International Journal of Nanomedicine
·
2023
·
IF 8
Xinyu Fan,Jiachen Shi,Ye Liu,Mengqiu Zhang,Min Lu,Ding Qu
Background Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.Methods The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.Results The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.Conclusion Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.
研究领域:
药学
·
胃肠病学
·
营养科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROGASTROENTEROLOGY AND MOTILITY
·
2019
·Vol. 31
·期 5
·e13556
·
IF 3.803
Yong Li,Tingting Yang,Qing Yao,Songsong Li,En Fang,Yankun Li,Chao Liu,Weimin Li
Background Intestinal barrier dysfunction is a key etiologic factor of irritable bowel syndrome (IBS). Metformin improves intestinal barrier function, although the underlying mechanism has yet to be fully explained. This study evaluates the protective effect of metformin on colonic barrier integrity and explores the underlying cellular mechanisms. Methods IBS-like rats were induced by maternal separation. Metformin was administered daily by gavage at 08:30, and rat pups were then separated from their mother. Visceral hyperalgesia and depression-like behaviors were evaluated by colorectal distension, sucrose preference tests, and forced swimming tests. Intestinal integrity was analyzed using sugar probes and transmission electron microscopy. Inflammatory factors and the levels of corticotropin-releasing factor were assessed by PCR and ELISA. The number of mast cells was evaluated by toluidine blue staining. Protein expression and localization were determined using Western blot and immunochemistry. Key Results Metformin pretreatment (a) reduced visceral hypersensitivity to colorectal distension, immobility time and enhanced sucrose consumption; (b) decreased urine lactulose/mannitol ratio and sucralose output; (c) inhibited the dilation of tight junction and prevented claudin-4 translocation; (d) inhibited mast cell activation and downregulated the expression of IL-6, IL-18, tryptase, PAR-2, and ERK activation; (e) inhibited claudin-4 phosphorylation at serine sites and interactions between clau-4 and ZO-1. Conclusions & Inferences Metformin may block mast cell activation to reduce PAR-2 expression and subsequently inhibit ERK activation and clau-4 phosphorylation at serine sites to normalize the interaction of clau-4 and ZO-1 and clau-4 distribution. Metformin may be clinically beneficial for patients with IBS or IBS-like symptoms.
研究领域:
胃肠病学
·
药理学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Sihao Zhang,Danmei Tian,Zixuan Xia,Fengge Yang,Yanhui Chen,Zhihong Yao,Yi He,Xinglong Miao,Guirong Zhou,Xinsheng Yao,Jinshan Tang
Ethnopharmacological relevance Chang-Kang-Fang (CKF), originated from traditional Chinese medicine (TCM) formulas, has been utilized to treat diarrhea predominant irritable bowel syndrome (IBS-D) based on clinical experience. However, the underlying mechanism of CKF for treating IBS-D remains unclear and need further clarification. Aim of the study The objective of this present investigation was to validate the efficacy of CKF on IBS-D model rats and to uncover its potential mechanism for the treatment of IBS-D. Materials and Methods We first established the IBS-D rat model through neonatal maternal separation (NMS) in combination with restraint stress (RS) and the administration of senna decoction via gavage. To confirm the therapeutic effect of CKF on treating IBS-D, abdominal withdrawal reflex (AWR) scores, the quantity of fecal pellets, and the fecal water content (FWC) were measured to evaluate the influence of CKF on visceral hypersensitivity and the severity of diarrhea symptom after the intragastric administration of CKF for 14 days. Subsequently, enzyme linked immunosorbent assay (ELISA) was applied to assess the effect of CKF on neuropeptides substance P (SP) and 5-hydroxytryptamine (5-HT), as well as inflammatory cytokines in serum and in intestinal tissues. Further, colonic pathological changes, the amount of colonic mast cells, and the expression level of occludin in rat colon tissues, were investigated by hematoxylin-eosin (HE) staining, toluidine blue staining, and immunohistochemistry, respectively. To explore the underlying mechanisms, alterations in colonic RNA transcriptomics for the normal, model, and CKF treatment groups were assessed using RNA sequencing (RNA-Seq). Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence (IF) assays were applied to validate the effect of CKF on predicted pathways in vivo and in vitro . In addition, to elucidate the potential active compounds in CKF, 11 representative components found in CKF were selected, and their anti-inflammation potentials were evaluated using LPS-treated RAW264.7 cell models. Results CKF treatment significantly reduced the number of fecal pellets, attenuated visceral hypersensitivity, and decreased 5-HT and SP concentrations in serum and colon tissues, along with a reduction in colonic mast cell counts, correlating with improved symptoms in IBS-D rats. Meanwhile, CKF treatment reduced the colonic inflammatory cell infiltration, lowered the levels of IL-6, TNF- α , and IL-1 β in serum and colon tissues, and increased the occludin protein expression in colon tissues to improve inflammatory response and colonic barrier function. RNA-Seq, in conjugation with our previous network pharmacology analysis, indicated that CKF might mitigate the symptoms of IBS-D rats by inhibiting the Toll like receptor 4/Nuclear factor kappa-B/NLR family pyrin domain-containing protein 3 (TLR4/NF- κ B/NLRP3) pathway, which was confirmed by WB, IF, and qRT-PCR experiments in vivo and in vitro . Furthermore, coptisine, berberine, hyperoside, epicatechin, and gallic acid present in CKF emerged as potential active components for treating IBS-D, as they demonstrated in vitro anti-inflammatory effects. Conclusion Our findings demonstrate that CKF effectively improves the symptoms of IBS-D rats, potentially through the inhibition of the TLR4/NF- κ B/NLRP3 pathway. Moreover, this study unveils the potential bioactive components in CKF that could be applied in the treatment of IBS-D.
研究领域:
药理学
·
胃肠病学
·
传统中药
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Physiological Reports
·
2026
·Vol. 14
·期 11
·e70975
·
IF 2.1
Yunxian Wang,Fenglan Chu,Yanhua Gong,Ruihong Guo,Hui Dong
Despite the ubiquitous use of monosodium glutamate (MSG) as a food additive, its specific effects on intestinal health and disease remain largely unclear. Here we found mucosal application of MSG induced an upward intestinal short-circuit current ( I sc ) in the murine ileum, which was significantly reduced by extracellular Cl − , Na + , and Ca 2+ removal. Mechanistically, MSG-induced I sc was significantly attenuated by pharmacological inhibition of key transporters (NCX, SGLT1, NKA) and secretory channels (CaCC, CFTR, IK Ca ). Furthermore, disrupting intracellular Ca 2+ homeostasis via endoplasmic reticulum (ER) chelation or blockade of IP 3 R, RyR, SOCE/CRAC, and VGCC significantly suppressed both the ileal I sc and MSG-stimulated Ca 2+ signaling in IECs. Importantly, MSG triggered a simultaneous elevation in intracellular Ca 2+ and a reduction in Na + , which were abolished by the blockers of NCX and SGLT1. In vivo, MSG-induced Ca 2+ -dependent ion transports were significantly reduced in irritable bowel syndrome with diarrhea (IBS-D) mice. Our findings indicate that MSG drives Ca 2+ -dependent intestinal ion transports through a complex network orchestrated by SGLT1 and NCX under healthy state, which is markedly attenuated in IBS-D. This study provides novel insights into the gastrointestinal impact of dietary MSG in both health and bowel disease.
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.7
Li Cui,Rongling Zhong,Wanqiu Peng,Zhenhai Zhang,Zhentao An,Hui Li
Current clinical management of diarrhea-predominant irritable bowel syndrome (IBS-D) faces substantial challenges due to the limited efficacy of existing therapeutic strategies. This study aimed to synthesize and characterize the hyaluronic acid-ethylenediamine-cinnamic acid conjugate (HA-EDA-CA), investigate its oral bioavailability and colonic tissue distribution, and validate its therapeutic potential along with underlying mechanisms of action in IBS-D models. Following oral administration of free CA or HA-EDA-CA, the colon concentration of CA released from the derivative was significantly higher than that of free CA alone. Both free and conjugated forms of CA likely contributed to the therapeutic effects against IBS-D. The IBS-D model was established by a combination of senna decoction administration and physical restraint stress. After HA-EDA-CA intervention, IBS-D model mice showed marked improvements in stool consistency, fecal water content, stool output, body weight, visceral hypersensitivity, and colon length. ELISA results indicated significant reduction in enteric neurotransmitter levels, including 5-hydroxytryptamine, substance P, and vasoactive intestinal peptide, after oral gavage administration of HA-EDA-CA. Additionally, intestinal permeability assessment and immunofluorescence analyse revealed that HA-EDA-CA improved intestinal barrier function. Western blot analysis indicated HA-EDA-CA inhibited 5-hydroxytryptamine signaling pathway. Furthermore, HA-EDA-CA modulated gut microbiota composition. These findings suggested the potential of HA-EDA-CA as a promising therapeutic candidate for IBS-D treatment. Key novelties: (i) First colon-targeted CA-HA conjugate: We developed and characterized the first hyaluronic acid-based conjugate specifically designed for colon-targeted delivery of cinnamic acid. (ii) Multi-mechanism rescue: The conjugate simultaneously restores gut homeostasis by modulating the 5-hydroxytryptamine signaling pathway, enhancing intestinal barrier function, and rebalancing gut microbiota. (iii) Enhanced therapeutic efficacy: HA-EDA-CA demonstrates superior colonic drug accumulation and integrated therapeutic outcomes compared to free cinnamic acid or simple drug mixtures. (iv) Open-source data availability: All relevant data and analysis scripts supporting the findings are publicly accessible to ensure reproducibility and further research.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY
·
2023
·
IF 2.8
Li Cui,Bin Zhang,Shuting Zou,Jing Liu,Pingrong Wang,Hui Li,Zhenhai Zhang
In this study we sought to elucidate the therapeutic effects of fenchone on constipation-predominant irritable bowel syndrome (IBS-C) and the underlying mechanisms. An IBS-C model was established in rats by administration of ice water by gavage for 14 days. Fenchone increased the reduced body weight, number of fecal pellets, fecal moisture, and intestinal transit rate, and decreased the enhanced visceral hypersensitivity in the rat model of IBS-C. In addition, fenchone increased the serum content of excitatory neurotransmitters and decreased the serum content of inhibitory neurotransmitters in the IBS-C rat model. Meanwhile, western blot and immunofluorescence experiments indicated that fenchone increased the expressions of SCF and c-Kit. Furthermore, compared with the IBS-C model group, fenchone increased the relative abundance of Lactobacillus , Blautia , Allobaculum , Subdoligranulum , and Ruminococcaceae_UCG-008 , and reduced the relative abundance of Bacteroides , Enterococcus , Alistipes , and Escherichia-Shigella on the genus level. Overall, fenchone ameliorates IBS-C via modulation of the SCF/c-Kit pathway and gut microbiota, and could therefore serve as a novel drug candidate against IBS-C.
研究领域:
药理学
·
胃肠病学
·
微生物学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Fengge Yang,Danmei Tian,Yuting Zhang,Zixuan Xia,Yunjuan Li,Xinsheng Yao,Yanxia Xiong,Guirong Zhou,Hongwei Liu,Jinshan Tang
CKF ameliorates intestinal dysfunction and neurobehavioral abnormalities in IBS-D mice. • CKF boosts L. johnsonii and tryptophan-derived indoles, notably ILA. • L. johnsonii acts as a psychobiotic for IBS-D and comorbidities. • ILA improves IBS-D intestinal and behavioral deficits mainly via AhR activation. • CKF targets the L. johnsonii -ILA-AhR/IL-22 gut-brain axis. Background Gut dysbiosis contributes to irritable bowel syndrome (IBS) by disrupting intestinal barrier functions and promoting inflammation. Chang‑kang‑fang (CKF), a Chinese herbal formula proven effective for diarrhea‑predominant IBS (IBS‑D) in a phase III trial, is thought to modulate the gut microbiota, yet the underlying mechanism remains unclear. Purpose To elucidate how CKF ameliorates IBS‑D by modulating the gut microbiota. Methods IBS‑D was induced by restraint stress, tail pinch, and senna gavage. Intestinal function, inflammation, and behavior were evaluated. Gut microbiota and metabolites were profiled via 16S rRNA sequencing and metabolomics. FMT confirmed the causal involvement of the microbiota. The key microbe and metabolite were validated in vivo . Mechanistic analyses evaluated intestinal barrier integrity, systemic inflammation, hippocampal blood‑brain barrier (BBB) function, neuroinflammation, and synaptic plasticity. Results CKF alleviated diarrhea, visceral hypersensitivity, inflammation, barrier dysfunction, and anxiety‑ and depression‑like behaviors. These benefits were associated with gut microbiota remodeling, featuring enrichment of Lactobacillus johnsonii and enhanced tryptophan metabolism. FMT confirmed that this microbial remodeling mediates the therapeutic effects of CKF. Supplementation with L. johnsonii or its metabolite indole‑3‑lactic acid (ILA) largely recapitulated these gut-brain benefits via AhR/IL‑22 activation. Mechanistically, CKF‑induced L. johnsonii enrichment activated the ILA-AhR-IL‑22 pathway, which enhanced intestinal and BBB integrity, thereby attenuating systemic and neuroinflammation, and restoring hippocampal synaptic plasticity. Conclusion This study positions CKF as a microbiota‑modulating therapy for IBS‑D that restores gut‑brain homeostasis via the L. johnsonii -ILA-AhR-IL‑22 axis, highlighting L. johnsonii and ILA as potential therapeutics for IBS and its comorbidities. Download: Download high-res image (278KB) Download: Download full-size image Chang-Kang-Fang alleviates IBS-D and comorbid depression by activating the Lactobacillus johnsonii -indole-3-lactic acid-aryl hydrocarbon receptor/interleukin-22 gut-brain axis.
✓ 已验证
DOI
高影响因子
Nutrients
·
2024
·Vol. 16
·期 22
·3854
·
IF 4.8
Yannan Zhang,Sijuan Huang,Shuai Zhang,Zhihui Hao,Jianzhong Shen
Background: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic functional gastrointestinal disorder that causes diarrheal and intestinal barrier disruptions. Although pomegranate peel extract (PPE) has been reported for the treatment of diarrheal and intestinal inflammation, its effectiveness and mechanisms specifically for the treatment of IBS-D remain unknown. Objectives: This study aimed to explore the therapeutic effect of PPE on IBS-D and elucidate its underlying mechanisms. Methods: A high-fat diet, restraint stress, and senna gavage were combined to establish a rat model mimicking IBS-D, to evaluate the therapeutic effects of PPE. Network pharmacology analysis, serum medicinal chemistry, and transcriptomics were employed to investigate potential downstream signaling pathways. Findings were further validated through molecular docking and Western blot analysis. Results: The findings revealed that PPE significantly improved the symptoms of IBS-D, ameliorated intestinal inflammation, and promoted intestinal barrier function. The target genes in the MAPK and NF-κB signaling pathways were significantly enriched and down-regulated. Molecular docking and Western blot assays were performed to verify that PPE had a high affinity for the protein candidates in these pathways, and significantly down-regulated the expression of p-IκB, p-p65, p-JNK, p-p38, and p-ERK1/2. Conclusions: The present study is the first to demonstrate that PPE alleviates diarrheal and intestinal damage in IBS-D, potentially by inhibiting MAPK and NF-κB signaling pathways. These findings suggest that PPE may provide a novel therapeutic option for IBS-D.
CAS / MDL:
研究领域:
胃肠病学
·
药理学
·
分子生物学
·
动物模型
·
功能基因组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
·
2023
·Vol. 68
·期 6
·2414-2426
·
IF 3.1
Lin Mengjuan,Hu Guiying,Wang Zhengqiang,Yu Baoping,Tan Wei
Background The mechanism underlying irritable bowel syndrome (IBS), a common disease with hyperalgesia, remains elusive. The spinal cholinergic system is involved in pain modulation, but its role in IBS is unknown. Aims To determine whether high-affinity choline transporter 1 (CHT1, a major determinant of the cholinergic signaling capacity), is implicated in spinal modulation of stress-induced hyperalgesia. Methods A rat IBS model was established by water avoidance stress (WAS). Visceral sensations were detected by abdominal withdrawal reflex (AWR) and visceromotor response (VMR) to colorectal distension (CRD). Abdominal mechanical sensitivity was determined by von Frey filaments (VFFs) test. RT-PCR, Western blot, and immunostaining were performed for spinal CHT1 expression. Spinal acetylcholine (ACh) was measured by ELISA; the influence of spinal CHT1 on hyperalgesia were evaluated by intrathecal administration of MKC-231 (a choline uptake enhancer) and hemicholinium-3 (HC-3, a specific inhibitor of CHT1). Minocycline treatment was used to explore the role of spinal microglia in hyperalgesia. Results After 10 days of WAS, AWR scores and VMR magnitude to CRD, and the number of withdrawal events in VFF test were increased. Double-labeling showed that CHT1 in the dorsal horn was expressed in most of the neurons and almost all the microglia. The CHT1 expression and ACh levels in the spinal cord and the density of CHT1-positive cell in the spinal dorsal horn were enhanced in WAS-exposed rats. HC-3 enhanced pain responses in WAS rats; MKC-231 alleviated pain in WAS rats by upregulating CHT1 expression and increasing ACh production in the spinal cord. Furthermore, microglial activation in the spinal dorsal horn promoted the stress-induced hyperalgesia, and MKC-231 achieved analgesic effects by inhibiting the spinal microglial activation. Conclusions CHT1 exerts antinociceptive effects in spinal modulation of chronic stress-induced hyperalgesia by increasing ACh synthesis and suppressing microglial activation. MKC-231 has potential for treating disorders accompanied by hyperalgesia.
研究领域:
神经科学
·
疼痛研究
·
胃肠病学
·
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）