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Highsucrose diet (HSD) was reported as a causative factor for multiorgan injuries. The underlying mechanisms and therapeutic strategies remain largely uncharted. In the present study, by using a metabolomics approach, we identified the soluble epoxide hydrolase (sEH) as a therapeutic target for HSD-mediated gut barrier dysfunction. Specifically, 16-week feeding on an HSD caused gut barrier dysfunction, such as colon inflammation and tight junction impairment in a murine model. A metabolomics analysis of mouse colon tissue showed a decrease in the 5(6)-epoxyeicosatrienoic acid [5(6)-EET] level and an increase in soluble epoxide hydrolase, which is related to HSD-mediated injuries to the gut barrier. The mice treated with a chemical inhibitor of sEH and the mice with genetic intervention by intestinal-specific knockout of the sEH gene significantly attenuated HSD-caused intestinal injuries by reducing HSD-mediated colon inflammation and improving the impaired tight junction caused by an HSD. Further, in vitro studies showed that treatment with 5(6)-EET, but not its hydrolytic product 5,6-dihydroxyeicosatrienoic acid (5,6-DiHET), significantly ablated high sucrose-caused intestinal epithelial inflammation and impaired tight junction. Additionally, 5(6)-EET is anti-inflammatory and improves gut epithelial tight junction while 5,6-DiHET cannot do so. This study presents an underlying mechanism of and a therapeutic strategy for the gut barrier dysfunction caused by an HSD.

Intestinal permeabilization is central to the pathophysiology of chronic gut inflammation. This study investigated the efficacy of glucoraphanin (GR), prevalent in cruciferous vegetables, particularly broccoli, and its derivative sulforaphane (SF), in inhibiting tumor necrosis factor alpha (TNFα)-induced Caco-2 cell monolayers inflammation and permeabilization through the regulation of redox-sensitive events. TNFα binding to its receptor led to a rapid increase in oxidant production and subsequent elevation in the mRNA levels of NOX1, NOX4, and Duox2. GR and SF dose-dependently mitigated both these short- and long-term alterations in redox homeostasis. Downstream, GR and SF inhibited the activation of the redox-sensitive signaling cascades NF-κB (p65 and IKK) and MAPK ERK1/2, which contribute to inflammation and barrier permeabilization. GR (1 μM) and SF (0.5-1 μM) prevented TNFα-induced monolayer permeabilization and the associated reduction in the levels of the tight junction (TJ) proteins occludin and ZO-1. Both GR and SF also mitigated TNFα-induced increased mRNA levels of the myosin light chain kinase, which promotes TJ opening. Molecular docking suggests that although GR is mostly not absorbed, it could interact with extracellular and membrane sites in NOX1. Inhibition of NOX1 activity by GR would mitigate TNFα receptor downstream signaling and associated events. These findings support the concept that not only SF, but also GR, could exert systemic health benefits by protecting the intestinal barrier against inflammation-induced permeabilization, in part by regulating redox-sensitive pathways. GR has heretofore not been viewed as a biologically active molecule, but rather, the benign precursor of highly active SF. The consumption of GR and/or SF-rich vegetables or supplements in the diet may offer a means to mitigate the detrimental consequences of intestinal permeabilization, not only in disease states but also in conditions characterized by chronic inflammation of dietary and lifestyle origin.

A disrupted circadian rhythm can cause liver and intestinal diseases, however, the mechanisms remain unclear. Therefore, we examined the effects of the gut-liver axis circadian locomotor output cycles kaput (Clock) gene, on mouse liver and intestinal to identify how Clock regulates gut-liver axis functions. Wild-type (WT) and gut-liver axis-specific Clock knockdown (Clock-KD) mice were fed a normal diet. Intestinal microflora diversity and species abundance changes were analysed by 16s rDNA sequencing. A Caco2 cell monolayer model was established and Clock-KD effects was examined following Clock small-hairpin RNA transfection. Clock-KD mouse livers were not significantly changed. However, microflora abundance and biodiversity in these mice were significantly lower when compared with WT mice. Moreover, Clock was shown to regulate intestinal tight junction protein expression both in vivo and in vitro. Interestingly, the CLOCK protein interacted with TJP1. Clock affects intestinal flora diversity and composition and regulates intestinal barrier integrity in mice. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading global liver disorder. Parsnip (Pastinaca sativa), rich in dietary fiber and medicinal properties, has shown health benefits, but its effects on MASLD are largely unexplored. This study evaluated the prebiotic and anti-MASLD effects of parsnip root water-soluble extract (PRE) in a mouse model. Mice fed a high-fat diet with 50 or 100 mg/kg PRE for eight weeks showed reduced fat accumulation, improved serum metabolic profiles, and decreased liver injury markers. PRE also lowered hepatic lipogenic protein levels induced by the high-fat diet. Additionally, PRE enhanced gut health by reducing endotoxins, improving intestinal permeability, and upregulating tight junction proteins. These results indicate that PRE can improve gut health, prevent MASLD, and support its potential as a dietary supplement to enhance metabolic health. [ABSTRACT FROM AUTHOR]

Existing gastrointestinal (GI) diagnostic tools are unable to non-invasively monitor mucosal tight junction integrity in vivo beyond the esophagus. In the GI tract, local inflammatory processes induce alterations in tight junction proteins, enhancing paracellular ion permeability. Although transepithelial electrical resistance (TEER) may be used in the laboratory to assess mucosal barrier integrity, there are no existing methodologies for characterizing tight junction dilation in vivo. Addressing this technology gap, intraluminal bioimpedance sensing may be employed as a localized, non-invasive surrogate to TEER electrodes used in cell cultures. Thus far, bioimpedance has only been implemented in esophagogastroduodenoscopy (EGD) due to the need for external electronics connections. In this work, we develop a novel, noise-resilient Bluetooth-enabled ingestible device for the continuous, non-invasive measurement of intestinal mucosal "leakiness." As a proof-of-concept, we validate wireless impedance readout on excised porcine tissues in motion. Through an animal study, we demonstrate how the device exhibits altered impedance response to tight junction dilation induced on mice colonic tissue through calcium-chelator exposure. Device measurements are validated using standard benchtop methods for assessing mucosal permeability. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disability condition arising from a combination of genetic and environmental factors. Despite the blood-brain barrier (BBB) serving as a crucial gatekeeper, conveying environmental influences into the brain parenchyma, the contributions of BBB in ASD pathogenesis remain largely uncharted. Here we report that SHANK3, an ASD-risk gene, expresses in the BBB-forming brain endothelial cells (BECs) and regulates tight junctional (TJ) integrity essential for BBB's barrier function. Endothelium-specific Shank3 (eShank3) knockout (KO) neonatal mice exhibit male-specific BBB-hyperpermeability, reduced neuronal excitability, and impaired ultra-sonic communications. Although BBB permeability is restored during adult age, the male mutant mice display reduced neuronal excitability and impaired sociability. Further analysis reveals that the BBB-hyperpermeability is attributed to the β-Catenin imbalance triggered by eShank3-KO. These findings highlight a pathogenic mechanism stemming from the ASD-risk Shank3, emphasizing the significance of neonatal BECs in the BBB as a potential therapeutic target for ASD. This study reveals that SHANK3 deficiency in brain endothelial cells disrupts BBB function during the neonatal period through β-Catenin imbalance, leading to ASD-related neuronal and behavioral abnormalities. [ABSTRACT FROM AUTHOR]

Numerous studies have confirmed that gut microbiota is a key driver in the occurrence and progression of inflammatory bowel disease (IBD). Based on the bacterial collection constructed in our previous studies, we founded that Bifidobacterium adolescentis AF91-08b2A has the potential beneficial function. We designed cohort studies, genomic studies and animal experiments to further explore the probiotic function of Bifidobacterium adolescentis AF91-08b2A and its therapeutic effect on IBD. The depletion of B. adolescentis in individuals with IBD suggested its significance for intestinal health. Genomic analysis highlighted the probiotic attributes of B. adolescentis AF91-08b2A, including resistance to antibiotics and stress, and metabolic pathways related to energy and carbohydrate metabolism, which are likely to enhance its therapeutic efficacy. In DSS-induced mice colitis model, the strain significantly enhanced the disease activity index (DAI), curbed weight loss, and attenuated colonic damage. It effectively modulated the immune response by reducing the levels of pro-inflammatory cytokines such as IL-6, IL-1β, IL-17A, IFN-γ, and TNF-α, while promoting the secretion of anti-inflammatory cytokines like IL-4, IL-10, and TGF-β1. The restoration of tight junction proteins ZO-1, occludin, and claudin-2 by B. adolescentis AF91-08b2A demonstrated its capacity to safeguard the intestinal epithelial barrier. Collectively, our findings indicate B. adolescentis AF91-08b2A as a valuable therapeutic option for UC, with its multifaceted approach to reducing inflammation and fortifying the intestinal barrier. [ABSTRACT FROM AUTHOR]

A mixed Eimeria spp. challenge model was designed to assess the effects of challenge on broiler chicken performance, intestinal integrity, and the gut microbiome for future use to evaluate alternative strategies for controlling coccidiosis in broiler chickens. The experimental design involved broiler chickens divided into two groups: a control group (uninfected) and a positive control group, infected with Eimeria acervulina (EA), Eimeria maxima (EM), and Eimeria tenella (ET). At day-of-hatch, 240 off-sex male broiler chicks were randomized and allocated to one of two treatment groups. The treatment groups included: (1) Non-challenged (NC, n = 5 replicate pens); and (2) challenged control (PC, n = 7 replicate pens) with 20 chickens/pen. Pen weights were recorded at d0, d16, d31, d42, and d52 to determine average body weight (BW) and (BWG). Feed intake was measured at d16, d31, d42, and d52 to calculate feed conversion ratio (FCR). Four diet phases included a starter d0–16, grower d16–31, finisher d31–42, and withdrawal d42–52 diet. At d18, chickens were orally challenged with 200 EA, 3,000 EM, and 500 ET sporulated oocysts/chicken. At d24 (6-day post-challenge) and d37 (19-day post-challenge), intestinal lesion scores were recorded. Additionally, at d24, FITC-d was used as a biomarker to evaluate intestinal permeability and ileal tissue sections were collected for histopathology and gene expression of tight junction proteins. Ileal and cecal contents were also collected to assess the impact of challenge on the microbiome. BWG and FCR from d16–31 was significantly (p < 0.05) reduced in PC compared to NC. At d24, intestinal lesion scores were markedly higher in the PC compared to the NC. Intestinal permeability was significantly increased in the PC group based on serum FITC-d levels. Cadherin 1 (CDH1), calprotectin (CALPR), and connexin 45 (Cx45) expression was also upregulated in the ileum of the PC group at d24 (6-day post-challenge) while villin 1 (VIL1) was downregulated in the ileum of the PC group. Additionally, Clostridium perfringens (ASV1) was enriched in the cecal content of the PC group. This model could be used to assess the effect of alternative coccidiosis control methods during the post-challenge with EA, EM, and ET. [ABSTRACT FROM AUTHOR]

Background: It is well-documented that house dust mite (HDM) exposure can cause tissue damage and activate innate immune responses. However, its role in promoting gastrointestinal sensitization and allergenicity to food proteins has been relatively unexplored. Methods: This study investigates the immunostimulatory effects of HDM in a murine model of oral sensitization to egg white (EW) in the absence of exogenous adjuvants. Additionally, we examined a proteolytically inactivated form of HDM (iHDM) to assess the contribution of HDM protease activity to its adjuvant potential. Results: Both HDM and iHDM enhanced allergic responses to EW proteins via the oral route, evidenced by mast cell degranulation in the intestinal tract upon EW challenge. Notably, only iHDM induced detectable concentrations of serum EW-specific IgE and IgG1 antibodies. Whereas HDM increased intestinal expression of genes encoding tight junction proteins and Th2-inducing alarmins to a greater extent than iHDM, active proteinases were not required for its adjuvant activity, as iHDM preferentially promoted Th2 responses in intestinal lymphoid tissues. Conclusions: These findings suggest that ingestion of environmental dust may contribute to food allergy development and highlight the complex and context-dependent nature of the adjuvant activity of HDM. [ABSTRACT FROM AUTHOR]

Background and aims: Patients with Crohn's disease (CD) exhibit excessive apoptosis of intestinal epithelial cells (IECs), which contributes to damage to the intestinal barrier structure and function, thereby playing a role in the progression of colitis. Preventing IEC apoptosis and protecting the intestinal barrier are critical to alleviating colitis. Natural plant monomers have been reported to possess multiple pharmacological properties, particularly with the potential to treat CD. This study focuses on Cynaroside (Cyn) to explore its effect on IEC apoptosis and evaluate its pharmacological impact on the intestinal barrier and colitis. Methods: The 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced CD-like colitis mice model was employed in this study. We assessed the therapeutic effect of Cyn on CD-like colitis by evaluating the disease activity index (DAI), body weight changes, intestinal tissue pathological damage, and inflammatory factor levels. Immunofluorescence and Western blotting were used to detect the expression and localization of tight junction (TJ) proteins, allowing us to analyze the intestinal barrier structure. The function of the intestinal barrier was examined using FITC-dextran (FD4), TEER values, and bacterial translocation. Network pharmacology enrichment analysis revealed that Cyn could inhibit cell apoptosis. We also explored the effect and underlying mechanism of Cyn in inhibiting IEC apoptosis on intestinal barrier function and colitis using both the TNF-α-induced colonic organoid model and the TNBS-induced mouse model. Results: Our findings show that Cyn significantly alleviates TNBS-induced colitis symptoms in mice, as evidenced by reduced body weight loss, colon shortening, DAI score, colon histopathology score, and lower levels of inflammatory factors (IL-1β, TNF-α, and IL-6) compared to the model group. Additionally, the Cyn intervention group showed significant improvements in both the intestinal barrier structure (elevated tight junction protein levels and proper localization) and function (reduced serum FD4 levels, increased intestinal TEER, and decreased bacterial translocation rates in mesenteric lymph nodes [MLNs] and livers). Combining network pharmacology prediction analysis with our validation data from animal models and colonic organoids, we demonstrated that Cyn significantly inhibits IEC apoptosis, as indicated by a decrease in the proportion of TUNEL-positive cells and changes in apoptosis-related protein levels. KEGG enrichment analysis and signaling pathway intervention experiments confirmed that Cyn inhibits the activation of PI3K/AKT signaling. Conclusion: Cyn inhibits IEC apoptosis by blocking the PI3K/AKT signaling pathway, which is the primary mechanism underlying its protective effects on the intestinal barrier and its ability to improve CD-like colitis. This study also supports the potential of the Chinese medicine monomer Cyn as a promising therapeutic agent for the treatment of CD. [ABSTRACT FROM AUTHOR]

Cereals are among the foods rich in myo-inositol hexakisphosphate (phytic acid, IP6), lower myo-inositol phosphates (IPx), a wide range of phenolic compounds, as well as vitamins, minerals, oligosaccharides, phytosterols and para-aminobenzoic acid, and are attributed with multiple bioactivities, particularly associated with the prevention of metabolic syndrome and colon cancer. The bran fraction of wheat, maize, brown rice and other cereals contains high levels of phytate, free and total phenolics, and endogenous enzymes such as amylases, phytase, xylanase, β-glucanase and feruloyl esterase, whose activities can be increased by germination. The preliminary steps of digestion begin in the oral cavity where substrates for the action of endogenous cereal and salivary enzymes start to be released from the food matrix. IP6 released from phytate complexes with arabinoxylans, starch and protein bodies would eventually enhance the absorption of nutrients, including phenolics, by regulating tight junctions and, together with ferulic acid (FA), would maintain cell barrier integrity and epithelial antibacterial immunity. In addition, both IP6 and FA exert potent and complementary antioxidant effects, while FA together with IPx generated through advanced hydrolysis of IP6 by endogenous and microbial phytases may affect digestive enzyme activity and incretin secretion, resulting in modulated insulin and glucagon release and prevention of various diabetic complications. Contrary to widespread negative attitudes towards phytate, in this review, we present the strategy of selecting cereals with high phytate and phenolic content, as well as high endogenous phytase, feruloyl esterase and endoxylanase activities, to produce value-added health-promoting foods. The advanced hydrolysis of phytate and phenolic compounds by cereal and/or microbial enzymes would generate substantial amounts of "enzymatically generated inositol" (EGI), including IP6, IPx and myo-inositol, the compounds that, together with free FA, provide enhanced bioavailability of cereal nutrients through multiple synergistic effects not previously realised. [ABSTRACT FROM AUTHOR]

Liposomal encapsulated phytogenics, such as liposomal hesperetin, are considered novel substitutes for antibiotics in the broiler industry owing to their improved nutritional and therapeutic properties. Therefore, our key goal was to investigate liposomal hesperetin impact on broiler growth performance, health, antioxidant status, tight junction proteins (TJP), and resistance against Listeria monocytogenes. Four broiler groups were fed 0, 150, 250, or 400 mg/kg of liposomal hesperetin-supplemented diets and experimentally infected with L. monocytogenes strain. Herein, liposomal hesperetin, especially at higher concentrations, augmented broilers FCR with upregulation of genes encoding TJP (occludin, JAM-2, MUC-2), and antioxidant attributes (GPX-1, SOD-1, CAT, HO-1, NQO1, COX2), which reflect enhancing health and welfare of broilers. Muscle antioxidant biomarkers were enhanced; meanwhile, muscle MDA, ROS, and H2O2 levels were reduced in response to 400 mg/kg of liposomal hesperetin. Liposomal hesperetin fortification reduced L. monocytogenes loads and expression levels of its virulence-related genes (flaA, hlyA, and ami). Remarkably, histopathological alterations in intestinal and brain tissues of L. monocytogenes-infected broilers were restored post-inclusion at higher levels of liposomal hesperetin, which reflects increase of the birds' resistance to L. monocytogenes infection. Transcription levels of genes encoding cytokines/chemokines (MyD88, AVBD6, CCL20, IL-1β, IL-18), and autophagy (Bcl-2, LC3, AMPK, AKT, CHOP, Bip, p62, XBP1) were ameliorated following dietary liposomal hesperetin fortification, which suggests enhancement of the birds' immunity and health. Collectively, our research recommends liposomal hesperetin application in broiler diets owing to its promoting impact on growth performance, antioxidant status, immunity, health, and welfare besides its antibacterial, and antivirulence characteristics to fight against L. monocytogenes. [ABSTRACT FROM AUTHOR]

Despite aggressive therapy, approximately 50% of patients with neuroblastoma (NB) fail to respond, and survivors endure lifelong toxicities. Sonopermeation increases drug uptake via cell bilayer disruption through focused ultrasound and microbubbles (MBs)—gas-filled, sound sensitive lipid spheres. MB response to a given ultrasound pulse (cavitation) varies according to MB size. We asked whether size-sorted MBs (SSMB) 4 to 5 µm in diameter will more consistently and predictably enhance doxorubicin uptake, compared with polydisperse MBs (PMB, 0.5–10 µm in diameter), thereby increasing drug delivery to NB xenografts. Human NB cells were implanted into the left kidney of nude mice and grown for 5 to 6 wk. Mice received sonopermeation alongside either PMB or SSMB at low (0.6 MPa) or high (2 MPa) negative pressures. Some mice also received different chemotherapy agents (doxorubicin, etoposide or cyclophosphamide). Circulating tumor cells were assessed by flow cytometry 1 h after treatment. Survival was assessed for up to 21 d, a subset of mice was euthanized 24 h after treatment for histological assessment of apoptosis, vascular lumen size and tight junctions. Tumors treated with SSMB and high pressure showed synergy with liposomal doxorubicin (L-DOX) owing to increased vascular lumen and disruption of tight junctions, resulting in drug uptake, apoptosis, lack of tumor growth and increased survival. We found no difference in the numbers of circulating tumor cells. Sonopermeation with SSMB at 2 MPa synergizes with L-DOX delivery, increasing apoptosis, perfusion and vascular permeability, suggesting that SSMB sonopermeation at high pressure is promising for NB-targeted treatment, especially in combination with L-DOX. [ABSTRACT FROM AUTHOR]

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Probiotics have been proposed as a potential strategy for managing ulcerative colitis (UC). However, the underlying mechanisms mediating microbiota-host crosstalk remain largely elusive. Here, we report that Limosilactobacillus reuteri (L. reuteri), as a probiotic, secretes cytoplasmic membrane vesicles (CMVs) that communicate with host cells, alter host physiology, and alleviate dextran sulfate sodium (DSS)-induced colitis. First, L. reuteri-CMVs selectively promoted the proliferation of the beneficial bacterium Akkermansia muciniphila (AKK) by upregulating the expression of glycosidases (beta-N-acetylhexosaminidase and alpha-N-acetylglucosaminidase) involved in glycan degradation and metabolic pathways and restored the disrupted gut microbiota balance. Second, L. reuteri-CMVs were taken up by intestinal epithelial cells (IECs), elevated the expression of ZO-1, E-cadherin (Cdh1), and Occludin (Ocln), decreased intestinal permeability, and exerted protective effects on epithelial tight junction functionality. RNA sequencing analysis demonstrated that L. reuteri-CMVs repaired intestinal barrier by activating the HIF-1 signaling pathway and upregulating HMOX1 expression. Third, L. reuteri-CMVs increased the population of double positive (DP) CD4+CD8+ T cells in the intestinal epithelial layer, suppressing gut inflammation and maintaining gut mucosal homeostasis. Finally, L. reuteri-CMVs exhibited satisfactory stability and safety in the gastrointestinal tract and specifically targeted the desired sites in colitis mice. Collectively, these findings shed light on how L. reuteri interact with the host in colitis, and provide new insights into potential strategies for alleviating colitis. [ABSTRACT FROM AUTHOR]

Palmatine (PAL) and berberine are both classified as protoberberine alkaloids, derived from several traditional Chinese herbs such as Coptis chinensis Franch. and Phellodendron chinense Schneid. These compounds are extensively used in treating dysentery and colitis. PAL is one of the crucial quality markers for these plants in the Chinese Pharmacopoeia. A key metabolite of PAL, 8-Oxypalmatine (OPAL), shows favorable anti-inflammatory activity and better safety compared to PAL, though its mechanisms in ulcerative colitis (UC) are not fully understood. This study used a dextran sodium sulfate-induced colitis mouse model to explore OPAL’s effects. The results indicated that OPAL provided superior therapeutic effects to those of PAL, alleviating colitis symptoms and reducing colon inflammation by modulating pro-inflammatory (tumor necrosis factor-α, interleukin-1β, and interleukin-6) and anti-inflammatory (transforming growth factor-β and interleukin-10) cytokines. Additionally, OPAL helped rebuild the mucus barrier and upregulated tight junction proteins, thereby restoring intestinal integrity. Notably, OPAL inhibited the M1 macrophages infiltration while promoting M2 macrophage distribution in the colon. Its role in fostering M2 polarization and modulating the inflammatory cytokine profile was further confirmed in vitro. Importantly, the anti-inflammatory effects were primarily linked to AMP-activated protein kinase activation, which subsequently inhibited the nuclear factor-kappa B pathway. These findings highlight OPAL as a crucial active metabolite responsible for the therapeutic effects of PAL against UC, emphasizing its potential as a novel treatment for this condition. [ABSTRACT FROM AUTHOR]

The correction notice in the journal "Cellular & Molecular Neurobiology" addresses errors in figures in the original article titled "Myosin IIA Regulated Tight Junction in Oxygen Glucose-Deprived Brain Endothelial Cells Via Activation of TLR4/PI3K/Akt/JNK1/2/14-3-3ε/NF-κB/MMP9 Signal Transduction Pathway." The incorrect images of p-PI3K in Fig. 8 and GAPDH in Fig. 10 have been replaced with the correct versions. The correction was made by Yanni Lv, Wen Liu, Zhaohui Ruan, Zixuan Xu, and Longsheng Fu, and the original article has been updated. [Extracted from the article]

Background: Bacterial toxins are emerging as promising hallmarks of colorectal cancer (CRC) pathogenesis. In particular, Cytotoxic Necrotizing Factor 1 (CNF1) from E. coli deserves special consideration due to the significantly higher prevalence of this toxin gene in CRC patients with respect to healthy subjects, and to the numerous tumor-promoting effects that have been ascribed to the toxin in vitro. Despite this evidence, a definitive causal link between CNF1 and CRC was missing. Here we investigated whether CNF1 plays an active role in CRC onset by analyzing pro-carcinogenic key effects specifically induced by the toxin in vitro and in vivo. Methods: Viability assays, confocal microscopy of γH2AX and 53BP1 molecules and cytogenetic analysis were carried out to assess CNF1-induced genotoxicity on non-neoplastic intestinal epithelial cells. Caco-2 monolayers and 3D Caco-2 spheroids were used to evaluate permeability alterations specifically induced by CNF1, either in the presence or in the absence of inflammation. In vivo, an inflammatory bowel disease (IBD) model was exploited to evaluate the carcinogenic potential of CNF1. Immunohistochemistry and immunofluorescence stainings of formalin-fixed paraffin-embedded (FFPE) colon tissue were carried out as well as fecal microbiota composition analysis by 16 S rRNA gene sequencing. Results: CNF1 induces the release of reactive oxidizing species and chromosomal instability in non-neoplastic intestinal epithelial cells. In addition, CNF1 modifies intestinal permeability by directly altering tight junctions' distribution in 2D Caco-2 monolayers, and by hindering the differentiation of 3D Caco-2 spheroids with an irregular arrangement of these junctions. In vivo, repeated intrarectal administration of CNF1 induces the formation of dysplastic aberrant crypt foci (ACF), and produces the formation of colorectal adenomas in an IBD model. These effects are accompanied by the increased neutrophilic infiltration in colonic tissue, by a mixed pro-inflammatory and anti-inflammatory cytokine milieu, and by the pro-tumoral modulation of the fecal microbiota. Conclusions: Taken together, our results support the hypothesis that the CNF1 toxin from E. coli plays an active role in colorectal carcinogenesis. Altogether, these findings not only add new knowledge to the contribution of bacterial toxins to CRC, but also pave the way to the implementation of current screening programs and preventive strategies. [ABSTRACT FROM AUTHOR]

• Post-infection depression poses significant clinical challenges. • Repeated NKS treatment prevents LPS-induced apathy-like behavior in mice. • NKS prevents neuroinflammation by increasing anti-inflammatory milieu. • NKS ameliorates brain vascular inflammation. • NKS may be useful for preventing post-infection depression. Infectious diseases are often concomitant with symptoms of lassitude and emotional disturbances, including depression, the so-called sickness behavior. Kososan, a Kampo (traditional Japanese herbal) formula, has been clinically used for depressive mood, with demonstrated efficacy in stress-induced depressive-like behavior mouse models. Additionally, our previous study has shown that nobiletin-rich kososan (NKS) prevents aging-related depressive-like behaviors and neuroinflammation in mice. Here, we examined whether NKS alleviates depressive-like behavior and neuroinflammation in a mouse model of sickness behavior induced by lipopolysaccharide (LPS). Repeated oral administration of NKS and the positive control antidepressant paroxetine (Paro) significantly prevented this behavior. NKS and Paro significantly increased the anti-inflammatory milieu in the hippocampus and prefrontal cortex (PFC), as well as brain microglia, of LPS-injected mice. The expression of the vascular tight junction protein claudin-5 was also significantly increased by the treatment with NKS, but not with Paro, in the hippocampus and PFC of LPS-injected mice. In vitro analysis using brain microvascular endothelial cells (BMVECs) showed that incubation with 5% serum derived from mice orally administered NKS resulted in a significant increase in the expression of anti-inflammatory heme oxygenase 1 as well as autophagic flux markers. Moreover, the claudin-5 levels in BMVECs were also increased under LPS-stimulated conditions. These results suggest that NKS exerts prophylactic effects against the LPS-induced apathy-like behavior, partly mediated by the increase in the anti-inflammatory milieu and in the levels of tight junction proteins in the brain. This study provides scientific evidence supporting the potential efficacy of NKS in preventing post-infection depression. [ABSTRACT FROM AUTHOR]

Background: von Hippel-Lindau (VHL) hereditary cancer syndrome is caused by mutations in the VHL tumor suppressor gene and is characterized by a predisposition to form various types of tumors, including renal cell carcinomas, hemangioblastomas, and pheochromocytomas. The protein products of the VHL gene, pVHL, are part of an ubiquitin ligase complex that tags hypoxia inducible factor alpha (HIF-α) for proteosomal degradation. pVHL has also been reported to bind to atypical protein kinase C (aPKC). Methods and results: To better understand the relationship between pVHL and aPKC, the PKC iota (PKCι) isoform of aPKC was knocked out in renal carcinoma cells, both pVHL-negative and those with replaced pVHL. Cellular properties associated with pVHL function were assayed. Knockout of PKCι in pVHL-expressing cells led to greater downregulation of HIF-α than seen with pVHL alone, suggesting that the presence of PKCι opposes complete regulation of HIF-α by pVHL. In contrast, absence of either pVHL or PKCι disrupted tight junction formation and led to upregulated levels of α5 integrin, both of which were phenocopied by lysosomal inhibition. LAMP1 (lysosome associated membrane protein 1), a marker for lysosomes, showed dysregulated localization and altered electrophoretic gel migration in the absence of pVHL. While the upregulated α5 integrin seen in the absence of either pVHL or PKCι loss was associated with increased cell adhesion, loss of pVHL caused increased cell motility whereas loss of PKCι decreased motility. Conclusions: These data are consistent with a known role of PKCι in endocytosis of α5 integrin and suggest a subsequent novel role of pVHL in targeting a pool of endocytosed α5 integrin for lysosomal degradation. [ABSTRACT FROM AUTHOR]

Background: Salmonella enterica Serovar Typhimurium (S. Typhimurium) infection can cause inflammation and oxidative stress in the body, leading to gastroenteritis, fever and other diseases in humans and animals. More and more studies have emphasized the broad prospects of probiotics in improving inflammation and oxidative stress, but the ability and mechanism of Lactobacillus acidophilus (LA) to alleviate the inflammatory/oxidative reaction caused by pathogens are still unclear. Methods and results: In this study, we treated the mice with LA for 14 days, infected them with S. Typhimurium for 24 h, and sacrificed the mice to collect samples. We found that the early intervention of LA alleviated the pathological injury and reversed the down-regulation of the duodenal and hepatic tight junction protein mRNA levels caused by S. Typhimurium infection. Compared with S. Typhimurium group, LA early intervention increased the expression of antioxidant enzymes, but decreased the levels of serum malondialdehyde (MDA), interleukin-8 and tumor necrosis factor-α (TNF-α). Additionally, LA early intervention significantly increased Nrf2 mRNA expression in the liver and decreased Keap1 mRNA expression in the duodenum compared to the S. Typhimurium group. Furthermore, early LA treatment reduced the abundance of Bacteroides acidificiens , increased the abundance of Akkermansia , and alleviated the decrease in SCFAs levels in the cecum of S. Typhimurium-infected mice. Spearman correlation analysis showed that there was a certain correlation between cecal flora and serum indicators and short chain fatty acids. Conclusion: Taken together, the results indicate that LA early intervention may alleviates S. Typhimurium-induced inflammation and oxidative responses in mice by activating the p62-Keap1-Nrf2 signaling pathway and regulating the gut microbial community. Significance and impact of the study: Exploring the ability of LA to resist animal oxidative stress and microflora regulation caused by pathogenic microbes, so as to provide more options for developing healthy disease-resistant feed additives. [ABSTRACT FROM AUTHOR]

Sertoli cells (SCs), as the somatic cells in the testis of male mammals, play a crucial role in the close association with germ cells. The blood-testicular barrier (BTB), established by their tight junctions, provides immune protection to germ cells, leading to their characterization as "sentinel" cells. Moreover, the physiological process of testicular development and spermatogenesis in male animals is intricately tied to the secretory activities of SCs. These cells secrete a diverse array of proteins and cytokines that interact with various targets, working in concert with mechanisms in the spermatogenesis pathway and contributing to each stage, from spermatogonial cell division to the maturation of spermatozoa. Hence, the secretory products of SCs are pivotal in fostering germ cell development and directing the appropriate maturation of sperm. This study is dedicated to investigating the varied secretions of SCs, outlining their critical functions throughout distinct phases of spermatogenesis, thus elucidating the substantial influence of SC secretion on male fertility. Furthermore, it offers valuable perspectives on reproductive disorders stemming from irregular spermatogenesis in clinical contexts. [ABSTRACT FROM AUTHOR]

Background: Intestinal larva invasion is a crucial step of Trichinella spiralis infection. Intestinal infective larvae (IIL) and their excretory/secretory proteins (ESP) interact with gut epithelium, which often results in gut epithelium barrier injuries. Previous studies showed when T. spiralis invaded intestinal epithelium cells, the IIL ESP disrupted the tight junctions (TJs) of Caco-2 monolayer, but the mechanism is not clear. The IIL ESP might cause gut epithelial apoptosis, weaken the gut barrier and aid the larval invasion. The aim of this study was to investigate whether T. spiralis IIL ESP participate in enterocyte apoptosis and disrupt gut epithelial barrier to promote the larval invasion. Methodology/Principal findings: Cell viability was assessed by CCK-8 assay and the results showed that 200 μg/ml of IIL ESP incubated with Caco-2 cells for 18 h inhibited the Caco-2 cell viability. The results of trans-epithelial electrical resistance (TEER) and FITC-dextran showed that IIL ESP decreased the TEER, increased FITC-dextran flux in Caco-2 monolayer. qPCR, Western blot and immunofluorescence test (IFT) showed that IIL ESP decreased the mRNA and protein expression of TJs (ZO-1, E-cad, Occludin and Claudin-1). The IIL ESP-induced Caco-2 cell apoptosis was observed by DAPI, Hoechst 33358, TUNEL and Annexin V/PI staining. Besides, flow cytometry revealed an increasing apoptosis rate in Caco-2 cells after the IIL ESP treatment. qPCR and Western blot analysis indicated that IIL ESP activated caspases (Caspase 3, Caspase 9 and Caspase 8), up-regulated the pro-apoptotic factors (Bax and Cytochrome c) and down-regulated the anti-apoptosis molecule Bcl-2. Interestingly, pretreatment of Caco-2 cells with apoptosis inhibitor Z-VAD-FMK abrogated and recovered the barrier function of Caco-2 monolayer destroyed by IIL ESP. Furthermore, the Z-VAD-FMK pretreatment also impeded the in vitro larva invasion of Caco-2 monolayer. Conclusions: T. spiralis IIL ESP induced gut epithelial apoptosis, reduced the TJs expression, damaged gut epithelial integrity and barrier function, and promoted larval invasion. These findings provided a basis of further understanding the interaction mechanism between T. spiralis and host gut epithelium, and they were valuable to the development new prevention and therapeutic strategy of early T. spiralis infection. Author summary: Trichinella spiralis is a nematode of genus Trichinella that infects a variety of mammals worldwide, and intestinal larva invasion is a crucial step of T. spiralis infection. T. spiralis intestinal infective larvae (IIL) and their excretory/secretory proteins (ESP) interact with the host gut epithelium, which promoted the larval invasion, but the IIL invasive mechanism is not clear. Apoptosis is involved in multitudinous pathological process in parasite infection. In this study, the effect of T. spiralis IIL ESP on Caco-2 monolayer barrier function was assessed by using trans-epithelial electrical resistance (TEER), FITC-dextran, qPCR, Western blot and IFT. The results showed that IIL ESP decreased the TEER, increased FITC-dextran flux in Caco-2 monolayer, decreased the expression of tight junctions (TJs; ZO-1, E-cad, Occludin and Claudin-1). These results suggested that IIL ESP damaged the integrity of intestinal epithelium barrier. The IIL ESP-induced Caco-2 cellular apoptosis was observed by DAPI, Hoechst 33358, TUNEL and Annexin V/PI staining. Besides, a flow cytometry exhibited an increasing apoptosis rate of Caco-2 cells treated with IIL ESP. qPCR and Western blot results showed that IIL ESP activated caspases (Caspase 3, Caspase 9 and Caspase 8), up-regulated the pro-apoptotic factors (Bax and Cytochrome c), down-regulated the anti-apoptosis molecule Bcl-2. Pretreatment with apoptosis inhibitor Z-VAD-FMK abrogated and recovered the barrier function of Caco-2 monolayer destroyed by IIL ESP. The inhibitor pretreatment also impeded the in vitro larva invasion of Caco-2 monolayer. These findings demonstrated that IIL ESP mediated larva invasion via inducing gut epithelial apoptosis and damaging gut barrier integrity. [ABSTRACT FROM AUTHOR]

Chemotherapeutic therapies for cancer are frequently associated with cytotoxic side effects that can be harmful to human health, including the development of intestinal mucositis (IM). It mostly affects the gastrointestinal tract, causing ulceration, inflammation, and the formation of lesions in the colon. Surprisingly, despite the frequency of IM, therapeutic choices remain restricted. In our search for new intestinal mucositis therapies, we wanted to see how Lentinan (LT), derived from Lentinus edodes, would fare in mouse models of intestinal mucositis. To create the intestinal mucositis model in mice, we gave them intra-peritoneal doses of 5-fluorouracil (5-FU) (50 mg/kg) and then tested the effects of Lentinan on intestinal mucositis. This examination required constant monitoring of several factors, such as body weight fluctuations, food consumption, and diarrhea. In addition, we measured the levels of certain inflammatory cytokines (Tumour Necrosis Factor-alpha (TNF-α), Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Interleukin-10 (IL-10), looked at the expression of tight junction proteins (Zonula Occludens-1(ZO-1), Claudin-1), measured mucin-2 levels, and looked into changes in the gut flora. In the mouse model of intestinal mucositis, our findings showed that LT effectively reduced weight loss, increased food intake, and relieved diarrhea. Concurrently, we saw a decrease in the expression of inflammatory cytokines such as TNF-α, IL-1, and IL-6, as well as a considerable increase in the concentration of IL-10. Furthermore, LT reduced intestinal mucositis by increasing the length and structural integrity of the colon. Furthermore, increased expression of tight junction proteins (ZO-1, Claudin-1), mucin-2, and an increase in the number of goblet cells all confirmed our previous findings. Notably, the makeup of beneficial bacteria in the stomach increased as well. Finally, our findings suggest that LT can effectively prevent 5-fluorouracil-induced intestinal mucositis in mice by improving immune function, restoring intestinal barrier integrity, and rebalancing gut microbial flora. [ABSTRACT FROM AUTHOR]

Background: A stable and reproducible experimental bacterial pneumonia model postintracerebral hemorrhage (ICH) is necessary to help investigating the pathogenesis and novel treatments of Stroke-associated pneumonia (SAP). Aim: To establish a Gram-negative bacterial pneumonia-complicating ICH rat model and an acute lung injury (ALI)-complicating ICH rat model. Methods: We established two standardized models of post-ICH pneumonia by nasal inoculation with Klebsiella pneumoniae (Kp) or intratracheal inoculation with lipopolysaccharide (LPS). Survival and neurological scores were monitored. Magnetic resonance imaging was performed to evaluate hematoma volume. Abdominal aortic blood was collected for leukocyte counting, serum was isolated to determine concentrations of S100β and proinflammatory cytokines using ELISAs. Histopathological changes of brain, lung and gut were assessed using hematoxylin−eosin staining. Lung was isolated for immunofluorescence staining for myeloperoxidase (MPO). Bronchoalveolar lavage fluid was collected for leukocyte counting, and supernatant was prepared to measure MPO activity. Ileum was isolated for immunofluorescence staining for tight junction proteins ZO-1 and γδ TCRs/IL-17A and for Alcian blue–nuclear fast red staining of acidic mucins. Feces were collected, 16S rRNA sequencing, untargeted metabolomics and Spearman's correlation analyses were performed to explore changes of gut microbiota, metabolites and their interactions. Results: In Kp -induced bacterial pneumonia-complicating ICH rats, we demonstrated that Kp challenge caused more severe neurological deficits, brain damage, neuroinflammation, and aggravated pneumonia and lung injury. Disruptions of the intestinal structure and gut barrier and the reductions of the protective intestinal IL-17A-producing γδT cells were also observed. Kp challenge exacerbated the gut microbiota dysbiosis and fecal metabolic profile disorders, which were characterized by abnormal sphingolipid metabolism especially elevated ceramide levels; increased levels of neurotoxic quinolinic acid and an upregulation of tryptophan (Trp)–serotonin–melatonin pathway. Spearman's correlation analyses further revealed that the reduction or depletion of some beneficial bacteria, such as Allobaculum and Faecalitalea , and the blooming of some opportunistic pathogens, such as Turicibacter , Dietzia , Corynebacterium and Clostridium_sensu_stricto_1 in Kp -induced SAP rats were associated with the disordered sphingolipid and Trp metabolism. Using an LPS-induced ALI complicating ICH model, we also characterized SAP-induced brain, lung and gut histopathology injuries; peripheral immune disorders and intense pulmonary inflammatory responses. Conclusions: These two models may be highly useful for investigating the pathogenesis and screening and optimizing potential treatments for SAP. Moreover, the differential genera and sphingolipid or Trp metabolites identified above seem to be promising therapeutic targets. [ABSTRACT FROM AUTHOR]

The intestinal epithelium, beyond its role in absorption and digestion, serves as a critical protective mechanical barrier that delineates the luminal contents and the gut microbiota from the lamina propria within resident mucosal immune cells to maintain intestinal homeostasis. The barrier is manifested as a contiguous monolayer of specialized intestinal epithelial cells (IEC), interconnected through tight junctions (TJs). The integrity of this epithelial barrier is of paramount. Consequently, excessive IEC death advances intestinal permeability and as a consequence thereof the translocation of bacteria into the lamina propria, subsequently triggering an inflammatory response, which underpins the clinical disease trajectory of inflammatory bowel disease (IBD). A burgeoning body of evidence illustrates a landscape where IEC undergoes several the model of programmed cell death (PCD) in the pathophysiology and pathogenesis of IBD. Apoptosis, necroptosis, and pyroptosis represent the principal modalities of PCD with intricate specific pathways and molecules. Ample evidence has revealed substantial mechanistic convergence and intricate crosstalk among these three aforementioned forms of cell death, expanding the conceptualization of PANoptosis orchestrated by the PNAoptosome complex. This review provides a concise overview of the molecular mechanisms of apoptosis, necroptosis, and pyroptosis. Furthermore, based on the crosstalk between three cell deaths in IEC, this review details the current knowledge regarding PANoptosis in IEC and its regulation by natural products. Our objective is to broaden the comprehension of innovative molecular mechanisms underlying the pathogenesis of IBD and to furnish a foundation for developing more natural drugs in the treatment of IBD, benefiting both clinical practitioners and research workers. [ABSTRACT FROM AUTHOR]

Introduction: Despite evidence of the efficacy of decursinol angelate (DA), a prescription medication derived farom traditional Chinese medicine, in alleviating inflammatory bowel disease (IBD), the precise mechanisms behind its action remain unclear. Methods: Lipopolysaccharides (LPS) and dextran sodium sulfate (DSS) induction were used as in vitro and in vivo models of IBD, respectively, to assess the role of DA in alleviating IBD. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the expression levels of pro-inflammatory cytokines in mouse serum, Western blot was performed to detect the expression of TXNIP/NLRP3 pathway tight junction (TJ) proteins in colon tissues and cells, and immunohistochemistry, immunofluorescence and immunohistochemistry, immunofluorescence and qRT-PCR were used to validate the proteins related to this signaling pathway. Molecular docking technique and co-immunoprecipitation (Co-IP) method assay were applied to evaluate the targeting effect of DA on NLRP3 proteins, and MCC950, a specific inhibitor of NLRP3, was used as a positive control for validation. Results: Our research indicates that DA's distinctive molecular mechanism could entail binding to the NLRP3 protein, thereby suppressing the activation of the NLRP3 pathway and diminishing the assembly and activation of the NLRP3 inflammasome, thus functioning as an anti-inflammatory agent. Conclusion: DA may play a role in improving BD by inhibiting the activation of the ROS/TXNIP/NLRP3 signaling pathway and the release of inflammatory mediators, and by repairing the intestinal barrier function. [ABSTRACT FROM AUTHOR]

Background: Oxyberberine (OBB) is a naturally occurring isoquinoline alkaloid that is believed to possess various health-promoting properties, including anti-fungus, hepatoprotection, anti-inflammation, and anti-intestinal mucositis effects. Despite several studies reporting the health benefits of OBB in treating ulcerative colitis (UC), its specific mechanism of action has yet to be fully elucidated. Purpose: This investigation is designed to explore the potential protective efficacy of OBB and the latent mechanism using an in vitro model of UC-like inflammatory intestinal cells. Methods: Caco-2 cells were pretreated with OBB and subsequently exposed to lipopolysaccharide (LPS). The transepithelial electrical resistance (TEER), paracellular permeability, and the distribution and expression of tight- and adherent junction proteins were determined to assess barrier integrity. The levels of proinflammatory cytokines, reactive oxygen species (ROS), Nrf2, and NF-κB signaling cascade were analyzed via ELISA, qRT-PCR, immunofluorescence, or Western blotting. Results: OBB was found to mitigate the effects of LPS on Caco-2 cell monolayers, as evidenced by the improvement in TEER and the decrease in FITC-dextran flux. Moreover, OBB ameliorated the LPS-induced decrease in the distribution and expression of several tight junction markers, including ZO-1, occludin, and E-cadherin. In addition, OBB treatment effectively inhibited LPS-induced increases in ROS, apoptosis, and Keap1 and decreases in Nrf2 and HO-1. LPS-induced elevations in nuclear NF-κB p65 and p-IκBα were suppressed by OBB. In addition, ML385, an antagonist of Nrf2, abolished the protective role of OBB. Conclusion: OBB has a pronounced beneficial effect on LPS-induced damage to enteral barrier function, and the regulation of the Nrf2/NF-κB pathway is an important mechanism responsible for the protection afforded by OBB. [ABSTRACT FROM AUTHOR]

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The blood-brain barrier (BBB) maintains brain homeostasis but also prevents most drugs from entering the brain. No paracellular diffusion of solutes is allowed because of tight junctions that are made impermeable by the expression of claudin5 (CLDN5) by brain endothelial cells. The possibility of regulating the BBB permeability in a transient and reversible fashion is in strong demand for the pharmacological treatment of brain diseases. Here, we designed and tested short BBB-active peptides, derived from the CLDN5 extracellular domains and the CLDN5-binding domain of Clostridium perfringens enterotoxin, using a robust workflow of structural modeling and in vitro validation techniques. Computational analysis at the atom level based on solubility and affinity to CLDN5 identified a CLDN5-derived peptide not reported previously called f1-C5C2, which was soluble in biological media, displayed efficient binding to CLDN5, and transiently increased BBB permeability. The peptidomimetic strategy described here may have potential applications in the pharmacological treatment of brain diseases. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Trichinella spiralis (T. spiralis) is a highly pathogenic zoonotic nematode that poses significant public health risks and causes substantial economic losses. Understanding its invasion mechanisms is crucial. This study explored how the serine protease inhibitors (SPIs) secreted by T. spiralis affect the host's intestinal epithelial barrier. Furthermore, the effects of T. spiralis infection on the jejunal barrier function in mice were investigated. The histopathological analysis indicated significant damage to the jejunum, which peaked at day 7 post-infection (dpi). The results of RT-qPCR and western blotting revealed marked reductions in tight junction proteins (ZO-1, occludin, claudin-3), mucins (MUC-1, MUC-2), and anti-inflammatory cytokines (TGF-β, IL-10) from 1 to 15 dpi. There was also increased expression of Toll-like receptors (TLR-1, TLR-2, TLR-4) and pro-inflammatory cytokines (TNF-α, IL-1β). Recombinant SPIs (rKaSPI, rAdSPI) were purified, co-cultured with intestinal epithelial cells (IPECs), and used in mouse models. The protein expression changes in IPECs and mice were consistent with those in T. spiralis-infected tissues. Both SPIs caused the down-regulation of ZO-1, occludin, claudin-3, MUC-1, MUC-2, TGF-β, and IL-10 while up-regulating TLR-4 and pro-inflammatory cytokines. As a result, the intestinal barrier was disrupted, and inflammation was exacerbated. Notably, rAdSPI had a more pronounced effect. In summary, T. spiralis infection caused significant jejunal damage and disrupted the intestinal barrier. T. spiralis-secreted SPIs, especially serpin-type serine protease inhibitors (AdSPI), were pivotal in facilitating invasion by compromising the host's intestinal barrier and promoting inflammation. This study provides insights into T. spiralis invasion mechanisms and the potential targets for trichinellosis prevention and control. [ABSTRACT FROM AUTHOR]

The intestinal barrier function is a critical defense mechanism in the human body, serving as both the primary target and initiating organ in cases of sepsis. Preserving the integrity of this barrier is essential for preventing complications and diseases, including sepsis and mortality. Despite this importance, the impact of resveratrol on intestinal barrier function remains unclear. Thus, this study aims to explore the potential beneficial effects of resveratrol on maintaining intestinal barrier function. Fifteen male Sprague Dawley rats, weighing between 180 g and 220 g, were randomly assigned to one of three groups: the control group (Con), the lipopolysaccharide (LPS) group, and the resveratrol (RSV) group. The resveratrol group received an intravenous administration of resveratrol at a dosage of 8 mg/kg, 10 min prior to lipopolysaccharide treatment. Each group comprised five rats. Various techniques including enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin staining (HE), periodic acid Schiff (PAS) staining, transmission electron microscopy (TEM), Western blot analysis (WB), and quantitative real-time polymerase chain reaction (qRT-PCR) were utilized to assess differences in inflammatory cytokine expression, histopathological changes, apoptosis, tight junction (TJ) protein, and the TLR4/MyD88/NF-кB signaling pathways. Resveratrol exhibited anti-inflammatory effects by decreasing levels of interleukin (IL)-1β, interleukin(IL)-6, and tumor necrosis factor (TNF)-α, while increasing interleukin (IL)-10. Additionally, in rats treated with resveratrol, there was a reduction in the expression of apoptosis-associated proteins Bax and Caspase-3. Resveratrol also significantly increased the expression of intestinal tight junction proteins (TJ), and decreased the levels of intestinal fatty acid binding protein (I-FABP) and D-lactic acid (D-LA). Furthermore, the expression of proteins in the related signaling pathways TLR4, MyD88, and NF-κB was decreased. Resveratrol has been shown to reduce the expression of intestinal apoptotic proteins, enhance the expression of intestinal tight junction proteins, and inhibit the inflammatory response mediated by the TLR4/MyD88/NF-κB signaling pathway, thereby alleviating LPS-induced septic intestinal injury. [ABSTRACT FROM AUTHOR]

Bacteroides fragilis (B. fragilis) is a Gram-negative, obligate anaerobic, commensal bacterium residing in the human gut and holds therapeutic potential for ulcerative colitis (UC). Previous studies have indicated that capsular polysaccharide A (PSA) of B. fragilis is a crucial component for its effectiveness, possessing various biological activities such as anti-inflammatory, anti-tumor, and immune-modulating effects. We previously isolated and characterized the B. fragilis strain ZY-312 from the feces of a healthy breastfed infant, and extracted its PSA, named TP2. In this study, we explored the impact of TP2 on colonic inflammation and delved into its potential mechanisms. Initially, we used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis in rats and found that TP2 treatment significantly ameliorated TNBS-induced weight loss, increased clinical scores, extensive ulcers, and intestinal epithelial damage in UC rats. Further analysis revealed that TP2 effectively restored the intestinal barrier integrity in UC rats by regulating the expression of Muc-2, tight junction proteins (ZO-1, occludin, claudin-1, and claudin-2), as well as apoptosis-related proteins Bcl-2, BAX, and Cleaved-Caspase-3. Additionally, TP2 suppressed the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL23, while promoting the secretion of anti-inflammatory cytokines IL-10 and IL-22, thereby inhibiting the occurrence of inflammation. TP2 also downregulated the phosphorylation levels of AKT and PI3K, effectively inhibiting the abnormal activation of the PI3K/AKT signaling pathway. More interestingly, 16S rRNA sequencing results showed that TP2 restored the ecological imbalance of the rat intestinal microbiota, with an increase in beneficial bacteria such as Lactobacillus and Limosilactobacillus observed in the treatment group. In conclusion, TP2 through the regulation of intestinal barrier-related cells and proteins, inhibition of apoptosis, modulation of inflammation-related cytokine levels, and control of abnormal activation of the PI3K/AKT signaling pathway, restores intestinal barrier integrity. Additionally, by reshaping the ecological imbalance of the gut microbiota, TP2 ultimately alleviates ulcerative colitis in rats. [ABSTRACT FROM AUTHOR]

AIM To elucidate the intervention and mechanism of 4'-hydroxychalcone (4-HC) in colitis mice through the regulation of Th17/Treg homeostasis. METHODS Using a dextran sodium sulfate (DSS)-induced colitis model in mice, we meticulously observed the pathological characteristics of colon tissue via HE staining. Additionally, we employed immune histochemical analysis and Western blot techniques to assess the expression levels of proteins associated with the JAK/STAT signaling pathway, as well as the specific content of tight junction proteins such as ZO-1 and occludin. The differentiation of Th17 and Treg cells was analyzed through flow cytometry. RESULTS Compared to the normal group, the DSS group exhibited a consistent decline in body weight, coupled with symptoms of diarrhea and hematochezia, an increase in the DAI score, and a notable reduction in colon length. In contrast, the body weight of the 4-HC group displayed an upward trend following an initial decrease, with improvements in diarrhea and hematochezia symptoms, a reduction in the DAI score, and a restoration of colon length relative to the model group. The integrity of colon tissue in the 4-HC group was significantly better than that in the DSS group, evidenced by a marked increase in the number of goblet cells and an enhancement in crypt integrity, while the average histology score showed a decrease. Western blot analysis revealed substantial increase in ZO-1 and occludin expression after 4-HC treatment. Flow cytometry results indicated a dramatic decrease in the differentiation rate of Th17 cells in spleen lymphocytes and mesenteric lymph nodes, while the differentiation rate of Treg cells was significantly elevated. Immunohistochemical and Western blot analyses demonstrated that 4-HC markedly reduced the phosphorylation of STAT1 and STAT3, while up-regulating the phosphorylation of STAT6, suggesting that 4-HC modulates CD4+ T cell activity through the JAK-STAT pathway. CONCLUSION The 4-HC may enhance the course of DSS-induced colitis in mice, alleviate colonic tissue damage, and modulate the balance between Th17 and Treg cells, potentially involving the JAK/STAT signaling pathway. [ABSTRACT FROM AUTHOR]

Fusarium mycotoxins often co-occur in broiler feed, and their presence negatively impacts health even at subclinical concentrations, so there is a need to identify the concentrations of these toxins that do not adversely affect chickens health and performance. The study was conducted to evaluate the least toxic effects of combined mycotoxins fumonisins (FUM), deoxynivalenol (DON), and zearalenone (ZEA) on the production performance, immune response, intestinal morphology, and nutrient digestibility of broiler chickens. A total of 960 one-day-old broilers were distributed into eight dietary treatments: T1 (Control); T2: 33.0 FUM + 3.0 DON + 0.8 ZEA; T3: 14.0 FUM + 3.5 DON + 0.7 ZEA; T4: 26.0 FUM + 1.0 DON + 0.2 ZEA; T5: 7.7 FUM + 0.4 DON + 0.1 ZEA; T6: 3.6 FUM + 2.5 DON + 0.9 ZEA; T7: 0.8 FUM + 1.0 DON + 0.3 ZEA; T8: 1.0 FUM + 0.5 DON + 0.1 ZEA, all in mg/kg diet. The results showed that exposure to higher mycotoxin concentrations, T2 and T3, had significantly reduced body weight gain (BWG) by 17% on d35 (p < 0.05). The T2, T3, and T4 groups had a significant decrease in villi length in the jejunum and ileum (p < 0.05) and disruption of tight junction proteins, occludin, and claudin-4 (p < 0.05). Higher mycotoxin groups T2 to T6 had a reduction in the digestibility of amino acids methionine (p < 0.05), aspartate (p < 0.05), and serine (p < 0.05); a reduction in CD4+, CD8+ T-cell populations (p < 0.05) and an increase in T regulatory cell percentages in the spleen (p < 0.05); a decrease in splenic macrophage nitric oxide production and total IgA production (p < 0.05); and upregulated cytochrome P450-1A1 and 1A4 gene expression (p < 0.05). Birds fed the lower mycotoxin concentration groups, T7 and T8, did not have a significant effect on performance, intestinal health, and immune responses, suggesting that these concentrations pose the least negative effects in broiler chickens. These findings are essential for developing acceptable thresholds for combined mycotoxin exposure and efficient feed management strategies to improve broiler performance. [ABSTRACT FROM AUTHOR]

Background: (-)-Fenchone is a bicyclic monoterpene present in the plant species Foeniculum vulgare Mill, Thuja occidentalis L. (tuja), and Lavandula stoechas (lavender). These plants have therapeutic value in the treatment of intestinal disorders. Aim: To evaluate intestinal anti-inflammatory activity in an acute and chronic trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. Methods: Intestinal anti-inflammatory effects were assessed using the acute and chronic TNBS-induced colitis model in rats. The mechanisms were evaluated from colonic tissue fragments of the acute and chronic models. Results: Oral administration of the (-)-fenchone (37.5–300 mg/kg) acute phase or (150 mg/kg) (p < 0.001) chronic phase reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. At a dose of 150 mg/kg, the acute and chronic phase decreased malondialdehyde (MDA) and myeloperoxidase (MPO) (p < 0.001), restored glutathione (GSH) levels and superoxide dismutase (SOD) (p < 0.001), decreased immunomarking for factor nuclear kappa B (NF-κB) and levels of interleukin (IL)-1 and tumor necrosis factor α (TNF-α), and maintained IL-10 and TGF-β basal levels. Furthermore, increased immunostaining for zonula occludens 1 (ZO-1) was observed. Conclusions: (-)-fenchone has intestinal anti-inflammatory activity related to cytoprotection of the intestinal barrier, as well as antioxidant and immunomodulatory effects. [ABSTRACT FROM AUTHOR]

Microplastics, defined as plastic fragments smaller than 5 mm, degrade from larger pollutants, with nanoscale microplastic particles presenting significant biological interactions. This study investigates the toxic effects of polystyrene nanoplastics (PS-NPs) on juvenile mice, which were exposed through lactation milk and drinking water at concentrations of 0.01 mg/mL, 0.1 mg/mL, and 1 mg/mL. The results show that PS-NP exposure during lactation and juvenile periods caused delayed weight gain and impaired organ development, particularly in the liver and kidneys, without causing functional abnormalities or toxic injuries. The primary toxicity of PS-NPs was observed in the intestinal tract, including shortened villi, disrupted tight junctions, inhibited epithelial cell proliferation, and oxidative stress responses. These findings highlight the importance of evaluating the developmental toxicity of nanoplastics at environmentally relevant doses. [ABSTRACT FROM AUTHOR]