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.

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.

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.

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.

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.

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.

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.

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.

[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.

Intestinal adipocytes transdifferentiate into myofibroblast-like cells and contribute to fibrosis in Crohn's disease.

BACKGROUND AND AIMS: Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD. METHODS: The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-ß signalling was also studied to explore the underlying mechanism. RESULTS: Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. LPS-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-ß signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue. CONCLUSIONS: Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-ß signalling.

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.

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.

Uncovering the Mechanism of Chinese Hawthorn Leaf on Myocardial Ischemia Based on Network Pharmacology, Molecular Docking Verification, and In Vitro Studies.

Hawthorn leaf has shown therapeutic effects in the patients with myocardial ischemia. Our study combines network pharmacology, molecular docking techniques, and in vitro experiment with the aim of revealing the mechanism of hawthorn leaves in the treatment of myocardial ischemia. The active ingredients and corresponding targets of hawthorn leaf through Traditional Chinese Medicine System Pharmacology and Swiss Target Prediction databases. Targets related to myocardial ischemia were retrieved by Gene Card, Online Mendelian Inheritance in Man, Disgenet, and Therapeutic Targets Database databases. Cytoscape software was used to construct an ingredient-target-organ network and enrichment analysis of common targets was analyzed. Molecular docking verification of the core compound and target interactions was performed using MOE software. In vitro cell experiment was performed to verify the findings from bioinformatics analysis. Six active components and 107 potential therapeutic targets were screened. The protein-protein interaction network analysis indicated that 10 targets, including AKT1 and EGFR, were hub genes. Quercetin, kaempferol and isorhamnetin were taken as core active components. Through pathway enrichment analysis, nearly 455 Gene Ontology entries and 77 Kyoto Encyclopedia of Genes and Genomes pathways were obtained, mainly including PI3K/Akt, estrogen and other signaling pathways. Molecular docking prediction showed that three main active ingredients were firmly combined with the core targets. Cellular experiments showed that quercetin alleviated oxidative damage in cells and regulated the expression of PI3K, P-AKT/AKT and Bax/Bcl-2 proteins. This study identified the potential targets of Hawthorn leaf against myocardial ischemia using network pharmacology and in vitro verification, which provided a new understanding of the pharmacological mechanisms of Hawthorn leaf in treatment of myocardial ischemia.

The Survival and Physiological Response of Calliptamus abbreviatus Ikonn (Orthoptera: Acrididae) to Flavonoids Rutin and Quercetin.

Insect-resistant substances from plants are important natural resources that human beings can potentially develop and use to control pests. In this study, we explored the adverse effects of rutin and quercetin on grasshopper (Calliptamus abbreviatus), as well as the insect's physiological response to these substances in laboratory and field experiments. These two plant compounds exhibited toxic effects on C. abbreviatus, with quercetin showing a stronger toxicity, indicated by a lower survival, slower development, and higher induced gene expression and activities of UDP-glucuronosyltransferase, cytochrome P450s, superoxide dismutase, peroxidase and catalase, compared to rutin. These compounds, especially quercetin, have the potential to be developed as biopesticides to control grasshoppers.

Dietary supplementation with short- and long-chain structured lipids alleviates obesity via regulating hepatic lipid metabolism, inflammation and gut microbiota in high-fat-diet-induced obese mice.

BACKGROUND: Obesity is closely associated with lipid accumulation, inflammation and intestinal microbiota dysbiosis. Short- and long-chain type structured lipids (SLCTs) are kinds of low-calorie structured lipids and demonstrate anti-obesity and hypolipidemia bioactivity. The objective of this study is to investigate the potential effects of dietary supplementation of SLCTs rich in short-chain fatty acids and polyunsaturated fatty acids on high-fat-diet-induced obesity and gut microbiota modulation in C57BL/6J mice. RESULTS: Results showed that SLCTs supplementation ameliorated body weight, dyslipidemia, liver lipid accumulation, liver injury and systemic inflammation in obese mice. As expected, immunohistochemical analysis showed that SLCTs significantly increased the expression of proliferator-activated receptor alpha and decreased the expression of Toll-like receptor 4 in liver tissue. Furthermore, SLCTs supplementation significantly downregulated the expression level of liver inflammation-related genes while upregulating the expression level of liver lipid metabolism-related genes. Additionally, SLCTs supplementation markedly enhanced the diversity of gut microbiota, reduced the Firmicutes/Bacteroidetes ratio and increased the diversity and richness of beneficial intestinal microorganisms, such as Bacteroides, Lactobacillus, Lachnospiraceae NK4A136 group, Alloprevotella and Ruminococcaceae UCG-014. CONCLUSION: Our work suggested that SLCTs may have the potential to reduce obesity associated with a high-fat diet by regulating liver metabolism, inflammation and gut microbiota. © 2024 Society of Chemical Industry.

Transcriptome Sequencing of Gingival Tissues from Impacted Third Molars Patients Reveals the Alterations of Gene Expression.

OBJECTIVE: The removal of impacted third molars by surgery may occur with a series of complications, whereas limited information about the postoperative pathogenesis is available. The objective of this study is to identify changes in gene expression after flap surgical removal of impacted third molars and provide potential information to reduce postoperative complications. METHODS: The gingival tissues of twenty patients with flap surgical removal of impacted third molars and twenty healthy volunteers were collected for gene expression testing. The collected gingival tissues were used RNA sequencing technology and quantitative real-time PCR validation was performed. DEG was mapped to protein databases such as GO and KEGG for functional annotation and, based on annotation information, for mining of differential expression genes in patients with mpacted third molars. RESULTS: A total of 555 genes were differentially expressed. Among the top up-regulated genes, HLA-DRB4, CCL20, and CXCL8 were strongly associated with immune response and signal transduction. Among the top down-regulated genes, SPRR2B, CLDN17, LCE3D and LCE3E were related to keratinocyte differentiation, IFITM5, and BGLAP were related to bone mineralization, UGT2B17 is associated with susceptibility to osteoporosis. KEGG results showed that the DEGs were related to multiple disease-related pathways. CONCLUSION: This first transcriptome analysis of gingival tissues from patients with surgical removal of impacted third molars provides new insights into postoperative genetic changes. The results may establish a basis for future research on minimizing the incidence of complications after flap-treated third molars.

A Transformer-Based microvascular invasion classifier enhances prognostic stratification in HCC following radiofrequency ablation.

BACKGROUND & AIMS: We aimed to develop a Transformer-based deep learning (DL) network for prognostic stratification in hepatocellular carcinoma (HCC) patients undergoing RFA. METHODS: A Swin Transformer DL network was trained to establish associations between magnetic resonance imaging (MRI) datasets and the ground truth of microvascular invasion (MVI) based on 696 surgical resection (SR) patients with solitary HCC ≤3 cm, and was validated in an external cohort (n = 180). The multiphase MRI-based DL risk outputs using an optimal threshold of .5 was employed as a MVI classifier for prognosis stratification in the RFA cohort (n = 180). RESULTS: Over 90% of all enrolled patients exhibited hepatitis B virus infection. Liver cirrhosis was significantly more prevalent in the RFA cohort compared to the SR cohort (72.2% vs. 44.1%, p < .001). The MVI risk outputs exhibited good performance (area under the curve values = .938 and .883) for predicting MVI in the training and validation cohort, respectively. The RFA patients at high risk of MVI classified by the MVI classifier demonstrated significantly lower recurrence-free survival (RFS) and overall survival rates at 1, 3 and 5 years compared to those classified as low risk (p < .001). Multivariate cox regression modelling of a-fetoprotein > 20 ng/mL [hazard ratio (HR) = 1.53; 95% confidence interval (95% CI): 1.02-2.33, p = .047], high risk of MVI (HR = 3.76; 95% CI: 2.40-5.88, p < .001) and unfavourable tumour location (HR = 2.15; 95% CI: 1.40-3.29, p = .001) yielded a c-index of .731 (bootstrapped 95% CI: .667-.778) for evaluating RFS after RFA. Among the three risk factors, MVI was the most powerful predictor for intrahepatic distance recurrence. CONCLUSIONS: The proposed MVI classifier can serve as a valuable imaging biomarker for prognostic stratification in early-stage HCC patients undergoing RFA.

Predicting glucocorticoid effectiveness in thyroid eye disease: combined value from serological lipid metabolism and an orbital MRI parameter.

Purpose: The aim was to determine the combined value of serological lipid metabolism and an orbital MRI quantitative parameter in predicting the effectiveness of glucocorticoid (GC) therapy in patients with thyroid eye disease (TED). Methods: This study retrospectively enrolled 46 patients with active and moderate-to-severe TED (GC-effective group, n = 29; GC-ineffective group, n = 17). Serological lipid metabolism, the orbital MRI-based minimum signal intensity ratio of extraocular muscles (EOM-SIRmin), as well as other clinical parameters before GC therapy were collected and compared between the two groups. Multivariate logistic regression and receiver operating characteristic curve analysis were adopted to identify independent predictable variables and assess their predictive performances. Results: Compared to the GC-ineffective group, the GC-effective group showed lower serum total cholesterol levels (P = 0.006), lower serum low-density lipoprotein cholesterol levels (P = 0.019), higher EOM-SIRmin values (P = 0.005), and shorter disease durations (P = 0.017). Serum total cholesterol and EOM-SIRmin were found to be independent predictors of GC-effective TED through multivariate analysis (odds ratios = 0.253 and 2.036 per 0.1 units, respectively) (both P < 0.05). The integration of serum total cholesterol ≤4.8 mmol/L and EOM-SIRmin ≥ 1.12 had a better predictive efficacy (area under the curve, 0.834) than EOM-SIRmin alone, with a sensitivity of 75.9% and a specificity of 82.4% (P = 0.031). Conclusion: Serological lipid metabolism, combined with an orbital MRI-derived parameter, was a useful marker for predicting the effectiveness of GCs in patients with active and moderate-to-severe TED.

Arjunolic acid protects the intestinal epithelial barrier, ameliorating Crohn's disease-like colitis by restoring gut microbiota composition and inactivating TLR4 signalling.

BACKGROUND AND AIMS: Crohn's disease (CD) is characterized by an overabundance of epithelial cell death and an imbalance in microflora, both of which contribute to the dysfunction of the intestinal barrier. Arjunolic acid (AA) has anti-apoptotic effects and regulates microbiota efficacy. The objective of this study was to assess the impact of the treatment on colitis resembling Crohn's disease, along with exploring the potential underlying mechanism. METHODS: CD animal models were created using Il-10-/- mice, and the impact of AA on colitis in mice was evaluated through disease activity index, weight fluctuations, pathological examination, and assessment of intestinal barrier function. To clarify the direct role of AA on intestinal epithelial cell apoptosis, organoids were induced by LPS, and TUNEL staining was performed. To investigate the potential mechanisms of AA in protecting the intestinal barrier, various methods including bioinformatics analysis and FMT experiments were employed. RESULTS: The treatment for AA enhanced the condition of colitis and the function of the intestinal barrier in Il-10-/- mice. This was demonstrated by the amelioration of weight loss, reduction in tissue inflammation score, and improvement in intestinal permeability. Moreover, AA suppressed the apoptosis of intestinal epithelial cells in Il-10-/- mice and LPS-induced colon organoids, while also reducing the levels of Bax and C-caspase-3. In terms of mechanism, AA suppressed the activation of TLR4 signaling in Il-10-/- mice and colon organoids induced by LPS. In addition, AA increased the abundance of short-chain fatty acid-producing bacteria in the stool of Il-10-/- mice, and transplantation of feces from AA-treated mice improved CD-like colitis. CONCLUSIONS: The results of our study demonstrate that AA has a protective effect on the intestinal barrier in Crohn's disease-like colitis by preventing apoptosis. Additionally, this groundbreaking study reveals the capacity of AA to hinder TLR4 signaling and alter the makeup of the intestinal microbiome. The findings present fresh possibilities for treating individuals diagnosed with Crohn's disease. AA offers a hopeful novel strategy for managing Crohn's disease by obstructing crucial pathways implicated in intestinal inflammation and enhancing the gut microbiota.