Ginkgetin improved experimental colitis by inhibiting intestinal epithelial cell apoptosis through EGFR/PI3K/AKT signaling.

Excessive apoptosis of intestinal epithelial cells leads to intestinal barrier dysfunction, which is not only one of the pathological features of inflammatory bowel disease (IBD) but also a therapeutic target. A natural plant extract, Ginkgetin (GK), has been reported to have anti-apoptotic activity, but its role in IBD is unknown. This study aimed to explore whether GK has anti-colitis effects and related mechanisms. An experimental colitis model induced by dextran sulfate sodium (DSS) was established, and GK was found to relieve colitis in DSS-induced mice as evidenced by improvements in weight loss, colon shortening, Disease Activity Index (DAI), macroscopic and tissue scores, and proinflammatory mediators. In addition, in DSS mice and TNF-α-induced colonic organoids, GK protected the intestinal barrier and inhibited intestinal epithelial cell apoptosis, by improving permeability and inhibiting the number of apoptotic cells and the expression of key apoptotic regulators (cleaved caspase 3, Bax and Bcl-2). The underlying mechanism of GK's protective effect was explored by bioinformatics, rescue experiments and molecular docking, and it was found that GK might directly target and activate EGFR, thereby interfering with PI3K/AKT signaling to inhibit apoptosis of intestinal epithelial cells in vivo and in vitro. In conclusion, GK inhibited intestinal epithelial apoptosis in mice with experimental colitis, at least in part, by activating EGFR and interfering with PI3K/AKT activation, explaining the underlying mechanism for ameliorating colitis, which may provide new options for the treatment of IBD.

A non-invasive osteopontin-targeted phase changeable fluorescent nanoprobe for molecular imaging of myocardial fibrosis.

Due to the elevated fatality rate of cardiovascular diseases, myocardial fibrosis emerges as a prominent pathological alteration in the majority of heart ailments and their associated pathologies, thereby augmenting the likelihood of sudden cardiac death. Consequently, the prompt and obligatory identification of myocardial fibrosis assumes paramount importance in averting malignant incidents among patients afflicted with cardiac disorders. Herein, with higher expression osteopontin (OPN) found in cardiac fibrosis tissue, we have developed a dual-modality imaging probe, namely OPN targeted nanoparticles (OPN@PFP-DiR NPs), which loaded perfluoropentane (PFP) for ultrasound (US) and 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) for near-infrared fluorescence (NIR) of molecular imaging, to investigate the molecular features of cardiac fibrosis using US and NIR imaging. Subsequently, the OPN@PFP-DiR NPs were administered intravenously to a mouse model of myocardial infarction (MI). The US and NIR molecular imaging techniques were employed to visualize the accumulation of the nanoparticles in the fibrotic myocardium. Hence, this research presents a valuable noninvasive, cost-effective, and real-time imaging method for evaluating cardiac fibrosis, with promising clinical applications.

Effects of natural products on angiogenesis in melanoma.

Melanoma is the most aggressive form of skin cancer and originates from genetic mutations in melanocytes. The disease is multifactorial, but its main cause is overexposure to UV radiation. Currently, available chemotherapy expresses little to no results, which may justify the extensive use of natural products to treat this cancer. In this study, we reviewed the inhibition of melanoma angiogenesis by natural products and its potential mechanisms using literature from PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases. According to summarizes 27 natural products including alkaloids, polyphenols, terpenoids, flavonoids, and steroids that effectively inhibit angiogenesis in melanoma. In addition to these there are 15 crude extracts that can be used as promising agents to inhibit angiogenesis, but their core components still deserve further investigation. There are current studies on melanoma angiogenesis involving oxidative stress, immune-inflammatory response, cell proliferation and migration and capillary formation. The above natural products can be involved in melanoma angiogenesis through core targets such as VE-cadherin, COX-2, iNOS, VEGF, bFGF, FGF2,MMP2,MMP9,IL-1ß,IL-6 play a role in inhibiting melanoma angiogenesis. Effective excavation of natural products can not only clarify the mechanism of drug action and key targets, but also help to promote the preclinical research of natural products for melanoma treatment and further promote the development of new clinical drugs, which will bring the gospel to the vast number of patients who are deeply afflicted by melanoma.

Building Vulnerability to Landslides: Broad-Scale Assessment in Xinxing County, China.

This study develops a model to assess building vulnerability across Xinxing County by integrating quantitative derivation with machine learning techniques. Building vulnerability is characterized as a function of landslide hazard risk and building resistance, wherein landslide hazard risk is derived using CNN (1D) for nine hazard-causing factors (elevation, slope, slope shape, geotechnical body type, geological structure, vegetation cover, watershed, and land-use type) and landslide sites; building resistance is determined through quantitative derivation. After evaluating the building susceptibility of all the structures, the susceptibility of each village is then calculated through subvillage statistics, which are aimed at identifying the specific needs of each area. Simultaneously, different landslide hazard classes are categorized, and an analysis of the correlation between building resistance and susceptibility reveals that building susceptibility exhibits a positive correlation with landslide hazard and a negative correlation with building resistance. Following a comprehensive assessment of building susceptibility in Xinxing County, a sample encompassing different landslide intensity areas and susceptibility classes of buildings was chosen for on-site validation, thus yielding an accuracy rate of the results as high as 94.5%.

[Bi10{RuPPh3}3]-: Paramagnetic 13-Vertex Polybismuthide Heteroanion.

Ru(PPh3)3Cl2 reacts with Binn- from an ethylenediamine (en) solution of K5Bi4 to yield a new architype of 13-vertex [Bi10{RuPPh3}3]- (1) composed of unprecedented incomplete cuboidal Bi73- and triangular Bi33- held together by {RuPPh3}2+.

Effect of Sheet Properties of Cellulosic Polyglycidyl Methacrylate-Grafted Fibers in a Cationic Polyacrylamide/SiO2/Anionic Polyacrylamide Retention Aid System.

As increasing fiber hydrophobicity can significantly improve the paper dewatering process, we found that replacing SBKP and HBKP with 0.5% superhydrophobic CPGMA can significantly improve the dewatering of paper sheets. Therefore, it can be concluded that if CPGMA has little effect on paper properties, it will have potential industrial value in the papermaking industry. Consequently, it is necessary to further study the effect of the CPGMAs@CPAM/SiO2/APAM system on paper properties. To evaluate the application potential of the system in the papermaking industry, we investigated the effects of CPGMAs, which replaced the fibers in the stocks, on the paper properties in the CPAM/SiO2/APAM system. The findings demonstrate that as the CPGMA replacement increased, the paper's tensile strength, bursting strength, tear resistance, and folding endurance all declined. The trend can be segmented into two phases: a rapid decrease for substitution amounts below 0.5% and a gradual decline for substitution amounts exceeding 0.5%. When replaced with a small amount of CPGMAs, there was a negligible effect on these properties. Second, the paper air permeability increased with the CPGMA substitution amount in the stock. Furthermore, the trend of paper air permeability can be divided into two stages-a rapid stage with a substitution amount of <0.5% and a slow stage with a substitution amount of >0.5%. A small amount of CPGMAs could distinctly improve the paper's air permeability. Third, CPGMAs, which replaced fibers in the stock, minutely affected the paper formation. A small amount of CPGMAs substantially boosted the efficacy of the process of paper manufacture and certain characteristics of the paper, and it had a negligible impact on the strength of paper. The CPGMAs@CPAM/SiO2/APAM technology has the potential to improve the retention and filtration performance of CPAM/SiO2/APAM.

Peiminine ameliorates Crohn's disease-like colitis by enhancing the function of the intestinal epithelial barrier through Nrf2/HO1 signal.

BACKGROUND AND AIMS: Impaired intestinal barrier function is key in maintaining intestinal inflammation in Crohn's disease (CD). However, no targeted treatment in clinical practice has been developed. Peiminine (Pm) strongly protects the epithelial barrier, the purpose of this study is to investigate whether Pm affects CD-like colitis and potential mechanisms for its action. METHODS: Trinitro-benzene-sulfonic acid (TNBS)-induced mice and Il-10-/- mice were used as CD animal models. Colitis symptoms, histological analysis, and intestinal barrier permeability were used to assess the Pm's therapeutic effect on CD-like colitis. The colon organoids were induced by TNF-α to evaluate the direct role of Pm in inhibiting apoptosis of the intestinal epithelial cells. Western blotting and small molecule inhibitors were used to investigate further the potential mechanism of Pm in inhibiting apoptosis of intestinal epithelial cells. RESULTS: Pm treatment reduced body weight loss, disease activity index (DAI) score, and inflammatory score, demonstrating that colonic inflammation in mice were alleviated. Pm decreased the intestinal epithelial apoptosis, improved the intestinal barrier function, and prevented the loss of tight junction proteins (ZO1 and claudin-1) in the colon of CD mice and TNF-α-induced colonic organoids. Pm activated Nrf2/HO1 signaling, which may protect intestinal barrier function. CONCLUSIONS: Pm inhibits intestinal epithelial apoptosis in CD mice by activating Nrf2/HO1 pathway. This partially explains the potential mechanism of Pm in ameliorating intestinal barrier function in mice and provides a new approach to treating CD.

Preparation of Al-doped mesoporous silica spheres (Al-MSSs) for the improvement of mechanical properties and aging resistance of dental resin composites.

OBJECTIVE: The purpose of this study was to synthesize Al-doped mesoporous silica spheres (Al-MSSs) and evaluate the effect of them as functional fillers on the mechanical properties and aging resistance of dental resin composites. METHODS: Al-MSSs were prepared by a two-step method. The effect of Al-MSSs on the performance of the composites was evaluated using neat resin matrix, commercial composites 3M Z350XT and samples containing mesoporous silica spheres (MSSs) and nonporous silica spheres (NSSs) as control. The neat resin matrix consisted of resin monomer (Bisphenol A glycerolate dimethacrylate/triethylene glycol dimethacrylate, 49.5/49.5, wt%) and photoinitiator (camphor quinone/Ethyl-4-dimethylaminobenzoate, 0.2/0.8, wt%). The mechanical properties (flexural strength, flexural modulus, compressive strength and microhardness) of them were evaluated by a universal testing machine and microhardness tester. The mechanical stabilities of the prepared composites in wet environment were evaluated by immersing them in deionized water at 37 °C. In addition, we evaluated the effect of Al-MSSs on other properties of the dental resin composites such as polymerization shrinkage, degree of conversion, curing depth, contact angle, water sorption and solubility according to ISO 4049: 2019. RESULTS: The synthesized Al-MSSs possessed good dispersibility with an average particle size of about 505 ± 16 nm. The mechanical properties of resin composites gradually increased with the increase of the loading amounts of inorganic fillers. The reinforcing effect of Al-MSSs was similar to that of MSSs and better than that of the NSSs groups at the same filler loading. After aging in deionized water at 37 °C for 30 days, the mechanical properties of all resin composites decreased. However, the decrease percentage of the composites filled with Al-MSSs was significantly lower than the other groups, indicating that the stability of the dental composites in wet environments was significantly improved by the Al-MSSs fillers. Furthermore, Al-MSSs had no obvious influence on the biocompatibility and other properties of dental resins. SIGNIFICANCE: The prepared Al-MSSs could effectively improve the mechanical properties and aging resistance without sacrificing other physic-chemical properties of dental resin composites.

Complanatuside A ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice by regulating the Th17/Treg balance via the JAK2/STAT3 signaling pathway.

Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti-inflammatory activities and our study aimed to identify its effect on TNBS-induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS-induced colitis, which may provide novel strategies for CD treatment.

Magnolin inhibits intestinal epithelial cell apoptosis alleviating Crohn's disease-like colitis by suppressing the PI3K/AKT signalling pathway.

BACKGROUND AND AIMS: Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved. METHODS: Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis. RESULTS: The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro. CONCLUSIONS: MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD.

Sclareol protected against intestinal barrier dysfunction ameliorating Crohn's disease-like colitis via Nrf2/NF-B/MLCK signalling.

BACKGROUND: Inflammation-induced intestinal barrier dysfunction is not only a pathological feature of Crohn's disease (CD) but also an important therapeutic target. Sclareol (SCL) is a nontoxic natural plant compound with anti-inflammatory effect, but its role in CD has not been established. METHODS: In vivo studies of mice with TNBS-induced colitis were carried out to evaluate the effects of SCL on CD-like colitis and intestinal barrier function. In vitro, a TNF-α-induced colonic organoid model was established to test the direct effect of SCL on inflammation-induced intestinal barrier injure and inflammatory response. The Nrf2/NF-κB/MLCK signalling was analysed to explore the mechanism of SCL. RESULTS: In vivo, SCL largely alleviated the colitis in TNBS mice, as evidenced by improvements in the weight loss, colitis symptoms, endoscopic score, macroscopic histological score, and histological inflammation score. Moreover, SCL significantly improved intestinal barrier dysfunction, manifested as reduced intestinal permeability and decreased intestinal bacterial translocation in TNBS mice. Importantly, SCL antagonised the intestinal mucosal inflammation while protecting tight junctions in TNBS mice. In vitro, SCL largely depressed pro-inflammatory cytokines levels and improved intestinal epithelial permeability in a TNF-α-induced colonic organoid model. In the context of CD, the protective effects of SCL against inflammation and intestinal barrier damage are at least partially results from the Nrf2 signalling activation and the NF-κB/MLCK signalling inhibition. CONCLUSIONS: SCL improved intestinal barrier dysfunction and alleviated CD-like colitis, possibly through modulation of Nrf2/NF-κB/MLCK signalling. In view of SCL's safety profile, there is hope that it will be useful in the clinic.

Bumblebee Foraging Dynamics and Pollination Outcomes for Cherry Tomato and Pear Varieties in Northern China.

Bumblebees (Bombus terrestris) have strong environmental adaptability and high pollen transfer efficiency, making them well-suited pollinators of economic crops. However, bumblebee pollination is still not widely applied in northern China due to the lack of data on foraging behavior and pollination effects. We conducted a three-year experiment involving cherry tomatoes (Solanum lycopersicum L.) and pears (Pyrus spp.) treated with bumblebee pollination to evaluate the foraging behavior and pollination effects on these two crops. Results showed that B. terrestris had enhanced foraging activities as daytime temperatures rose from 18 °C to 26 °C, as indicated by the increased number of bees leaving the hive and returning bees carrying pollen in greenhouses in winter. There were two peaks in the foraging activity of bumblebees in pear orchards in early spring, which was closely related to the temperature change in the daytime. Undoubtedly, cherry tomatoes treated with B. terrestris had higher fruit setting rate, weight, seed number, and fruit yields compared to those with hormone 2,4-dichlorophenoxyacetic acid treatments, as well as a lower rate of deformed fruits. B. terrestris pollination can significantly increase the fruit setting rate and fruit yield of pears, compared with open pollination, and can fully achieve the effect of hand pollination. B. terrestris pollination can improve cultivation efficiency, increase yield, and produce more economic benefits. Moreover, it can also contribute to reducing hormone residues and ensure the safety of agricultural products. We recommend its application to cherry tomatoes in greenhouses in winter and potential application to pears in orchards in early spring in northern China. However, the risk to local bumblebee species of introducing commercially available bumblebees into orchards should be considered and evaluated in future research. This study provides both empirical support and a theoretical basis for the selection of bumblebees as pollinators in the production of economically important crops and the improvement of crop cultivation management in northern China.

HA2-FimA DNA Vaccine Treats Experimental Periodontitis.

PURPOSE: To study the therapeutic effect of hemagglutinin-2 and fimbrial (HA2-FimA) vaccine on experimental periodontitis in rats. MATERIALS AND METHODS: The first batch of rats was divided into two groups and immunised with pure water or pVAX1-HA2-FimA at the age of 6, 7, and 9 weeks. After sacrificing the animals, total RNA was extracted from the spleens for RNA high-throughput sequencing (RNA-Seq) analysis. The second batch of rats was divided into four groups (A, B, C, D), and an experimental periodontitis rat model was established by suturing silk thread around the maxillary second molars of rats in groups B, C, and D for 4 weeks. The rats were immunised with pure water, pVAX1-HA2-FimA vaccine, empty pVAX1 vector, and pure water at 10, 11, and 13 weeks of age, respectively. Secretory immunoglobulin A (SIgA) antibodies and cathelicidin antimicrobial peptide (CAMP) levels in saliva were measured by enzyme-linked immunosorbent assay (ELISA). All rats were euthanised at 17 weeks of age, and alveolar bone loss was examined using micro-computed tomography (Micro-CT). RESULTS: Through sequencing analysis, six key genes, including Camp, were identified. Compared with the other three groups, the rats in the periodontitis+pVAX1-HA2-FimA vaccine group showed higher levels of SIgA and CAMP (p < 0.05). Micro-CT results showed significantly less alveolar bone loss in the periodontitis+pVAX1-HA2-FimA vaccine group compared to the periodontitis+pVAX1 group and periodontitis+pure water group (p < 0.05). CONCLUSION: HA2-FimA DNA vaccine can increase the levels of SIgA and CAMP in the saliva of experimental periodontitis model rats and reduce alveolar bone loss.

A novel GSK3ß inhibitor 5n attenuates acute kidney injury.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality caused by various factor. The specific strategies for AKI are still lacking. GSK3ß is widely expressed in the kidneys. In acute models of injury, GSK3ß promotes the systemic inflammatory response, increases the proinflammatory release of cytokines, induces apoptosis, and alters cell proliferation. We screened a series of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives which are recognized as new GSK3ß inhibitors, and found that 5n had the least toxicity and the best cell protection. We then tested the anti-inflammatory and reno-protective effect of 5n in cisplatin-treated tubular epithelial cells. 5n had anti-inflammation effect indicated by phosphor-NF-κB detection. Finally, we found that 5n ameliorated renal injury and inflammation in cisplatin-induced AKI mouse model. Silencing GSK3ß inhibited cell injury and inflammation induced by cisplatin. We found that GSK3ß interacted with PP2Ac to modulate the activity of NF-κB. In conclusion, 5n, the novel GSK3ß inhibitor, protects against AKI via PP2Ac-dependent mechanisms which may provide a potential strategy for the treatment of AKI in clinic.

Dietary intakes of vitamin D promote growth performance and disease resistance in juvenile grass carp (Ctenopharyngodon idella).

Vitamin D3 (VD3) is an essential nutrient for fish and participates in a variety of physiological activities. Notably, both insufficient and excessive supplementation of VD3 severely impede fish growth, and the requirements of VD3 for fish vary considerably in different species and growth periods. The present study aimed to evaluate the appropriate requirements of VD3 for juvenile grass carp (Ctenopharyngodon idella) according to growth performance and disease prevention capacity. In this study, diets containing six supplemental levels of VD3 (0, 300, 600, 1200, 2400, and 4800 IU/kg diet) were formulated to investigate the effect(s) of VD3 on the growth performance, antioxidant enzyme activities, and antimicrobial ability in juvenile grass carp. Compared with the VD3 deficiency group (0 IU/kg), the supplementation of 300-2400 IU/kg VD3 significantly enhanced growth performance and increased antioxidant enzyme activities in the fish liver. Moreover, dietary supplementation of VD3 significantly improved the intestinal health by manipulating the composition of intestinal microbiota in juvenile grass carp. In agreement with this notion, the mortality of juvenile grass carp fed with dietary VD3 was much lower than that in VD3 deficient group upon infection with Aeromonas hydrophila. Meanwhile, dietary supplementation of 300-2400 IU/kg VD3 reduced bacterial load in the spleen and head kidney of the infected fish, and 1200 IU/kg VD3 supplementation could decrease enteritis morbidity and increase lysozyme activities in the intestine. These findings strengthened the essential role of dietary VD3 in managing fish growth and antimicrobial capacity. Additionally, based on weight gain ratio and lysozyme activities, the appropriate VD3 requirements for juvenile grass carp were estimated to be 1994.80 and 2321.80 IU/kg diet, respectively.

Mild hypothermia reduces lipopolysaccharide-induced microglial activation via down-regulation of Tent5c.

Microglial activation is a critical factor in the pathogenesis and progression of neuroinflammatory diseases. Mild hypothermia, known for its neuroprotective properties, has been shown to alleviate microglial activation. In this study, we explore the differentially expressed (DE) mRNAs and long non-coding RNAs (lncRNAs) in BV-2 microglial cells under different conditions: normal temperature (CN), mild hypothermia (YT), normal temperature with lipopolysaccharide (LPS), and mild hypothermia with LPS (LPS + YT). Venn analysis revealed 119 DE mRNAs that were down-regulated in the LPS + YT vs LPS comparison but up-regulated in the CN vs LPS comparison, primarily enriched in Gene Ontology terms related to immune and inflammatory responses. Furthermore, through Venn analysis of YT vs CN and LPS + YT vs LPS comparisons, we identified 178 DE mRNAs and 432 DE lncRNAs. Among these transcripts, we validated the expression of Tent5c at the protein and mRNA levels. Additionally, siRNA-knockdown of Tent5c attenuated the expression of pro-inflammatory genes (TNF-α, IL-1ß, Agrn, and Fpr2), cellular morphological changes, NLRP3 and p-P65 protein levels, immunofluorescence staining of p-P65 and number of cells with ASC-speck induced by LPS. Furthermore, Tent5c overexpression further potentiated the aforementioned indicators in the context of mild hypothermia with LPS treatment. Collectively, our findings highlight the significant role of Tent5c down-regulation in mediating the anti-inflammatory effects of mild hypothermia.

[Prunetin inhibits TLR4/MyD88 pathway to attenuate intestinal epithelial inflammatory response and ameliorate mouse Crohn's disease-like colitis].

Objective To investigate the regulatory role of natural plant compound prunetin (PRU) on the intestinal epithelial inflammation and the barrier structure in Crohn's disease-like colitis. Methods A lipopolysaccharide (LPS)-induced inflammatory injury model of colonic organoids and a 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model were established to evaluate the effects of PRU on the intestinal epithelial inflammation and intestinal barrier. In addition, network pharmacological predictions, combined with in vitro and in vivo studies, were used to analyze the molecular mechanisms by which PRU modulates intestinal epithelial inflammation and intestinal barrier in CD-like colitis. Results PRU inhibited the release of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß in LPS-induced colonic organoids, and ameliorated the colitis symptoms in TNBS-induced mice, including body mass loss, elevated disease activity index and increased inflammation scores. Meanwhile, PRU promoted the expression of tight junction proteins (ZO-1 and claudin-1) and improved their translocation restoration in LPS-induced colonic organoids and TNBS-induced intestinal epithelial cells, while maintaining the intestinal barrier structure. Mechanistically, PRU targeted the Toll-like receptor 4 (TLR4) and inhibited the activation of the TLR4/myeloid differentiation primary response gene 88 (MyD88) signaling pathway. Conclusion PRU can antagonize TLR4/MyD88 signaling, thereby inhibiting intestinal epithelial inflammation and protecting against intestinal barrier damage, which helps ameliorate Crohn's disease-like colitis.

Sophoricoside improved Crohn's disease-like colitis by inhibiting intestinal epithelial cell apoptosis through PI3K/AKT signaling.

BACKGROUND AND AIMS: Increased apoptosis of intestinal epithelial cells (IECs) is a significant cause of intestinal barrier dysfunction in Crohn's disease (CD). Sophoricoside (SOP) is an isoflavone glycoside known for its anti-apoptotic properties. The aim of this study was to investigate the effects of SOP on mice with CD-like colitis and to understand the underlying mechanisms. METHODS: Mice treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS) were used to examine the therapeutic effect of SOP on CD-like colitis and intestinal barrier damage. To further explore SOP's impact on IECs apoptosis and intestinal barrier protection, an in vitro colonic organoid apoptosis model induced by TNF-α was utilized. Network pharmacology was employed to predict the relevant pathways and molecular processes associated with SOP in the treatment of CD. RESULTS: Treatment with SOP significantly improved colitis symptoms in TNBS mice, as demonstrated by reductions in the Disease Activity Index (DAI), weight loss, colon shortening, macroscopic scores, colonic tissue inflammatory scores, and the expression of pro-inflammatory factors. Our experiments confirmed that SOP protects the intestinal barrier by counteracting IECs apoptosis. Additionally, this study established that SOP reduced IECs apoptosis by inhibiting the PI3K/AKT signaling pathway. CONCLUSIONS: SOP can reduce IECs apoptosis through the inhibition of the PI3K/AKT signaling pathway, thereby protecting the intestinal barrier. This study is the first to illustrate how SOP ameliorates colitis and protects the intestinal barrier, suggesting SOP has potential clinical application in treating CD.

Inter-Individual Responses to a Blueberry Intervention across Multiple Endpoints.

Inter-individual variation exists in response to diet and in the endpoints related to vascular diseases and cognitive impairment. Therefore, the evaluation and characterisation of responses to a dietary intervention targeting these endpoints is important. A dietary intervention with 37 participants has been performed comparing two forms of blueberry, either whole fresh blueberry (160 g), freeze-dried blueberry powder (20 g) or a placebo control (microcrystalline cellulose), in a 1-week single-blinded cross-over randomised controlled trial (RCT) in a healthy population. The response to the intervention was calculated for each endpoint using the percentage change (±%) compared to the baseline. Extensive inter-individual variation was found in vascular health parameters (-141 to +525%) and cognitive domains (-114 to +96%) post-intervention, but there was no consistent response following the two interventions between and within participants for each endpoint measured. No significant putative discriminating urinary metabolites between interventions were found using supervised multivariate analysis. Although several discriminatory metabolites were found between the responder and non-responder groups, it was not possible to identify predictors of the response using receiver operating curve analysis. To conclude, this is the first blueberry intervention applying quartile divisions to characterise individual responses in vascular and cognitive endpoints following a specific dietary intervention; however, we did not find any consistency in the individual responses to the interventions, and we could not identify a predictive urinary metabolite as a potential biomarker for differentiation between responders and non-responders. However, the overall approach of defining a metabolic signature of response could be used in the future for tailored personalised nutritional advice.