for vaccine delivery systems due to their inherent immune adjuvant property and the ability to protect the antigen from degradation, sustain the release of loaded antigen, and increase the residence time of antigen at the administration site. The current review outlined the complex structure of mucosa, the mechanism of interaction between NPs and mucosa, factors affecting the mucoadhesion of NPs, and the application of the delivery system based on mucoadhesive NPs in the field of vaccines. Moreover, this review demonstrated that the biodegradable and mucoadhesive NP-based delivery system has the potential for mucosal administration of vaccines.

Fibroblast growth factor 21: a novel long-acting hypoglycemic drug for canine diabetes.

Currently, insulin is commonly used in the clinical management of canine diabetes. However, it must be injected preprandially causing much inconvenience to the owners. Therefore, the development of long-acting hypoglycemic agents has attracted much attention in the scientific community. This study aimed to investigate the long-acting hypoglycemic effect of canine fibroblast growth factor 21 (cFGF-21) in diabetic dogs. Diabetic dogs were administered with cFGF-21, polyethylene glycol-modified cFGF-21 (PEG-cFGF-21), or insulin once a day, once every 2, 3, or 4 days subcutaneously. The results showed that cFGF-21 and PEG-cFGF-21 maintained blood glucose comparable to normal levels for 2 and 3 days respectively while insulin maintained the blood glucose for only 2 h after a single injection. After treatment with cFGF-21, oral glucose tolerance test (OGTT) was significantly improved with glycosylated hemoglobin (HbA1c) close to the normal levels. In addition, cFGF-21 significantly repaired islet ß cells, increased insulin content, and protected the pancreas from streptozotocin-induced injury. Furthermore, cFGF-21 exhibited both antioxidant and anti-inflammatory properties in the pancreas. We conclude, therefore, that cFGF-21 and PEG-cFGF-21 can maintain blood glucose comparable to normal levels for 2 and 3 days respectively after a single dose. The long-acting efficacy of cFGF-21 can be attributed to improvement in oxidative stress and the reduction of inflammation in the pancreas.

FGF21 Enhances Therapeutic Efficacy and Reduces Side Effects of Dexamethasone in Treatment of Rheumatoid Arthritis.

In order to investigate efficacy of FGF21 combine dexamethasone (Dex) on rheumatoid arthritis (RA) meanwhile reduce side effects of dexamethasone. We used combination therapy (Dex 15 mg/kg + FGF21 0.25 mg/kg, Dex 15 mg/kg + FGF21 0.5 mg/kg or Dex 15 mg/kg + FGF21 1 mg/kg) and monotherapy (Dex 15 mg/kg or FGF21 1 mg/kg) to treat CIA mice induced by chicken type II collagen, respectively. The effects of treatment were determined by arthritis severity score, histological damage, and cytokine production. The levels of oxidative stress parameters, liver functions, and other blood biochemical indexes were detected to determine FGF21 efficiency to side effects of dexamethasone. Oil red O was performed to detect the effects of FGF21 and dexamethasone on fat accumulation in HepG2 cells. The mechanism of FGF21 improves the side effects of dexamethasone which was analyzed by Western blotting. This combination proved to be therapeutically more effective than dexamethasone or FGF21 used singly. FGF21 regulates oxidative stress and lipid metabolism by upregulating dexamethasone-inhibited SIRT-1 and then activating downstream Nrf-2/HO-1and PGC-1. FGF21 and dexamethasone are highly effective in the treatment of arthritis; meanwhile, FGF21 may overcome the limited therapeutic response and Cushing syndrome associated with dexamethasone.