FOOD RESEARCH INTERNATIONAL
·
2026
·
IF 8.8
Qiuyu Chen,Huadi Mei,Mengyao Fang,Yiyan Cui,Ting Rong,Dun Deng,Zhimei Tian,Min Song,Zhenming Li,Zhichang Liu,Xianyong Ma,Miao Yu
Intestinal barrier dysfunction can cause gastrointestinal diseases and retardation in both human infants and young animals. Quercetin, a natural flavonoid, exhibits diverse physiological activities such as anti-inflammatory and antioxidant effects and has demonstrated potential to enhance intestinal health. However, the exact underlying mechanisms linking quercetin with the intestinal barrier integrity remains unclear. Thus, this study aimed to evaluate whether and how quercetin can ameliorate intestinal barrier dysfunction in LPS-challenged weaned piglets and TNF-α challenged IPEC-J2 cells models. The results showed that quercetin supplementation significantly reduced serum, jejunal, and ileal mucosa TNF-α and IFN-γ concentrations in the LPS-challenged piglets ( P < 0.05). Quercetin also decreased crypt depth in jejunum and ileum ( P < 0.05), while significantly increasing the villus height:crypt depth ratio in the jejunum ( P < 0.05). Meanwhile, quercetin improved intestinal barrier function, as evidenced by decreased serum endotoxin levels and diamine oxidase activity ( P < 0.05) as well as up-regulated jejunal protein expression and immunofluorescence intensity of tight junction proteins (ZO-1, occludin, and claudin-1) ( P < 0.05), ileal occludin and claudin-1 protein expression ( P < 0.05). In vitro studies further revealed that quercetin pretreatment effectively ameliorated ( P < 0.05) TNF-α-induced intestinal barrier dysfunction by suppressing the key proteins expression in PKCα-/MLCK signaling pathway in IPEC-J2 cells. These findings indicated that quercetin ameliorates intestinal barrier dysfunction by upregulating the expression of tight junction proteins, potentially through the suppression of the PKCα/MLCK signaling pathway.
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高影响因子
Food & Function
·
2022
·Vol. 13
·期 8
·4562-4575
·
IF 6.317
Luqing Song,Tao Wu,Li Zhang,Jin Wan,Zheng Ruan
Phenolic acids play an active role in protecting the intestinal barrier, the structural integrity and function of which are crucial for host health. In the present study, we aimed to identify phenolic compounds that protect the intestine and explore the underlying mechanisms. We performed an imaging-based, quantitative, high-content screening (using Caco-2 and LS174T incubated with lipopolysaccharide/palmitic acid, respectively) to identify phenolic acids that could improve the mucosal barrier. We found that chlorogenic acid (CGA), 5-caffeoylquinic acid, protocatechuic acid, and caffeic acid alleviated intestinal barrier disruption. Furthermore, CGA increased transepithelial electrical resistance (TEER) and decreased paracellular permeability. Mechanistically, CGA inhibited the activation of myosin light chain kinase (MLCK) and Rho-associated kinase 1 (ROCK1) signals, thereby downregulating the expression of the downstream molecules phosphorylated myosin phosphatase target subunit 1 (p-MYPT1), MLCK, and phosphorylated myosin light chain (p-MLC), and upregulating the expression of tight junction proteins. In addition, CGA alleviated endoplasmic reticulum (ER) stress by inhibiting the expression levels of ER markers [glucose-regulated protein78 (GRP78) and C/EBP homologous protein (CHOP)] and the nuclear translocation of activating transcription factor 6 (ATF6), thereby promoting the expression of mucin [mucin 2 (Muc2), mucin 5AC (MUC5AC)] and secretory factor trefoil factor family 3 (TFF3) proteins. In summary, we identified four substances that can stabilise intestinal homeostasis. Of these, CGA protects the intestinal barrier by inhibiting ROCK/MLCK signalling pathways and relieving ER stress. These findings highlight the importance of rapidly screening potential active ingredients that benefit the intestinal barrier and provide a theoretical basis for enteral nutrition.
研究领域:
胃肠病学
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药理学
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细胞生物学
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PubMed
高影响因子
Biology-Basel
·
2025
·Vol. 14
·期 11
·1573
·
IF 3.5
Shize Zhang,Tian Cheng,Yuang Chen,Mengqin Wang,Guangji Wang,Jiye Aa
Based on emerging evidence linking vitamin homeostasis to inflammatory bowel disease, this study investigated the causal role and therapeutic potential of folate in ulcerative colitis. By employing Mendelian randomization and experimental models, we demonstrated that folate supplementation markedly attenuated colitis severity, suppressed inflammatory responses, and restored the structure and function of the epithelial barrier. Mechanistically, folate acts through inhibition of the PI3K/AKT/NF-κB/MLCK/MLC2 signaling axis, leading to improved barrier integrity and reduced mucosal inflammation. These findings establish folate not only as a protective nutrient but also as a potential therapeutic agent, supporting its use in clinical nutritional strategies for ulcerative colitis management. Vitamin homeostasis plays a critical role in inflammatory bowel disease management, yet the protective mechanisms and clinical utility of specific vitamins remain incompletely characterized. Within this context, a two-sample Mendelian randomization analysis leveraging genetic instruments for measuring circulating vitamin levels identified folate as a protective factor against ulcerative colitis (UC). To validate these findings, a DSS-induced colitis model was established with serial serum folate measurements. Therapeutic folate supplements were subsequently administered, followed by a comprehensive evaluation of epithelial barrier modulation through in vivo and recombinant TNF-α/IFN-γ-induced in vitro models. This included assessment of junctional proteins, ultrastructural analysis by transmission electron microscopy, and functional quantification of barrier integrity using transepithelial electrical resistance with paracellular permeability assays in epithelial monolayers. Molecular mechanisms were investigated through RNA sequencing complemented by immunoblot validation of key pathway components. The results demonstrated decreased serum folate levels in DSS-induced colitis mice, whereas folate supplementation ameliorated disease severity and attenuated intestinal inflammation and histopathological damage. Crucially, folate restored epithelial barrier structural integrity and function both in vivo and in vitro. Mechanistically, folate mediated barrier restoration through suppression of the PI3K/AKT/NF-κB/MLCK/MLC2 signaling axis. Collectively, the results of this study provide mechanistic insights that support the use of folate as an active therapeutic molecule in patients with UC.
研究领域:
免疫学
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胃肠病学
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营养科学
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分子生物学
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药理学
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PubMed
高影响因子
MEDIATORS OF INFLAMMATION
·
2021
·
IF 4.711
Huan Lan,Lu-Ying Zhang,Wen He,Wan-Ying Li,Zhen Zeng,Bo Qian,Chengqiang Wang,Jia-Le Song
The integrity and permeability of the intestinal epithelial barrier are important indicators of intestinal health. Impaired intestinal epithelial barrier function and increased intestinal permeability are closely linked to the onset and progression of various intestinal diseases. Sinapic acid (SA) is a phenolic acid that has anti-inflammatory, antihyperglycemic, and antioxidant activities; meanwhile, it is also effective in the protection of inflammatory bowel disease (IBD), but the specific mechanisms remain unclear. Here, we evaluated the anti-inflammatory of SA and investigated its potential therapeutic activity in LPS-induced intestinal epithelial barrier and tight junction (TJ) protein dysfunction. SA improved cell viability; attenuated epithelial permeability; restored the protein and mRNA expression of claudin-1, ZO-1, and occludin; and reversed the redistribution of the ZO-1 and claudin-1 proteins in LPS-treated Caco-2 cells. Moreover, SA reduced the inflammatory response by downregulating the activation of the TLR4/NF-κB pathway and attenuated LPS-induced intestinal barrier dysfunction by decreasing the activation of the MLCK/MLC pathway. This study demonstrated that SA has strong anti-inflammatory activity and can alleviate the occurrence of high intercellular permeability in Caco-2 cells exposed to LPS.
研究领域:
药理学
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免疫学
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细胞生物学
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胃肠病学
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DOI
PubMed
高影响因子
Food & Function
·
2023
·Vol. 14
·期 14
·6482-6495
·
IF 6.1
Wei Liu,Yuan-Yuan Liu,Meng-Qiu Zhang,Miao-Zhen Qin,Yuan-Yuan Yang,Bi-Wen Liu,Dong-Jian Zhang,Cui-Hua Jiang,Zhi-Qi Yin,Min Lu,Jian-ping Shen,Jian Zhang
As a dietary supplement, hyaluronic acid (HA) has exhibited appreciable immunomodulatory activity and an ameliorative effect on rodent colitis. However, its high viscosity is not only refractory to absorb through the gut, but also causes flatulence. In contrast to HA, hyaluronic acid oligosaccharides (o-HAs) can overcome the above-mentioned constraints, but their treatment effect still remains ill-defined contemporarily. Herein, the current study intends to compare the modulatory effects of HA and o-HA on colitis and assess the underlying molecular mechanism. We first showed that o-HA had a better preventive effect than HA in alleviating colitis symptoms, as evidenced by lower body weight loss, lower disease activity index scores, a lower inflammatory response (TNF-α, IL-6, IL-1β, p-NF-κB), and more intact colon epithelial integrity in vivo. The best efficiency was observed in the o-HA treated group with a dosage of 30 mg kg−1. In an in vitro barrier function assay, o-HA exerted a better protective effect on the transepithelial electrical resistance (TEER), FITC permeability, and wound healing and modulated the expression of tight junction (TJ) proteins (ZO-1, occludin) in lipopolysaccharide (LPS)-stimulated Caco-2 cells. In summary, both HA and o-HA showed the potential to reduce inflammation and ameliorate intestinal damage in DSS-induced colitis and LPS-induced inflammation, but o-HA had improved outcomes. The results also provided a glimpse of the latent mechanism by which HA and o-HA enhanced intestinal barrier function via MLCK/p-MLC signaling pathway suppression.
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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PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2016
·Vol. 37
·期 8
·1091-1100
·
IF 3.166
Xiong Yong-jian,Chu Hong-wei,Lin Yuan,Han Fang,Li Ya-chan,Wang Ai-guo,Wang Fu-jin,Chen Da-peng,Wang Jing-yu
Aim: Postoperative ileus (POI) is a postoperative dysmotility disorder of gastrointestinal tract, which remains one of the most perplexing problems in medicine. In the present study we investigated the effects of hesperidin, a major flavonoid in sweet oranges and lemons, on POI in rats. Methods: SD rats were administered hesperidin (5, 20, and 80 mg·kg −1 ·d −1 , ig) for 3 consecutive days. POI operation (gently manipulating the cecum for 1 min) was performed on d 2. The gastrointestinal motility and isolated intestinal contraction were examined 1 d after the operation. Then the myosin phosphorylation and inflammatory responses in cecum tissue were assessed. Smooth muscle cells were isolated from rat small intestine for in vitro experiments. Results: The gastric emptying and intestinal transit were significantly decreased in POI rats, which were reversed by administration of hesperidin. In ileum and cecum preparations of POI rats in vitro , hesperidin (2.5–160 μmol/L) dose-dependently increased the spontaneous contraction amplitudes without affecting the contractile frequency, which was blocked by the myosin light chain kinase (MLCK) inhibitor ML-7 or verapamil, but not by TTX. Furthermore, administration of hesperidin increased the phosphorylation of MLC 20 in the cecum tissue of POI rats. Moreover, administration of hesperidin reversed the increased levels of inflammatory cytokines, iNOS and COX-2 in cecum tissue of POI rats. In freshly isolated intestinal smooth muscle cells, hesperidin (5–80 μmol/L) dose-dependently increased the intracellular Ca 2+ concentration as well as the phosphorylation of MLC 20 , which was abrogated by ML-7 or siRNA that knocked down MLCK. Conclusion: Oral administration of hesperidin effectively alleviates rat POI through inhibition of inflammatory responses and stimulation of Ca 2+ -dependent MLC phosphorylation.
研究领域:
药理学
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胃肠病学
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外科
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yuan-Yuan Li,Jing-Wen Sun,Lei Chen,Yong-Ming Lu,Qing-Xi Wu,Chao Yan,Yan Chen,Mei Zhang,Wen-Na Zhang
A new polysaccharide fraction (ATP) was obtained from Armillariella tabescens mycelium. Structural analysis suggested that the backbone of ATP was →4)- α -D-Glc p (1 → 2)- α -D-Gal p (1 → 2)- α -D-Glc p (1 → 4)- α -D-Glc p (1→, which branched at O-3 of →2)- α -D-Glc p (1 → and terminated with T- α -D-Glc p or T- α -D-Man p . Besides, ATP significantly alleviated ulcerative colitis (UC) symptoms and inhibited the production of pro-inflammation cytokines (IL-1 β , IL-6). Meanwhile, ATP could improve colon tissue damage by elevating the expression of MUC2 and tight junction proteins (ZO-1, occludin and claudin-1) levels and enhance intestinal barrier function through inhibiting the activation of MMP12/MLCK/ p -MLC2 signaling pathway. Further studies exhibited that ATP could increase the relative abundance of beneficial bacteria such as f. Muribaculacese , g. Muribaculaceae , and g. Alistips , and decrease the relative abundance of g. Desulfovibrio , g. Colidextribacter , g. Ruminococcaceae and g .Oscillibacter , and regulate the level of short-chain fatty acids. Importantly, FMT intervention with ATP-derived microbiome certified that gut microbiota was involved in the protective effects of ATP on UC. The results indicated that ATP was potential to be further developed into promising therapeutic agent for UC.
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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微生物学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Fang Shi,Yong-Sheng Gao,Shu-Mei Han,Cheng-Suo Huang,Qing-Sheng Hou,Xiao-wen Wen,Ben-Shi Wang,Zhen-Yu Zhu,Lei Zou
Metabolic changes have been linked to the development of inflammatory bowel disease (IBD), which includes colitis. Allulose, an endogenous bioactive monosaccharide, is vital to the synthesis of numerous compounds and metabolic processes within living organisms. Nevertheless, the precise biochemical mechanism by which allulose inhibits colitis remains unknown. Allulose is an essential and intrinsic protector of the intestinal mucosal barrier, as it maintains the integrity of tight junctions in the intestines, according to the current research. It is also important to know that there is a link between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), chemically-induced colitis in rodents, and lower levels of allulose in the blood. Mice with colitis, either caused by dextran sodium sulphate (DSS) or naturally occurring colitis in IL-10 -/- mice, had less damage to their intestinal mucosa after being given allulose. Giving allulose to a colitis model starts a chain of reactions because it stops cathepsin B from ejecting and helps lysosomes stick together. This system effectively stops the activity of myosin light chain kinase (MLCK) when intestinal epithelial damage happens. This stops the breakdown of tight junction integrity and the start of mitochondrial dysfunction. To summarise, the study's findings have presented data that supports the advantageous impact of allulose in reducing the advancement of colitis. Its ability to stop the disruption of the intestinal barrier enables this. Therefore, allulose has potential as a medicinal supplement for treating colitis.
研究领域:
胃肠病学
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药理学
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分子生物学
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Jianwei Wang,Xiaojia Lv,Ying Li,Haiqiang Wu,Meiwan Chen,Hua Yu,Jianwei Wu,Chenyang Li,Wei Xiong
Intestinal mucosal barrier loss is responsible for the chronic and recurrent ulcerative colitis. Myosin light chain kinase (MLCK) is a potential therapeutic target of the intestinal mucosal barrier dysfunction. Here, we developed a reactive oxygen species (ROS)-sensitive hydrogel (ATG-CS-Gel) derived from a diselenide-bridged arctigenin (ATG) and chitosan (CS) conjugate, with the aims of targeting to inflamed mucosa and modulating MLCK. Our results demonstrated that ATG-CS-Gel achieved ROS-responsive release and significantly inhibited ROS production and mitochondrial depolarization in the Caco-2 and HT-29/MTX-E12 cells under H 2 O 2 -induced stress conditions. Compared with normal tissues, orally-administrated ATG-CS-Gel preferentially adhered to the inflamed mucosa for 24 h, which was attributed to the adhesion between CS and mucin. Therapeutically, ATG-CS-Gel reduced inflammatory symptoms, accelerated intestinal mucosal healing, scavenged excessive ROS, reshaped intestinal flora, and eventually achieved much better therapeutic efficacy in DSS-induced colitis mice when compared to 5-aminosalicylic acid. Moreover, ATG-CS-Gel was demonstrated to reverse intestinal mucosal barrier loss by blocking MLCK activation and maintaining tight junction expression. In summary, this study highlights the potential of MLCK modulation in the restoration of intestinal mucosal barrier using ATG-CS-Gel. The development of ATG-CS-Gel represents a novel and promising strategy for the treatment of ulcerative colitis.
研究领域:
药理学
·
胃肠病学
·
生物材料科学
·
炎症性肠病
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PubMed
高影响因子
MEDICAL SCIENCE MONITOR
·
2020
·
IF 1.918
Feng Liu,Xuesong Zhang,Yong Ji
Background Intestinal epithelial barrier dysfunction is involved in the development and pathogenesis of intestinal diseases, such as irritable bowel syndrome, inflammatory bowel disease, and celiac disease. This study was performed to evaluate the ability of total flavonoid extract from hawthorn (TFH) to improve TNF-α-evoked intestinal epithelial barrier deficit. Material/Methods Caco-2 cells monolayers were exposed to TNF-α in different concentrations of TFH. Intestinal epithelial barrier function was evaluated using epithelial permeability and transepithelial electrical resistance (TER). Results Our findings showed that TFH alleviated the increase of paracellular permeability and the decline of transepithelial electrical resistance (TER) evoked by TNF-α. Additionally, 24-h pre-incubation with TFH inhibited TNF-α-evoked secretion of pro-inflammatory factors (IL-6, IL-8, MCP-1, and IL-1β). Furthermore, TFH inhibited TNF-α-evoked overexpression of pMLC and MLCK and alleviated breakdown of TJs protein (ZO-1 and occludin). The activations of Elk-1 and NFκBp65 were inhibited by TFH pre-incubation. Conclusions TFH can alleviate TNF-α-evoked intestinal epithelial barrier deficit via the NFκBp65-mediated MLCK-MLC signaling pathway.
研究领域:
药理学
·
免疫学
·
胃肠病学
·
细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Minxuan Xu,Fang Shi,Yongshen Gao,Shumei Han,Chensuo Huang,Qinsheng Hou,Xiaoweng Wen,Bengshi Wang,Zhenyu Zhu,Lei Zou,Mingxin Xiong,Wei Dong,Jun Tan
There is a growing amount of research that highlights the significant involvement of metabolic imbalance and the inflammatory response in the advancement of colitis. Arabinose is a naturally occurring bioactive monosaccharide that plays a crucial role in the metabolic processes and synthesis of many compounds in living organisms. However, the more detailed molecular mechanism by which the administration of arabinose alleviates the progression of colitis and its associated carcinogenesis is still not fully understood. In the present study, arabinose is recognized as a significant and inherent protector of the intestinal mucosal barrier through its role in preserving the integrity of tight junctions within the intestines. Also, it is important to note that there is a positive correlation between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), as well as chemically-induced colitis in mice, and lower levels of arabinose in the bloodstream. In two mouse models of colitis, caused by dextran sodium sulfate (DSS) or by spontaneous colitis in IL-10 -/- mice, damage to the intestinal mucosa was reduced by giving the mice arabinose. When arabinose is administrated to model with colitis, it sets off a chain of events that help keep the lysosomes together and stop cathepsin B from being released. During the progression of intestinal epithelial injury, this process blocks myosin light chain kinase (MLCK) from damaging tight junctions and causing mitochondrial dysfunction. In summary, the results of the study have provided evidence supporting the beneficial effects of arabinose in mitigating the progression of colitis. This is achieved through its ability to avoid dysregulation of the intestinal barrier. Consequently, arabinose may hold promise as a therapeutic supplementation for the management of colitis.
研究领域:
胃肠病学
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免疫学
·
分子生物学
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DOI
PubMed
高影响因子
FITOTERAPIA
·
2014
·
IF 2.216
Yong-Jian Xiong,Da-Peng Chen,Bo-Chao Lv,Fang-Fei Liu,Li Wang,Yuan Lin
Nobiletin , a citrus polymethoxylated flavone , exhibits multiple biological properties including anti-inflammatory, anti-carcinogenic, and anti-insulin resistance effects. The present study found that nobiletin exerted significant stimulatory effects on the contractility of isolated rat jejunal segments in all 6 different low contractile states, and meanwhile significant inhibitory effects in all 6 different high contractile states, showing characteristics of bidirectional regulation (BR). Nobiletin-exerted BR on jejunal contractility was abolished in the presence of c-kit receptor tyrosine kinase inhibitor imatinib or Ca 2 + channel blocker verapamil . In the presence of neuroxin tetrodotoxin , nobiletin only exerted stimulatory effects on jejunal contractility in both low and high contractile states. Hemicholinium-3 and atropine partially blocked nobiletin-exerted stimulatory effects on jejunal contractility in low-Ca 2 + -induced low contractile state. Phentolamine or propranolol or l -NG-nitro-arginine significantly blocked nobiletin-exerted inhibitory effects on jejunal contractility in high-Ca 2 + -induced high contractile state respectively. The effects of nobiletin on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin light chain phosphorylation extent were also bidirectional. In summary, nobiletin-exerted BR depends on the contractile states of rat jejunal segments. Nobiletin-exerted BR requires the enteric nervous system, interstitial cell of Cajal, Ca 2 + , and myosin phosphorylation-related mechanisms.
研究领域:
药理学
·
胃肠病学
·
分子生物学
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DOI
PubMed
高影响因子
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