International Journal of Pharmaceutics-X
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2025
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IF 6.4
Jie-Zhou,Tian-Le Li,Bo-Wei,Yue-Feng Ruan,Ye-Qin Wang,Jiao-Yan Liu,Meng-Meng Song,Yu-Xian Shen
Midbrain astrocyte-derived neurotrophic factor (MANF) is a secreted protein induced by endoplasmic reticulum stress. Previous studies have indicated that intravenous administration of 1 mg/kg/day recombinant human MANF protein with His tag (His-MANF) for 3 days can ameliorate acute ulcerative colitis in mice. However, long-term intravenous therapy has many disadvantages. In this paper, His-MANF protein was successfully encapsulated into alginate and hyaluronic acid hybrid hydrogel microcapsules in one step using the gas shear method and then coated by Eudragit S100 to construct an oral colon-targeted delivery system (MSH@E). The MSH@E microcapsules exhibited controlled and sustained release behavior and colon-targeting properties. Both fluorescent imaging and immunohistochemistry staining results showed that His-MANF protein could accumulate in the colitis colon for a longer residence time after oral delivery. In vivo studies demonstrated that oral administration of MSH@E microcapsules could alleviate DSS-induced colitis in mice without systemic toxicity. Importantly, even if the oral His-MANF dose was half of the intravenous His-MANF dose, oral delivery was still much more effective than intravenous injection, suggesting the development of the oral colon-targeted delivery system (MSH@E) has great significance and makes a breakthrough from intravenous to oral administration for His-MANF treatment of ulcerative colitis (UC).
研究领域:
药剂学
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胃肠病学
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 5
·2561-2574
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IF 2.936
Yan Yan,Jinyao Sun,Xianting Xie,Pengchong Wang,Ying Sun,Yalin Dong,Jianfeng Xing
The aim of this study was to design and synthesize four colon-targeting mutual prodrugs of 5-aminosalicylic acid (5-ASA) and butyrate, and evaluate their therapeutic effects on ulcerative colitis. Herein, 5-ASB, 5-ASDB, Ols-DB and Ols-DBP were prepared and characterized, and their lipophilicity, solubility, in vitro and in vivo stability were investigated. Finally, the ameliorative effects of the prodrugs on experimental colitis were evaluated via a series of indicators, including the body weight and survival rates of mice, the colon index and colonic damage score, the disease activity index, the myeloperoxidase activity and levels of superoxide dismutase, malondialdehyde, glutathione and glutathione peroxidase in colonic tissues. As a result, 5-ASB was very stable but Ols-DB showed extreme instability in the environment of the gastrointestinal tract, while 5-ASDB and Ols-DBP showed desirable colon-targeting properties. The four prodrugs all had certain therapeutic effects on the experimental colitis. When orally administered to mice, 5-ASDB and Ols-DBP had significantly greater effects than the mixture of 5-ASA and sodium butyrate. Ols-DB was used as an enema and could be as effective as 5-ASDB and Ols-DBP. In addition, the therapeutic effects of the synthesized prodrugs might be associated with their anti-oxidative damage ability.
研究领域:
药理学
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消化系统疾病
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2016
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IF 4.843
Aiguo Zeng,Kai Dong,Maoling Wang,Jinyao Sun,Yalin Dong,Ke Wang,Chenning Guo,Yan Yan,Lu Zhang,Xianpeng Shi,Jianfeng Xing
Context: Dexamethasone is the major drug in the treatment of ulcerative colitis (UC). However, the extensive or long-time use of dexamethasone causes many toxic side-effects. Ion exchange resins react with external-ions through their own functional groups and Eudragit S occurs degradation when pH > 7. These features make them suitable for oral delivery system.Objective: Resin microcapsule (DRM) composed by 717 anion exchange resin and Eudragit S100 was used to target dexamethasone to the colon to improve its treatment effect on UC and reduce its toxic side-effects.Results: Dexamethasone sodium phosphate (DXSP) was sequentially encapsulated in 717 anion-exchange resin and Eudragit S100 to prepare the DXSP-loaded resin microcapsule (DXSP-DRM). The in vitro release study and in vivo study of pharmacokinetics and the intestinal drug residues in rat demonstrated the good colon-targeting of DXSP-DRM. Moreover, the DXSP-DRM can reduce the toxic side-effects induced by DXSP and have good therapeutic effects on colitis mouse induced by 2,4,6-trinitrobenzenesulfonic acid.Discussion: Dexamethasone can be targeted to the colon by DRM, thereby enhancing its treatment effect and reducing its toxic side effects.Conclusion: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeted preparations.
研究领域:
药理学
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药物递送系统
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炎症性肠病
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 10
·4299-4309
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IF 5.251
Ya Wu,Minghui Sun,Dan Wang,Genyun Li,Jiangeng Huang,Songwei Tan,Lin Bao,Qian Li,Gao Li,Luqin Si
To effectively alleviate acute severe ulcerative colitis (ASUC), we developed a colon-specific delivery system—PLGA–KPV/MMT/CS multifunctional medicinal nanoparticles loaded with cyclosporine A (CyA). The lysine–proline–valine (KPV) tripeptide, which possesses anti-inflammatory properties and high affinity to peptide transporter 1 (PepT1), can target therapy-related cells (colonic epithelial cells and macrophages) via overexpression of PepT1. Montmorillonite (MMT)/chitosan (CS) coating can reduce CyA leakage in the upper gastrointestinal tract (GIT) and enhance nanoparticle adhesion to the inflamed colon. The bio-distribution demonstrated that nanoparticles can specifically accumulate in the inflamed tissues and can be retained for up to 36 h. After being treated with the CyA–PLGA–KPV/MMT/CS nanoparticles (PKMCN), the mice with DSS-induced ulcerative colitis exhibited significant improvements in body weight, colon length, and disease activity index. Moreover, biochemistry and immunohistochemical analysis showed that the PKMCN treatment group performed as well as the healthy group. Intriguingly, PKMCN without CyA also presented marked therapeutic effects. Our results suggested that PKMCN could be a promising drug delivery system for ASUC therapy by targeting inflamed cells, prolonging curative time, and mitigating colitis.
研究领域:
药学
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胃肠病学
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纳米医学
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炎症性肠病
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2025
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IF 5.9
Sitong Ma,Jingbo Liu,Yajuan Li,Yingying Liu,Shanglin Li,Yang Liu,Ting Zhang,Meng Yang,Chunmei Liu,Zhiyang Du
Oral co-delivery of nutraceuticals at colon sites has been considered the preferable strategy for targeted ulcerative colitis (UC) relief. This study aimed to develop oral colon-targeting nanoparticles (NPs) co-loaded with egg white-derived peptides (EWDP) and hydrophobic quercetin (Que) using Zein/chondroitin sulfate (CS) templates. The fabricated NPs showed excellent pH-sensitive size tunability (488.0–128.6 nm) and Que co-encapsulation efficiency (99.3%, pH 7.0), owing to the EWDP co-assembly with templates driven by three main noncovalent interactions (hydrogen bonding, electrostatic and hydrophobic interaction). Notably, the less active EWDP could act as the promising co-assembly enhancers and excipient analogs to sufficiently exert the preferable oral synergism (e.g., antioxidant and anti-inflammatory) of the two nutraceuticals, mainly through enhancing its aqueous solubility, controlled release, and transport stability of Que (>20%) under gastrointestinal conditions. Moreover, EWDP could jointly co-assembly with active targeting biopolymers (e.g., CS) to induce the superior colon-targeted accumulation of NPs, thereby dramatically repairing intestinal barriers (tight junction and mucus layer) and restoring gut microbiota balance (e.g., enriching Lachnospiraceae and eliminating Bacteroidota ). Overall, this study provides a facile and efficient orally colon-targeted nano-strategy for multiple nutraceuticals in precise UC mitigation. Meanwhile, the co-assembly profiles of EWDP could offer an insightful and widely applicable insight into the ingenious formulation of biopolymer nanoplatforms (active targeting or passive targeting) in food processing and healthcare areas.
研究领域:
食品科学
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生物医学工程
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药剂学
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产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Yajie Cai,Bing Xu,Fei Zhou,Jianzhi Wu,Shuo Li,Qi Zheng,Yajing Li,Xiaojiaoyang Li,Feng Gao,Shifen Dong,Runping Liu
Background Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that markedly elevates the risk of colon cancers and results in disability. The disrupted immune homeostasis has been recognized as a predominant player in the pathogenesis of UC. However, the overall remission rate of current therapies based on immunoregulation is still unsatisfactory. Si-Ni-San (SNS) has been found effective in relieving UC through thousands of years of clinical practice, yet the specific mechanisms of the protective effect of SNS were not fully elucidated. Purpose We aim to investigate the therapeutic effects of SNS against the development of chronic colitis and the underlying mechanisms. Methods We established a DSS-induced chronic experimental colitis mouse model to evaluate the effect of SNS. RNA-sequencing, bioinformatic analysis, and in vitro studies were performed to investigate the underlying mechanisms. Results Our data demonstrated that SNS significantly ameliorated chronic experimental colitis via inhibiting the expression of genes associated with inflammatory responses. Interestingly, SNS significantly suppressed DSS-induced type I interferon (IFN) responses instead of directly downregulating the production of pro-inflammatory cytokines, such as Il-6. In vitro study further found that SNS selectively inhibited STING and RIG-I pathway-induced type I IFN responses by modulating TBK1- and IRF3-dependent signaling transduction. SNS also suppressed the expression of IFN-stimulated genes by directly inhibiting STAT1 and STAT2 activation. Conclusion Our study not only provides novel insights into the pathogenic role of type I IFN responses in colitis but also suggested that SNS or bioactive compounds derived from SNS may serve as novel therapeutic strategies for the treatment of UC via interfering type I IFN-mediated inflammation.
研究领域:
药理学
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免疫学
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胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
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IF 8.5
Yingjie Geng,Yuan Li,Haolong Qi,Jianguo Gao,Yanqing Wu,Xiaoqing Cai
Mesalazine (MSZ), a first-line treatment for ulcerative colitis (UC), was formulated into acid-resistant, colon-targeted gel microspheres to reduce upper gastrointestinal tract (GIT) exposure and extend drug retention in the colon. In this study, we used MSZ/hydroxypropyl-β-cyclodextrin (MSZ/HP-β-CD) as the model drug, dopamine-modified sodium alginate (DA-SA) and konjac glucomannan (KGM) as the carrier matrix, and chitosan (CS) as the coating material. The colon-targeted gel microspheres (MSZ/HP-β-CD/DA-SA/KGM/CS) were prepared using the drop method. These microspheres had a drug loading capacity of 7.9 ± 0.01 % and an encapsulation efficiency of 72.5 ± 0.03 %. The drug primarily released in the colon environment, showing pH and β-mannanase sensitivity. The dried microspheres measured approximately 0.6 mm, suitable for oral administration. In the rat UC model, after oral administration of gel microspheres, the colon length increased, while the DAI score, spleen index, and the expression levels of IL-6, IL-1β, TNF-α, TLR4, MyD88 and NF-κB p65 all decreased. Histopathological examination showed that treated UC rats' colon tissues closely resembled those of healthy controls. These findings indicate that pH-enzyme-responsive coated gel microspheres can effectively target the colon and show potential for UC treatment.
研究领域:
药剂学
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消化病学
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生物医学工程
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Zhiran Ju,Junde Xu,Keshuang Tang,Fener Chen
COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a - 4w , triazoles 6a - 6m , and cyclic imides 7a and 7b , were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC 50 = 1.53 μM; selectivity ((IC 50 (COX-1)/IC 50 (COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects.
研究领域:
药理学
·
药物化学
·
炎症研究
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
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IF 4.319
Yiting Luo,Jin Wu,Yingchao Liu,Yan Shen,Fangyuan Zhu,Jiaqian Wu,Yuyao Hu
Purpose Shaoyao decoction (SYD) is a traditional Chinese medicine used to treat ulcerative colitis (UC). The exact mechanism of action of SYD in UC treatment is still unclear. Here, we examined the therapeutic effects of SYD in mice with dextran sulfate sodium (DSS)-induced colitis and explored the underlying mechanism. Methods The experimental group was divided into normal control, UC, and SYD treatment groups. The UC model of C57BL/6 mice was induced using 3% (w/v) DSS for 7 days. SYD was orally administered for 7 days. The proximal and distal colonic metabolic profiles were detected using quadrupole-time-of-flight mass spectrometry-based untargeted metabolomics. Results SYD significantly increased weight, reduced disease activity index scores, and ameliorated colon length shortening and pathological damage in mice. In the distal colon, SYD increased the abundance of phosphatidic acid and lysophosphatidylethanolamine and decreased the abundance of lactosylceramide, erythrodiol 3-palmitate, and lysophosphatidylcholine. In the proximal colon, SYD increased the abundance of palmitic acid, cyclonormammein, monoacylglyceride, 13S-hydroxyoctadecadienoic acid, and ceanothine C and decreased the abundance of tetracosahexaenoic acid, phosphatidylserine, and diglyceride. Conclusion Our findings revealed that SYD could alleviate UC by regulating metabolic dysfunction, which provides a reference for further studies on SYD.
研究领域:
中药学
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代谢组学
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消化系统疾病
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2016
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IF 6.008
Zhen-Gang Ma,Rui Ma,Xiao-Lin Xiao,Yong-Hui Zhang,Xin-Zi Zhang,Nan Hu,Jin-Lai Gao,Yu-Feng Zheng,De-Li Dong,Zhi-Jie Sun
Colon-targeted drug delivery and circumventing drug resistance are extremely important for colon cancer chemotherapy. Our previous work found that dimethyl fumarate (DMF), the approved drug by the FDA for the treatment of multiple sclerosis, exhibited anti-tumor activity on colon cancer cells. Based on the pharmacological properties of DMF and azo bond in olsalazine chemical structure , we designed azo polymeric micelles for colon-targeted dimethyl fumarate delivery for colon cancer therapy. We synthesized the star-shape amphiphilic polymer with azo bond and fabricated the DMF-loaded azo polymeric micelles. The four-arm polymer star-PCL-azo-mPEG (sPCEG-azo) (constituted by star-shape PCL (polycaprolactone) and mPEG (methoxypolyethylene glycols)-olsalazine) showed self-assembly ability. The average diameter and polydispersity index of the DMF-loaded sPCEG-azo polymeric micelles were 153.6 nm and 0.195, respectively. In vitro drug release study showed that the cumulative release of DMF from the DMF-loaded sPCEG-azo polymeric micelles was no more than 20% in rat gastric fluid within 10 h, whereas in the rat colonic fluids, the cumulative release of DMF reached 60% in the initial 2 h and 100% within 10 h, indicating that the DMF-loaded sPCEG-azo polymeric micelles had excellent colon-targeted property. The DMF-loaded sPCEG-azo polymeric micelles had no significant cytotoxicity on colon cancer cells in phosphate buffered solution (PBS) and rat gastric fluid. In rat colonic fluid, the micelles showed significant cytotoxic effect on colon cancer cells. The blank sPCEG-azo polymeric micelles (without DMF) showed no cytotoxic effect on colon cancer cells in rat colonic fluids. In conclusion, the DMF-loaded sPCEG-azo polymeric micelles show colon-targeted DMF release and anti-tumor activity, providing a novel approach potential for colon cancer therapy. Statement of Significance Colon-targeted drug delivery and circumventing drug resistance are extremely important for colon cancer chemotherapy. Our previous work found that dimethyl fumarate (DMF), the approved drug by the FDA for the treatment of multiple sclerosis, exhibited anti-tumor activities on colon cancer cells ( Br J Pharmacol . 2015 172 ( 15 ): 3929-43 .). Based on the pharmacological properties of DMF and azo bond in olsalazine chemical structure, we designed azo polymeric micelles for colon-targeted dimethyl fumarate delivery for colon cancer therapy. We found that the DMF-loaded sPCEG-azo polymeric micelles showed colon-targeted DMF release and anti-tumor activities, providing a novel approach potential for colon cancer therapy.
研究领域:
药理学
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肿瘤学
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生物材料
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
·
IF 3.8
Jiaxi Chen,Mengyue Pan,Jingjie Wang,Mengling Zhang,Mingmei Feng,Xiaoming Chai,Qi Zhang,Yang Sun
Hydroxysafflor yellow A (HSYA), a chalcone glycoside, is a component of Carthamus tinctorius L. and exerts anti-inflammatory and antioxidative effects. However, the therapeutic effect and the underlying mechanism of HSYA on ulcerative colitis is unclear. This study aimed to investigate the unexplored protective effects and underlying mechanisms of HSYA on UC. In vitro analyses showed that HSYA reduced the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 and inhibited nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD)-mediated pyroptosis in lipopolysaccharide/ adenosine-5′-triphosphate (LPS/ATP)-stimulated macrophages. Gas chromatography–mass spectrometry (GC–MS) profiling of intracellular metabolites showed that HSYA reduced the increased levels of glucose, glucose 6-phosphate, and lactic acid, and inhibited the increased hexokinase 1 (HK1) expression caused by LPS/ATP stimulation. HK1 shRNA transfection further confirmed that HSYA inhibited the NLRP3/GSDMD-mediated pyroptosis via HK1 downregulation. In vivo analyses showed that HSYA drastically attenuated UC symptoms by relieving body weight loss, a decline in colon length, and inflammatory infiltration in colonic tissues induced by dextran sulfate sodium (DSS). HSYA also reduced the secretion of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IL-18. Moreover, HSYA inhibited HK1/NLRP3/GSDMD-mediated pyroptosis in DSS-induced colitis mice. Finally, 16S rRNA sequencing analyses of gut microbiota revealed that HSYA reversed gut microbiota dysbiosis by reducing the abundance of Proteobacteria and increasing that of Bacteroidetes. This study demonstrated that HSYA not only exerted anti-inflammatory effects by inhibiting HK1/NLRP3/GSDMD and suppressing pyroptosis but also regulated gut microbiota in mice with DSS-induced colitis. Our findings provide new experimental evidence that HSYA might be a potential candidate for treating inflammatory bowel diseases.
研究领域:
药理学
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免疫学
·
微生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
Cellular & Molecular Immunology
·
2023
·
IF 24.1
Luo Ya,Liu Cheng,Luo Yuan,Zhang Xianglian,Li Jing,Hu Changjiang,Yang Shiming
Thiostrepton (TST) is a natural antibiotic with pleiotropic properties. This study aimed to elucidate the therapeutic effect of TST on experimental colitis and identify its targets. The effect of TST on colon inflammation was evaluated in a dextran sulfate sodium (DSS)-induced colitis model and a T-cell transfer colitis model. The therapeutic targets of TST were investigated by cytokine profiling, immunophenotyping and biochemical approaches. The effect of TST on the gut microbiota and its contribution to colitis were evaluated in mice with DSS-induced colitis that were subjected to gut microbiota depletion and fecal microbiota transplantation (FMT). Alterations in the gut microbiota caused by TST were determined by 16S rDNA and metagenomic sequencing. Here, we showed that TST treatment significantly ameliorated colitis in the DSS-induced and T-cell transfer models. Specifically, TST targeted the retinoic acid-related orphan nuclear receptor RORγt to reduce the production of IL-17A by γδ T cells, type 3 innate lymphoid cells (ILC3s) and Th17 cells in mice with DSS-induced colitis. Similarly, TST selectively prevented the development of Th17 cells in the T-cell transfer colitis model and the differentiation of naïve CD4 + T cells into Th17 cells in vitro. Mechanistically, TST induced the ubiquitination and degradation of RORγt by promoting the binding of Itch to RORγt. Moreover, TST also reversed dysbiosis to control colonic inflammation. Taken together, these results from our study describe the previously unexplored role of TST in alleviating colonic inflammation by reducing IL-17A production and modulating dysbiosis, suggesting that TST is a promising candidate drug for the treatment of IBD.
研究领域:
免疫学
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胃肠病学
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微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）