Stachyose Exerts Anticolitis Efficacy by Re-balancing Treg/Th17 and Activating the Butyrate-Derived PPARγ Signaling Pathway.

Ulcerative colitis (UC) is a complex chronic inflammatory disease closely associated with gut homeostasis dysfunction. The previous studies have shown that stachyose, a functional food additive, has the potential to enhance gut health and alleviate UC symptoms. However, the underlying mechanism of its effects remains unknown. In this study, our findings showed that dietary supplements of stachyose had a significant dose-dependent protective effect on colitis symptoms, regulation of gut microbiota, and restoration of the Treg/Th17 cell balance in dextran sulfate sodium (DSS) induced colitis mice. To further validate these findings, we conducted fecal microbiota transplantation (FMT) to treat DSS-induced colitis in mice. The results showed that microbiota from stachyose-treated mice exhibited a superior therapeutic effect against colitis and effectively regulated the Treg/Th17 cell balance in comparison to the control group. Moreover, both stachyose supplementation and FMT resulted in an increase in butyrate production and the activation of PPARγ. However, this effect was partially attenuated by PPARγ antagonist GW9662. These results suggested that stachyose alleviates UC symptoms by modulating gut microbiota and activating PPARγ. In conclusion, our work offers new insights into the benefical effects of stachyose on UC and its potential role in modulating gut microbiota.

Application of high intensity focused ultrasound combined with nanomaterials in anti-tumor therapy.

High intensity focused ultrasound (HIFU) has demonstrated its safety, efficacy and noninvasiveness in the ablation of solid tumor. However, its further application is limited by its inherent deficiencies, such as postoperative recurrence caused by incomplete ablation and excessive intensity affecting surrounding healthy tissues. Recent research has indicated that the integration of nanomaterials with HIFU exhibits a promising synergistic effect in tumor ablation. The concurrent utilization of nanomaterials with HIFU can help overcome the limitations of HIFU by improving targeting and ablation efficiency, expanding operation area, increasing operation accuracy, enhancing stability and bio-safety during the process. It also provides a platform for multi-therapy and multi-mode imaging guidance. The present review comprehensively expounds upon the synergistic mechanism between nanomaterials and HIFU, summarizes the research progress of nanomaterials as cavitation nuclei and drug carriers in combination with HIFU for tumor ablation. Furthermore, this review highlights the potential for further exploration in the development of novel nanomaterials that enhance the synergistic effect with HIFU on tumor ablation.

The association and application of sonodynamic therapy and autophagy in diseases.

Sonodynamic therapy (SDT) is a new non-invasive treatment method proposed based on photodynamic therapy (PDT). It has advantages such as high precision, strong tissue penetration, minimal side effects, and good patient compliance. With the maturation of nanomedicine, the application of nanosonosensitizers has further propelled the development of SDT. In recent years, people have developed many new types of sonosensitizers and explored the mechanisms of SDT. Among them, the studies about the relationship between autophagy and SDT have attracted increasing attention. After the SDT, cells usually undergo autophagy as a self-protective mechanism to resist external stimuli and reduce cell damage, which is beneficial for the treatment of atherosclerosis (AS), diabetes, and myocardial infarction but counterproductive in cancer treatment. However, under certain treatment conditions, excessive upregulation of autophagy can also promote cell death, which is beneficial for cancer treatment. This article reviews the latest research progress on the relationship between SDT and autophagy in cancers, AS, diabetes, and myocardial infarction. We also discuss and propose the challenges and prospects in enhancing SDT efficacy by regulating autophagy, with the hope of promoting the development of this promising therapeutic approach.

Pectic oligosaccharides ameliorate high-fat diet-induced obesity and hepatic steatosis in association with modulating gut microbiota in mice.

Accumulating evidence has shown that gut microbiota and its metabolites have important significance in the etiology of obesity and related disorders. Prebiotics prevent and alleviate obesity by modulating the gut microbiota. However, how pectin oligosaccharides (POS) derived from pectin degradation affect gut microbiota and obesity remains unclear. To investigate the potential anti-obesity effects of POS, mice were fed a high-fat diet (HFD) for 12 weeks and a POS supplement with drinking water during the last 8 weeks. The outcomes demonstrated that POS supplementation in HFD-fed mice decreased body weight (P < 0.01), improved glucose tolerance (P < 0.001), reduced fat accumulation (P < 0.0001) and hepatic steatosis, protected intestinal barrier, and reduced pro-inflammatory cytokine levels. After fecal metagenomic sequencing, the POS corrected the gut microbiota dysbiosis caused by the HFD, as shown by the increased populations of Bifidobacterium, Lactobacillus taiwanensis, and Bifidobacterium animalis, and decreased populations of Alistipes and Erysipelatoclostridium, which were previously considered harmful bacteria. Notably, the changed gut microbiota was associated with the obesity prevention of POS. These findings demonstrate that POS regulates particular gut microbiota, which is essential owing to its ability to prevent disorders associated with obesity.

The function of human milk oligosaccharides and their substitute oligosaccharides as probiotics in gut inflammation.

Gut inflammation seriously affects the healthy life of patients, and has a trend of increasing incidence rate. However, the current methods for treating gut inflammation are limited to surgery and drugs, which can cause irreversible damage to patients, especially infants. As natural oligosaccharides in human breast milk, human milk oligosaccharides (HMOs) function as probiotics in treating and preventing gut inflammation: improving the abundance of the gut microbiota, increasing the gut barrier function, and reducing the gut inflammatory reaction. Meanwhile, due to the complexity and high cost of their synthesis, people are searching for functional oligosaccharides that can replace HMOs as a food additive in infants milk powder and adjuvant therapy for chronic inflammation. The purpose of this review is to summarize the therapeutic and preventive effects of HMOs and their substitute functional oligosaccharides as probiotics in gut inflammation, and to summarize the prospect of their application in infant breast milk replacement in the future.

Polysaccharides from Paecilomyces hepiali Prevent Acute Colitis in Association with Modulating Gut Microbiota and Treg/Th17 Immune Balance in Mice.

Cordyceps exopolysaccharide (CEP) has shown emerging potential in adjustment of gut microbiota and immune cell function. In this study, a water-soluble CEP with a molecular weight of 58.14 kDa was extracted from the fermentation broth of Paecilomyces hepiali, an endophytic fungus of Cordyceps sinensis. Our results indicated that Paecilomyces hepiali polysaccharide (PHP) showed significantly preventive potential on dextran sulfate sodium (DSS)-induced colitis in mice, which can prevent colon shortening, reduce intestinal epithelial cell (IEC) destruction, suppress inflammatory cell infiltration, and regulate the balance between regulatory T (Treg) cells and T helper type 17 (Th17) cells. Meanwhile, the disturbed gut microbiota was partially restored after PHP treatment. Further Pearson correlation coefficient analyses exhibited that the alteration of the gut microbiota was significantly related to adjustment of the IEC barrier and Treg/Th17 balance. In conclusion, all findings proposed that purified PHP has the potential to develop into a promising agent for colitis prevention and adjuvant therapy via maintaining intestinal homeostasis of gut microbiota and immune system.

Co-delivery of doxorubicin and hydroxychloroquine via chitosan/alginate nanoparticles for blocking autophagy and enhancing chemotherapy in breast cancer therapy.

Breast cancer (BC) is the most common malignancy in women worldwide, and the standard treatment is chemotherapy or radiotherapy after surgery. In order to reduce the side effects of chemotherapy, various nanoparticles (NPs) have been discovered and synthesized, which has become a promising treatment for BC. In this study, a co-delivery nanodelivery drug system (Co-NDDS) was designed and synthesized with 2,3-dimercaptosuccinic acid (DMSA) coated Fe3O4 NPs as core encapsulated into chitosan/alginate nanoparticles (CANPs) shell, doxorubicin (DOX) and hydroxychloroquine (HCQ) as loading drugs. Smaller NPs carrying DOX (FeAC-DOX NPs) were loaded into larger NPs containing HCQ (FeAC-DOX@PC-HCQ NPs) by ionic gelation and emulsifying solvent volatilization methods. The physicochemical properties of this Co-NDDS were characterised, followed by in vitro studies of the anticancer effects and mechanisms using two different BC cell lines, MCF-7 cells and MDA-MB-231 cells. The results indicated that the Co-NDDS showcases exemplary physicochemical qualities and encapsulation capacity, facilitating accurate intracellular release through pH-sensitive attributes. Importantly, NPs can significantly increase the in vitro cytotoxicity of co-administered drugs and effectively inhibit the autophagy level of tumour cells. The Co-NDDS constructed in this study provides a promising strategy for the treatment of BC.

Lactate regulators contribute to tumor microenvironment and predict prognosis in lung adenocarcinoma.

Background: Lactic acid, as a product of glycolysis, increases tumor cell migration and the invasion of tumor cells in the tumor microenvironment. Besides this, lactic acid promotes the expression of programmed death-1 expression (PD-1) in regulatory T cells, which could cause the failure of PD-1 blockade therapy. However, the implications of lactic acid in the tumor microenvironment of lung adenocarcinoma (LUAD) remain largely unclear. Methods: We performed unsupervised consensus clustering to identify lactic-associated subtypes using expression profile of lactate regulators in LUAD. Differentially expressed genes (DEGs) associated with lactic-associated subtypes was used to construct lactate signature (LaSig) using LASSO regression algorithm. Immune infiltration analysis was conducted by ESTIMATER and drug sensitivity was estimated by R package called "pRRophetic". The difference between two groups was calculated using Wilcox rank sum test and correlation analysis was calculated using Pearson correlation coefficient. Results: In this study, we evaluated DNA methylation and the mutation frequency of lactate regulators and found lactate regulators showed low mutation frequency in the TCGA-LUAD cohort, except TP53. At the RNA level, the expression level of lactate regulators was significantly associated with the immune cell component. In particular, expression of LDHA was positively correlated with CD4 T cell, CD8 T cell, M1 macrophages, and the enrichment score of multiple immune pathways. Two clusters were defined using the gene expression level of lactate regulators, and LDHA was significantly upregulated in cluster 1 with poor overall survival. A lactate signature (LaSig) had a robust performance in predicting the survival rate and immunotherapy response of LUAD patients. Moreover, patients in the high LaSig group may be more likely to benefit from these drugs (Cisplatin, Erlotinib, Gemcitabine, and Vinblastine) than those in the low LaSig group. Conclusion: In summary, our study explores the role of lactate regulators in guiding the clinical treatment of lung adenocarcinoma and provides additional help to supplement traditional molecular subtypes.

Algal polysaccharides and derivatives as potential therapeutics for obesity and related metabolic diseases.

The worldwide upward trend in obesity has been dramatic, but there is a lack of effective and safe drug treatment. Marine-derived algal polysaccharides, including fucoidan, alginate, polysaccharide of Spirulina platensis (PSP), ulvan, rhamnan sulfate (RS), laminarin, agar, and carrageenan, are widely used in combination with wound healing, drug delivery, and tissue-related biomedical research engineering. Recently, the prebiotic effects of algal polysaccharides and their related derivatives have received more and more attention. In this review, we discuss the potential and challenges of algal polysaccharides and their derivatives as potential therapeutic agents for obesity and its related metabolic diseases. Relevant studies have demonstrated that a variety of algal polysaccharides can play a significant role in weight loss and treatment of obesity-related metabolic diseases by improving the composition of gut microbiota, promoting bile acid formation, and upregulating cholesterol receptors in the liver. Because of their low price, non-toxic properties, and easy availability, algal polysaccharides have the potential to be developed as weight loss products.

Identification and exploration of pharmacological pyroptosis-related biomarkers of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Its etiology is unclear. Much evidence suggests that the death of abnormal intestinal epithelial cells (IECs) leads to intestinal barrier disruption, and the subsequent inflammatory response plays a vital role in UC. Pyroptosis is a form of programmed inflammatory cell death, and the role of pyroptosis in UC etiology remains to be explored. This study identified 10 hub genes in pyroptosis by gene expression profiles obtained from the GSE87466 dataset. Meanwhile, the biomarkers were screened based on gene significance (GS) and module membership (MM) through the Weighted Gene Co-Expression Network Analysis (WGCNA). The following analysis indicated that hub genes were closely associated with the UC progression and therapeutic drug response. The single-cell RNA (scRNA) sequencing data from UC patients within the GSE162335 dataset indicated that macrophages were most related to pyroptosis. Finally, the expression of hub genes and response to the therapeutic drug [5-aminosalicylic acid (5-ASA)] were verified in dextran sulfate sodium (DSS)-induced colitis mice. Our study identified IL1B as the critical pyroptosis-related biomarker in UC. The crosstalk between macrophage pyroptosis and IEC pyroptosis may play an essential role in UC, deserving further exploration.

Collagen peptide promotes DSS-induced colitis by disturbing gut microbiota and regulation of macrophage polarization.

Ulcerative colitis (UC) is an inflammatory bowel disease caused by mucosal immune system disorder, which has increased steadily all over the world. Previous studies have shown that collagen peptide (CP) has various beneficial biological activities, it is not clear whether the effect of CP on UC is positive or negative. In this study, 2.5% dextran sulfate sodium (DSS) was used to establish acute colitis in mice. Our results suggested that CP supplementation (200, 400 mg/kg/day) promoted the progression of colitis, increased the expression of inflammatory factors and the infiltration of colonic lamina propria macrophages. Gut microbiota analysis showed the composition changed significantly and inflammation promoted bacteria was after CP treatment. Meanwhile, the effect of CP on macrophage polarization was further determined in Raw264.7 cell line. The results showed that CP treatment could increase the polarization of M1 macrophages and promote the expression of inflammatory factors. In conclusion, our results showed that CP treatment could disrupt the gut microbiota of host, promote macrophage activation and aggravate DSS-induced colitis. This may suggest that patients with intestinal inflammation should not take marine derived CP.

Preventive effect of pectic oligosaccharides on acute colitis model mice: modulating epithelial barrier, gut microbiota and Treg/Th17 balance.

Pectin as a dietary fiber supplement has shown emerging potential in clinical ulcerative colitis (UC) adjuvant therapy. In this study, the preventive and prebiotic effects of enzymatically degraded pectic oligosaccharides (POS) were further explored in dextran sodium sulfate (DSS)-induced colitis mice. The POS supplement (400 mg kg-1) was significantly effective at improving preventive efficacy, promoting colonic epithelial barrier integrity and reducing inflammatory cytokines. Meanwhile, the changes in T regulatory (Treg) cells and T helper 17 (Th17) cells indicated that POS treatment regulated the Treg/Th17 balance. Gut microbiota analysis showed that the POS supplement reshaped the dysfunctional gut microbiota. Further Spearman's correlation coefficient analysis indicated that the changes of the gut microbiota were highly associated with modulating the epithelial barrier, promoting the development of Treg cells and suppressing the differentiation of pro-inflammatory Th17 cells. All of these results suggest that enzymatically- degraded POS is a promising therapeutic agent for UC prevention and adjuvant treatment by maintaining intestinal homeostasis.

Isomaltulose alleviates acute colitis via modulating gut microbiota and the Treg/Th17 balance in mice.

Food-grade isomaltulose exhibits significant modulation of gut microbiota and its metabolites in healthy populations. This study further explored the preventive therapeutic effect and anti-colitis potential of isomaltulose on dextran sulfate sodium-induced colitis in mice. Our results suggested that isomaltulose played a significant role in preventing colon shortening, reducing intestinal epithelial destruction and inhibiting inflammatory cell infiltration. Meanwhile, the isomaltulose supplement greatly reduced the production of pro-inflammatory cytokines and restored the balance between T helper type 17 (Th17) cells and regulatory T (Treg) cells. Pathway enrichment analysis for differentially expressed genes (DEGs) also indicated that the anti-inflammatory effect of isomaltulose was closely related to intestinal immunity. Moreover, the disturbed gut microbiota in ulcerative colitis (UC) was partially restored after treatment with isomaltulose. These results suggest that isomaltulose is a promising therapeutic agent for the prevention and adjunctive treatment of UC by maintaining intestinal immune homeostasis and remodeling the gut microbiota.

The role of functional oligosaccharides as prebiotics in ulcerative colitis.

The incidence rate of ulcerative colitis (UC) has increased significantly over the past decades and it places an increasing burden on health and social systems. The current studies on UC implicate a strong correlation between host gut microbiota immunity and the pathogenesis of UC. Meanwhile, more and more functional oligosaccharides have been reported as prebiotics to alleviate UC, since many of them can be metabolized by gut microbiota to produce short-chain fatty acids (SCFAs). The present review is focused on the structure, sources and specific applications of various functional oligosaccharides related to the prevention and treatment of UC. The available evidence for the usage of functional oligosaccharides in UC treatment are summarized, including fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), chito-oligosaccharides (COS), alginate-oligosaccharides (AOS), xylooligosaccharides (XOS), stachyose and inulin.

Application of chitosan/alginate nanoparticle in oral drug delivery systems: prospects and challenges.

Oral drug delivery systems (ODDSs) have various advantages of simple operation and few side effects. ODDSs are highly desirable for colon-targeted therapy (e.g. ulcerative colitis and colorectal cancer), as they improve therapeutic efficiency and reduce systemic toxicity. Chitosan/alginate nanoparticles (CANPs) show strong electrostatic interaction between the carboxyl group of alginates and the amino group of chitosan which leads to shrinkage and gel formation at low pH, thereby protecting the drugs from the gastrointestinal tract (GIT) and aggressive gastric environment. Meanwhile, CANPs as biocompatible polymer, show intestinal mucosal adhesion, which could extend the retention time of drugs on inflammatory sites. Recently, CANPs have attracted increasing interest as colon-targeted oral drug delivery system for intestinal diseases. The purpose of this review is to summarize the application and treatment of CANPs in intestinal diseases and insulin delivery. And then provide a future perspective of the potential and development direction of CANPs as colon-targeted ODDSs.

Characterization and Application of a New ß-Galactosidase Gal42 From Marine Bacterium Bacillus sp. BY02.

ß-Galactosidase plays an important role in medicine and dairy industry. In this study, a new glycoside hydrolase family 42 (GH42) ß-galactosidase-encoding gene, gal42, was cloned from a newly isolated marine bacterium Bacillus sp. BY02 and expressed in Escherichia coli. Structural characterization indicated that the encoding ß-galactosidase, Gal42, is a homotrimer in solution, and homology modeling indicated that it retains the zinc binding sites of the Cys cluster. The reaction activity of Gal42 was significantly increased by Zn2+ (229.6%) and other divalent metal ions (Mn2+, Mg2+, and Co2+), while its activity was inhibited by EDTA (53.9%). Meanwhile, the thermo-stability of the Gal42 was also significantly enhanced by 5 and 10 mM of zinc ion supplement, which suggested that the "Cys-Zn" motif played important roles in both structural stability and catalytic function. Furthermore, Gal42 showed effective lactose hydrolysis activity, which makes the enzyme hydrolyze the lactose in milk effectively. These properties make Gal42 a potential candidate in food technology.

Preparation of MSZ Hydrogel and Its Treatment of Colitis.

In order to control the release of mesalazine (MSZ) in the gastrointestinal tract to achieve better pharmacological effects in the colon, in this study, MSZ was added to hydroxypropyl-ß-cyclodextrin (HP-ß-CD) to form a water-soluble HP-ß-CD/MSZ inclusion complex. Then, the inclusion compound was loaded into the structure of the bilayer polyelectrolyte complex microsphere formed by alginate (Alg), chitosan (Cs), and kappa carrageenan (κ-Car) as the hydrogel carrier, and the hydrogel beads with colon-specific release MSZ after oral administration were formed. The formed hydrogel beads have different swelling capabilities in different pH media and have the greatest swelling degree under pH 7.4. The encapsulation efficiency and drug loading of hydrogel beads can reach up to 83.23 and 18.31%, respectively, and the size of hydrogel beads can be reduced to less than 1 mm after drying, so that the size of oral administration can be reached. In vivo experiments also showed that the formed hydrogel beads had a better therapeutic effect on colitis than free drugs, and the microspheres were biodegradable, so the double-layer pH-sensitive microspheres could be effectively used in colon-targeting drug delivery.

Preventive and Prebiotic Effect of α-Galacto-Oligosaccharide against Dextran Sodium Sulfate-Induced Colitis and Gut Microbiota Dysbiosis in Mice.

ß-Galacto-oligosaccharide (ß-GOS) showed great potential in ulcerative colitis (UC) adjuvant therapy. Herein, the preventive and prebiotic effect of enzymatic-synthesized α-linked galacto-oligosaccharide (α-GOS) was investigated in dextran sodium sulfate-induced colitis and gut microbiota dysbiosis mice. Compared with ß-GOS, the α-GOS supplement was more effective in improving preventive efficacy, promoting colonic epithelial barrier integrity, and alleviating inflammation cytokines. Moreover, the activation of the NOD-like receptor (NLR) family member NLRP3 inflammasome-mediated inflammation was significantly inhibited by both α-GOS and ß-GOS. Gut microbiota analysis showed that α-GOS treatment reshaped the dysfunctional gut microbiota. The subsequent Spearman's correlation coefficient analysis indicated that these gut microbiota changes were significantly correlated with the inflammatory parameters. These results suggested that the enzymatic-synthesized α-GOS is a promising therapeutic agent in UC prevention and adjuvant treatment by maintaining intestinal homeostasis.

Construction of Chitosan/Alginate Nano-Drug Delivery System for Improving Dextran Sodium Sulfate-Induced Colitis in Mice.

(1) Background: In the treatment of ulcerative colitis (UC), accurate delivery and release of anti-inflammatory drugs to the site of inflammation can reduce systemic side effects. (2) Methods: We took advantage of this goal to prepare resveratrol-loaded PLGA nanoparticles (RES-PCAC-NPs) by emulsification solvent volatilization. After layer-by-layer self-assembly technology, we deposited chitosan and alginate to form a three-layer polyelectrolyte film. (3) Results: It can transport nanoparticles through the gastric environment to target inflammation sites and slowly release drugs at a specific pH. The resulting RES-PCAC-NPs have an ideal average diameter (~255 nm), a narrow particle size distribution and a positively charged surface charge (~13.5 mV). The Fourier transform infrared spectroscopy showed that resveratrol was successfully encapsulated into PCAC nanoparticles, and the encapsulation efficiency reached 87.26%. In addition, fluorescence imaging showed that RES-PCAC-NPs with positive charges on the surface can effectively target and accumulate in the inflammation site while continuing to penetrate downward to promote mucosal healing. Importantly, oral RES-PCAC-NPs treatment in DSS-induced mice was superior to other results in significantly improved inflammatory markers of UC. (4) Conclusions: Our results strongly prove that RES-PCAC-NPs can target the inflamed colon for maximum efficacy, and this oral pharmaceutical formulation can represent a promising formulation in the treatment of UC.