Explore the vast range of titles available.

The intestinal epithelium provides an important barrier against bacterial endotoxin translocation, which can regulate the absorption of water and ions. The disruption of epithelial barrier function can result in water transport and tight junction damage, or further cause diarrhea. Therefore, reducing intestinal epithelial barrier injury plays an important role in diarrhea. Inflammatory response is an important cause of intestinal barrier defects. Daidzein improving the barrier integrity has been reported, but the effect on tight junction proteins and aquaporins is not well-described yet, and the underlying mechanism remains indistinct in the human intestinal epithelium. This study aimed to investigate the effects and mechanisms of daidzein on intestinal epithelial barrier injury induced by LPS, and a barrier injury model induced by LPS was established with human colorectal epithelial adenocarcinoma cell line Caco-2 cells. We found that daidzein protected the integrity of Caco-2 cell monolayers, reversed LPS-induced downregulation of ZO-1, occludin, claudin-1, and AQP3 expression, maintained intercellular junction of ZO-1, and suppressed NF-κB and the expression of inflammatory factors (TNF-α, IL-6). Furthermore, we found that daidzein suppressed the phosphorylation of the PI3K/AKT and P38 pathway-related proteins and the level of the related genes, and the PI3K/AKT and P38 pathway inhibitors increased ZO-1, occludin, claudin-1, and AQP3 expression. The study showed that daidzein could resist LPS-induced intestinal epithelial barrier injury, and the mechanism is related to suppressing the PI3K/AKT and P38 pathways. Therefore, daidzein could be a candidate as a dietary supplementation or drug to prevent or cure diarrhea.

Objective Colonic ischaemia is frequently observed in clinical practice. This study provides a novel insight into the pathophysiology of colon ischaemia/reperfusion (IR) using a newly developed human and rat experimental model. Design In 10 patients a small part of colon that had to be removed for surgical reasons was isolated and exposed to 60 min of ischaemia (60I) with/without different periods of reperfusion (30R and 60R). Tissue not exposed to IR served as control. In rats, colon was exposed to 60I, 60I/30R, 60I/120R or 60I/240R (n=7 per group). The tissue was snap-frozen or fixed in glutaraldehyde, formalin or methacarn fixative. Mucins were stained with Periodic Acid Schiff/Alcian Blue (PAS/AB) and MUC2/Dolichos biflorus agglutinin (DBA). Bacteria were studied using electron microscopy (EM) and fluorescent in situ hybridisation (FISH). Neutrophils were studied using myeloperoxidase staining. qPCR was performed for MUC2, interleukin (IL)-6, IL-1β and tumour necrosis factor α. Results In rats, PAS/AB and MUC2/DBA staining revealed mucus layer detachment at ischaemia which was accompanied by bacterial penetration (in EM and FISH). Human and rat studies showed that, simultaneously, goblet cell secretory activity increased. This was associated with expulsion of bacteria from the crypts and restoration of the mucus layer at 240 min of reperfusion. Inflammation was limited to minor influx of neutrophils and increased expression of proinflammatory cytokines during reperfusion. Conclusions Colonic ischaemia leads to disruption of the mucus layer facilitating bacterial penetration. This is rapidly counteracted by increased secretory activity of goblet cells, leading to expulsion of bacteria from the crypts as well as restoration of the mucus barrier.

Increasing evidences have shown that resveratrol could protect the brain from ischemic injury; the mechanisms underlying its neuroprotective effects are multifactorial and not fully understood. It remains unclear whether resveratrol could exert neuroprotection through modulating gut-brain axis, which plays important roles in stroke pathology. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 3 days. Resveratrol, when applied immediately after MCAO onset for 3 days, promoted Th1/Th2 balance towards Th2 polarization and skewed Treg/Th17 balance towards Treg in the small intestinal lamina propria (SI-LP), and decreased small intestinal pro-inflammatory cytokines expression through modulating intestinal flora at 3 days post-ischemia (dpi). Resveratrol attenuated cerebral ischemia-induced increase in the epithelial and vascular permeability of small intestine as evidenced by reduced evans blue extravasasion and decreased protein leakage by feces/plasma albumin ratio at 3 dpi. The blood levels of pro-inflammatory cytokines at 3 dpi were also attenuated by resveratrol due to inhibiting intestinal pro-inflammatory immunity and decreasing epithelial and vascular permeability. Resveratrol robustly protected against post-stroke inflammation-induced blood–brain barrier disruption not only in the cortex but also in the striatum at 3 dpi. Furthermore, resveratrol mediated smaller cerebral infarcts and less neurological deficits via decreasing the levels of pro-inflammatory cytokines in the peri-infarct area at 3 dpi. Our results for the first time demonstrated that resveratrol may inhibit systemic post-stroke inflammation and neuroinflammation via modulating intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift in SI-LP, which may be one of the mechanisms underlying the neuroprotective effects of resveratrol.

Indole-3-propionic acid (IPA), a product of Clostridium sporogenes metabolism, has been shown to improve intestinal barrier function. In the present study, in vitro experiments using NCM460 human colonic epithelial cells were performed to investigate how IPA alleviates lipopolysaccharide (LPS)-induced intestinal epithelial cell injury, with the aim of improving intestinal barrier function. In addition, the underlying mechanism was explored. NCM460 cell viability and apoptosis were measured using the Cell Counting Kit-8 assay and flow cytometry, respectively. The integrity of the intestinal epithelial barrier was evaluated by measuring transepithelial electrical resistance (TEER). The underlying molecular mechanism was explored using western blotting, immunofluorescence staining, a dual luciferase reporter gene assay and quantitative PCR. The results showed that 10 µg/ml LPS induced the most prominent decrease in cell viability after 24 h of treatment. By contrast, IPA effectively inhibited LPS-induced apoptosis in the intestinal epithelial cells. Additionally, >0.5 mM IPA improved intestinal barrier function by increasing TEER and upregulating the expression of tight junction proteins (zonula occludens-1, claudin-1 and occludin). Furthermore, IPA inhibited the release of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in a dose-dependent manner and this was achieved via regulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88/NF-κB and TLR4/TRIF/NF-κB pathways. In conclusion, IPA may alleviate LPS-induced inflammatory injury in human colonic epithelial cells. Taken together, these results suggest that IPA may be a potential therapeutic approach for the management of diseases characterized by LPS-induced intestinal epithelial cell injury and intestinal barrier dysfunction.

Background Radiation-induced intestinal injury (RIII) represents a significant dose-limiting complication of radiotherapy, characterized by substantial loss of intestinal epithelial cells (IECs). While the activation of cannabinoid receptor 2 (CB2R) is protective in immune‑mediated colitis, the intrinsic role of CB2R in IECs and its potential therapeutic relevance in RIII have not been defined. Methods An RIII mouse model was established in wild-type and CB2R −/− mice. Small-molecule CB2R agonists were screened for radioprotective efficacy, followed by pharmacological and siRNA-based interrogation of CB2R signaling in intestinal epithelial cell lines and primary mouse intestinal epithelial cells. RNA sequencing and bioinformatics were combined with permeability assays, immunofluorescence, electron microscopy, and molecular analyses of oxidative stress and ferroptosis to elucidate underlying mechanisms. Results Irradiation induced CB2R expression in the intestinal epithelium, and genetic ablation of CB2R markedly aggravated RIII. A focused pharmacological screen identified a recently synthesized dual‑target compound, CB2R/FAAH modulator‑2 (CF‑2), which combines CB2R agonistic activity with fatty acid amide hydrolase (FAAH) inhibition and significantly mitigated radiation‑induced colonic injury while exerting protective effects on the small intestine and spleen. Mechanistically, CB2R activation attenuated irradiation‑induced ferroptosis and preserved intestinal epithelial integrity. Integrative transcriptomic analyses identified Homeobox A10 (HoxA10) as a critical epithelial‑enriched transcriptional amplifier that reinforced CB2R/β‑catenin signaling through a positive‑feedback loop, thereby enhancing CB2R‑mediated epithelial protection. Conclusions This study defines an epithelial‑intrinsic CB2R signaling axis in RIII, linking ferroptosis suppression to preservation of intestinal barrier integrity. CF‑2 is positioned as a promising mechanism‑based candidate for radioprotection.

Objective This study investigates the protective effects of citraconic acid (CA) on radiation-induced intestinal injury (RIII) and elucidates its relationship with the interleukin-17 (IL-17) signaling pathway. Methods A mouse model of whole-abdominal irradiation (IR) was established, and CA (10, 20, 40 mg/kg) was administered intraperitoneally as an intervention. Assessments included body weight, Disease Activity Index (DAI), and colon length measurements. Serum and tissue inflammatory markers were quantified using enzyme-linked immunosorbent assay. Histological analysis was performed using Hematoxylin and Eosin (HE) staining, Ki67 and Lgr5 immunohistochemistry, Alcian Blue-Periodic Acid-Schiff (AB-PAS) staining, and immunofluorescence for Zonula Occludens-1 (ZO-1) and Occludin. Transcriptomic sequencing with functional enrichment analyses was conducted, followed by Western blot validation of IL-17 A, CCL7, CXCL2, and MMP13 protein expression. IL-17 inhibitor experiments were performed to validate the causal relationship. Results CA administration attenuated body weight loss and reduced DAI scores in a dose-dependent manner while preserving colon length. CA treatment suppressed the elevation of IL-6 and TNF-α levels induced by irradiation. Furthermore, CA enhanced the abundance of Ki67-positive and Lgr5-positive cells, increased goblet cell numbers and mucus secretion, and restored the expression of tight junction proteins ZO-1 and Occludin, thereby improving histological damage. Transcriptomic analysis revealed significant enrichment of IL-17 signaling pathways associated with regeneration and inflammation. Protein levels of IL-17 A, CCL7, CXCL2, and MMP13 were upregulated following CA treatment. Importantly, IL-17 inhibition abolished the protective effects of CA, confirming the dependence on IL-17 signaling. Conclusion CA exerts protective effects against radiation-induced intestinal injury by modulating the IL-17-related signaling network, thereby promoting intestinal epithelial regeneration and barrier repair. These findings suggest that CA may represent a potential metabolic intervention strategy for the prevention and treatment of radiation-induced gastrointestinal damage. Graphical Abstract

Damage of intestinal barrier function (BF) after ischemia/reperfusion (I/R) injury can induce serious complications and high mortality. MicroRNAs (miRNAs) are involved in intestinal mucosal BF and epithelial proliferation after I/R injury have been reported. We aimed to investigate the role and regulatory mechanism of miR-142-3p (miR-142) in intestinal epithelial proliferation and BF after I/R injury. We detected the proliferation, barrier function and miR-142 expression in clinical ischemic intestinal tissues. Furthermore, we induced an in vivo intestinal I/R injury mouse model and in vitro IEC-6 cells hypoxia/reoxygenation (H/R) injury model. After increasing and decreasing expression of miR-142, we detected the proliferation and barrier function of intestinal epithelial cells after I/R or H/R injury. We found that miR-142 expression was significantly increased in clinical ischemic intestinal mucosa and mouse intestinal mucosa exposed to I/R injury, and there was an inverse relationship between miR-142 and proliferation/BF. Inhibition of miR-142 significant promoted intestinal epithelial proliferation and BF after I/R injury. Furthermore, inhibition of miR-142 improved overall survival rate of mice after I/R injury. MiR-142 directly targeted FoxM1 which was identified by bioinformatics analysis and luciferase activity assay in IEC-6 cells. Inhibition of miR-142 promotes intestinal epithelial proliferation and BF after I/R injury in a FoxM1-mediated manner.

Shikonin has been reported to regulate caudal-type homeobox 2 (CDX2)-mediated intestinal epithelial cell (IEC) differentiation, and ferroptosis has been identified a critical event during this process. However, the exact role of ferroptosis in shikonin-induced IEC differentiation remains unclear. Accordingly, the aim of this study was to elucidate the involvement of ferroptosis in CDX2-mediated IEC differentiation induced by shikonin. Real-time polymerase chain reaction, western blotting, luciferase assay, immunoprecipitation, and chromatin immunoprecipitation were used to reveal the mechanism underlying shikonin-modulated ferroptosis-dependent IEC differentiation in HT-29 and Caco-2 cells. Shikonin treatment reduced ferroptosis in IECs, as evidenced by the increased expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 (cationic amino acid transporter) member 11, which enhanced CDX2 expression and improved IEC barrier function. Mechanistically, shikonin activated the protein kinase A (PKA)/cAMP-responsive element-binding protein (CREB) signaling cascade, promoting CREB binding to the GPX4 promoter and initiating GPX4 transactivation. GPX4 inhibition reversed the effects of shikonin on CDX2 expression. Endogenous pyruvate kinase isozyme M2 interacted with phosphodiesterase 4; this interaction was disrupted by shikonin, leading to the activation of PKA/CREB signaling. The findings of this study indicate that a low dose of shikonin improves IEC barrier function through GPX4-mediated inhibition of ferroptosis, highlighting its potential as a therapeutic agent for intestinal mucosal injury.

Clostridium perfringens (C. perfringens) causes intestinal injury through overgrowth and the secretion of multiple toxins, leading to diarrhea and necrotic enteritis in animals, including pigs, chickens, and sheep. This study aimed to investigate the protective effects of Lactobacillus plantarum (L. plantarum) Lac16 on C. perfringens infection-associated injury in intestinal porcine epithelial cell line (IPEC-J2). The results showed that L. plantarum Lac16 significantly inhibited the growth of C. perfringens, which was accompanied by a decrease in pH levels. In addition, L. plantarum Lac16 significantly elevated the mRNA expression levels of host defense peptides (HDPs) in IPEC-J2 cells, decreased the adhesion of C. perfringens to IPEC-J2 cells, and attenuated C. perfringens-induced cellular cytotoxicity and intestinal barrier damage. Furthermore, L. plantarum Lac16 significantly suppressed C. perfringens-induced gene expressions of proinflammatory cytokines and pattern recognition receptors (PRRs) in IPEC-J2 cells. Moreover, L. plantarum Lac16 preincubation effectively inhibited the phosphorylation of p65 caused by C. perfringens infection. Collectively, probiotic L. plantarum Lac16 exerts protective effects against C. perfringens infection-associated injury in IPEC-J2 cells.

Intestinal impairment plays a pivotal role in many chronic conditions, including chronic kidney disease (CKD), a progressive disorder affecting over 800 million people worldwide. CKD does not only affect the kidney, but it is recognized as a systemic condition characterized by chronic low-grade inflammation, that contributes to disease progression and associated complications. The intestine is one of the major sources of CKD-associated inflammation, also due to the production and accumulation of some uremic toxins, normally excreted by healthy kidneys, such as indoxyl sulfate (IS). IS is a pro-inflammatory and pro-oxidant protein-bound uremic toxin that increases intestinal epithelial permeability, promotes microbial translocation, and enhances inflammatory and oxidative responses. Although IS-induced intestinal damage has been documented, the underlying molecular mechanisms and effective therapeutic strategies to counteract its effects remain to be elucidated. Against this backdrop in the present study, we investigated the impact of plumericin, an iridoid spironolactone, on IS-induced intestinal impairment using IEC-6, an intestinal epithelial cells model. In IS-treated IEC-6, plumericin reduces apoptosis, inhibits inflammation and oxidative stress, and restores epithelial wound repair. In these conditions plumericin also promotes Nrf-2 and inhibits NF-kB and AhR activation induced by IS. Moreover, the same inhibitory effect of plumericin on inflammation and oxidative stress and in promoting wound repair is also observed in the presence of IS and pro-inflammatory stimuli, as occurs in CKD considering the associated systemic low-grade inflammation. These findings suggest that plumericin may represent a promising therapeutic candidate for intestinal impairment in CKD acting with an integrated mechanism.