ObjectiveTo explore effect of Xianlian Jiedu prescription on the recurrence of colorectal cancer （CRC） and investigate the related mechanisms. MethodsA postoperative recurrence model was established in 25 Balb/c mice by injecting CT26 cells subcutaneously into the armpit， followed by surgical removal of 99% of the subcutaneous tumor. The mice were randomly divided into model group， low-dose Xianlian Jiedu prescription （XLJDP-L） group （6.45 g·kg^-1·d^-1）， medium-dose Xianlian Jiedu prescription （XLJDP-M） group （12.9 g·kg^-1·d^-1）， high-dose Xianlian Jiedu prescription （XLJDP-H） group （25.8 g·kg^-1·d^-1）， and 5-fluorouracil （5-FU） group （1×10^-3 g·kg^-1·d^-1）. The mice were euthanized after 14 days of continuous intervention， and recurrent tumor tissue was harvested. Hematoxylin and eosin （HE） staining was used to observe pathological and morphological changes in the recurrent tumor tissue. Immunohistochemistry （IHC） was employed to assess the expression of proliferating cell nuclear antigen （Ki67）， vascular endothelial growth factor （VEGF）， and platelet-endothelial cell adhesion molecule （CD31） in recurrent tumor tissue. The Western blot was used to detect the protein expression levels of angiopoietin-2 （ANG-2）， VEGF， phosphorylated-protein kinase B （p-Akt）， protein kinase B （Akt）， phosphorylated-phosphatidylinositol 3-kinase （p-PI3K）， and phosphatidylinositol 3-kinase （PI3K） in recurrent tumor tissue. ResultsBefore treatment， there were no statistical differences in tumor volume， tumor weight， and body mass among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group， indicating model stability. After treatment， compared with those in the model group， the tumor volume and tumor weight in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01）， showing dose dependency. Meanwhile， there were no significant differences in body weight among the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group compared to the model group. HE staining showed that compared with that in the model group， tumor tissue in the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group had loosely arranged cells， increased intercellular spaces， small and shriveled nuclei， light staining， fewer mitotic figures and atypical nuclei， and increased necrotic areas. IHC showed that compared with those of the model group， the positive rates of Ki67， VEGF， and CD31 in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly reduced （P<0.01） in a dose-dependent manner. Western blot results showed that compared with those of the model group， the protein expression levels of ANG-2 and VEGF in the recurrent tumor tissue of the XLJDP-L， XLJDP-M， and XLJDP-H groups and the 5-FU group were significantly downregulated （P<0.05， P<0.01）， and the p-Akt/Akt and p-PI3K/PI3K ratios were significantly decreased in a dose-dependent manner （P<0.05， P<0.01）. ConclusionXianlian Jiedu prescription significantly inhibits the recurrence of CRC in mice after subcutaneous tumor surgery. The mechanism may involve regulating the PI3K/Akt pathway and downregulating key angiogenic proteins such as ANG-2， VEGF， and CD31.

Identifying drug-drug interactions (DDIs) is essential to prevent adverse effects from polypharmacy. Although deep learning has advanced DDI identification, the gap between powerful models and their lack of clinical application and evaluation has hindered clinical benefits. Here, we developed a Multi-Dimensional Feature Fusion model named MDFF, which integrates one-dimensional simplified molecular input line entry system sequence features, two-dimensional molecular graph features, and three-dimensional geometric features to enhance drug representations for predicting DDIs. MDFF was trained and validated on two DDI datasets, evaluated across three distinct scenarios, and compared with advanced DDI prediction models using accuracy, precision, recall, area under the curve, and F1 score metrics. MDFF achieved state-of-the-art performance across all metrics. Ablation experiments showed that integrating multi-dimensional drug features yielded the best results. More importantly, we obtained adverse drug reaction reports uploaded by Xiangya Hospital of Central South University from 2021 to 2023 and used MDFF to identify potential adverse DDIs. Among 12 real-world adverse drug reaction reports, the predictions of 9 reports were supported by relevant evidence. Additionally, MDFF demonstrated the ability to explain adverse DDI mechanisms, providing insights into the mechanisms behind one specific report and highlighting its potential to assist practitioners in improving medical practice.

Introduction::Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis.Methods::In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10 –8). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR–Egger, and weighted median regression) were used to ensure that our results more reliable. Results::All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30–1.58, P = 2.51 × 10 -13). The results of MR–Egger and weighted median regression exhibited similar trends (MR–Egger OR = 1.40 [95% CI, 1.08–1.81], P = 1.61 × 10 -2; weighted median OR = 1.39 [95% CI, 1.21–1.61], P = 1.62 × 10 -6). MR–Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. Conclusions::Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.

BACKGROUND:In recent years,there have been many studies on the mechanism of exosomal non-coding RNA in gestational diabetes mellitus,but there is a lack of the latest systematic review of exosomes from different sources,especially placental sources. OBJECTIVE:To summarize the changes and potential roles of microRNA(miRNA),long non-coding RNA(lncRNA),circular RNA(circRNA),and exosomes in gestational diabetes mellitus to provide potential targets for early screening and treatment of clinical gestational diabetes mellitus. METHODS:A literature search was conducted on PubMed,Web of Science,China National Knowledge Infrastructure,WanFang Data,and VIP databases to retrieve relevant articles on non-coding RNA or exosomal non-coding RNA in relation to gestational diabetes mellitus.A total of 74 articles were included for review. RESULTS AND CONCLUSION:(1)Non-coding RNAs play important pathological and physiological roles in the lifecycle activities,and increasing evidences suggest that non-coding RNAs are involved in the occurrence and development of gestational diabetes mellitus by regulating various physiological functions.This provides a new direction for the research of gestational diabetes mellitus.(2)Exosomes are widely present in the human body.Various cells can secrete exosomes,such as red blood cells,epithelial cells,and placental cells.Non-coding RNAs found in exosomes from different sources have been demonstrated to play a role in the pathogenesis,diagnosis,and treatment of gestational diabetes mellitus.(3)MiRNA and gestational diabetes mellitus:The role of peripheral blood miRNA in gestational diabetes mellitus is mainly to affect the functions of trophoblast cells,pancreatic beta cells and blood glucose levels in gestational diabetes mellitus;placental miRNA can reflect the severity of gestational diabetes and impair the function of trophoblast cells.(4)LncRNA and gestational diabetes mellitus:Peripheral blood lncRNA can induce insulin resistance through the phosphatidylinositol 3-kinase/protein kinase B pathway and may provide new insights for the diagnosis and treatment of gestational diabetes mellitus;placental lncRNA can regulate proliferation and migration of placental trophoblast cells,promoting the occurrence and development of gestational diabetes mellitus.(5)CircRNA and gestational diabetes mellitus:Peripheral blood and placental circRNA can induce the occurrence and development of gestational diabetes mellitus by impairing the proliferation,migration and metabolism of placental trophoblast cells.(6)Non-coding RNA in exosomes and gestational diabetes mellitus:Peripheral blood non-coding RNA in exosomes can affect gestational diabetes mellitus blood glucose levels and glucose homeostasis,and participate in the occurrence and development of gestational diabetes mellitus by influencing placental function.(7)Non-coding RNA has the potential to serve as biomarkers for early diagnosis of gestational diabetes mellitus.Additionally,engineered exosomes can better achieve targeted therapy for gestational diabetes mellitus.These latest findings provide a reference for both basic research and clinical translation of gestational diabetes mellitus.(8)In the future,improvements in the extraction and purification methods of peripheral blood exosomes should be improved,and factors such as race,diet and physical activity should be excluded to improve the reproducibility of results.Further prospective clinical studies are required to explore the clinical application of circulating non-coding RNA and exosomes in the prediction and diagnosis of gestational diabetes mellitus.

Objective To investigate the involvement of calmodulin(CaM)in the pathogenesis of Alzheimer disease(AD)and the mechanism by which CaM binds to amyloid-β(Aβ).Methods The hub genes expressed in AD and predicted to be the target proteins for AD prevention and treatment were obtained using bioinformatics methods.The GST-Aβ1-42 recombinant plasmid was constructed through genetic recombination and was then sequenced.The recombinant plasmids were identified using agarose gel electrophoresis,while the extracted and purified GST-Aβ1-42 fusion protein was confirmed using SDS-PAGE gel electrophoresis.GST pull-down assay was used to detect the interaction between GST-Aβ1-42 protein and CaM,expressed in the plasmid.Results The top 20 hub genes in degree ranking were obtained.The DNA sequencing results of the plasmid proved that the recombinant plasmid was successfully constructed.The agarose gel electrophoresis results indicated that the fragment digested by the enzyme was similar to the molecular weight of the Aβ1-42 gene seg-ments,further proving the successful construction of the recombinant plasmid.Binding of GST-Aβ1-42 protein to CaM in a concentration dependent manner was revealed through the GST pull down experiment.Conclusion The GST-Aβ1-42 recombinant plasmid is success-fully constructed and is shown to bind to CaM.

Objective: Anesthesia-induced cognitive impairments are common for elder patients after surgery. Oxidative stress is the predominant factor contributing to the impairments. This study was to assess the therapeutic potential of an anti-oxidative naturally occurring flavonoid, chrysin, in attenuating sevoflurane-induced cognitive impairments in rat models. Methods: Rat models of cognitive impairments were constructed by exposing aged rats (18 months old) to sevoflurane for 2 h. Chrysin was administered via oral gavage at the dose of 25, 50, and 100 mg/kg/day for seven days. The elevated plus maze test was used to assess anxiety and explorative behaviors. Spatial memory tests were performed using novel object recognition test, object location memory task, and water maze experiments. Oxidative stress was evaluated by measuring levels of malondialdehyde, nicotinamide adenine dinucleotide phosphate, 4-hydroxynonenal, and glutathione using colorimetric assays. Quantitative real-time polymerase chain reaction and Western blot were used to analyze how chrysin affects nuclear factor E2-related factor (Nrf) signaling. Results: While sevoflurane anesthesia led to significant decline in cognitive performance in object recognition test, object location memory task, and water maze test, chrysin exerted significant effects in alleviating the impairments. Oxidative stress was also reduced in the hippocampus tissue of rats after chrysin intake. Nrf signaling was activated by chrysin treatment in sevoflurane-induced cognitive impairment models. Conclusion Chrysin was effective in alleviating cognitive impairments induced by sevoflurane anesthesia, which was at least in part facilitated by its effects in reducing oxidative stress via activating Nrf signaling.

Objective:To investigate the influencing factors for lymph node metastasis and prognosis in early gastric cancer.Methods:The retrospective cohort study was conducted. The clinicopathological data of 1 011 patients with early gastric cancer who were admitted to the Zhejiang Cancer Hospital from January 2010 to December 2019 were collected. There were 561 males and 450 females, aged (58±11)years. All patients underwent radical resection of gastric cancer and the lymph node metastasis of each group was identified according to the pathological examination on patients' surgical specimens. Observation indicators: (1) lymph node metastasis in early gastric cancer; (2) influencing factors for lymph node metastasis in early gastric cancer; (3) influencing factors for prognosis in early gastric cancer. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data was analyzed using the non‐parameter rank sum test. Univariate analysis was conducted using the Log-Rank test and Logistic regression model, and multivariate analysis was conducted using the Logistic stepwise regression model and COX step-wise regression model. The Kaplan-Meier method was used to calculate survival rate and draw survival curve, and the Log-Rank test was used for survival analysis. Results:(1) Lymph node metastasis in early gastric cancer. The lymph node metastasis rate of 1 011 patients with early gastric cancer was 23.640%(239/1 011), in which the lymph node metastasis rate of patients with T1a stage gastric cancer was 11.883%(53/446), and the lymph node metastasis rate of patients with T1b stage gastric cancer was 32.920%(186/565). There were 239 patients with lymph node metastasis mainly concentrated in the first station, including 7 cases with No.1 lymph node metastasis, 11 cases with No.2 lymph node metastasis, 135 cases with No.3 lymph node metastasis, 59 cases with No.4 lymph node metastasis, 39 cases with No.5 lymph node metastasis, 91 cases with No.6 lymph node metastasis, 6 cases with No.7 lymph node metastasis, 8 cases with No.8 lymph node metastasis, 8 cases with No.9 lymph node metastasis and 6 cases with No.10 lymph node metastasis. Multiple lymph node metastases may exist in the same patient. For lymph node metastasis in different tumor sites, there were 4 cases, 2 cases and 1 case of lymph node metastasis in the No.2, 3 and 5 lymph node in patients with upper gastric cancer. There were 3 cases, 7 cases, 36 cases, 15 cases, 3 cases and 5 cases of lymph node metastasis in the No.1, 2, 3, 4, 5 and 6 lymph node in patients with middle gastric cancer. There were 4 cases, 97 cases, 44 cases, 35 cases and 86 cases of lymph node metastasis in the No.1, 3, 4, 5 and 6 lymph node in patients with lower gastric cancer. (2) Influencing factors for lymph node metastasis in early gastric cancer. Results of multivariate analysis showed that tumor diameter, tumor location, degree of tumor invasion, vascular thrombus, degree of tumor differentiation were independent factors influencing lymph node metastasis in early gastric cancer ( odds ratio=1.80, 1.49, 2.65, 5.76, 0.60, 95% confidence interval as 1.29-2.50, 1.11-2.00, 1.81-3.88, 3.87-8.59, 0.48-0.76, P<0.05). (3) Influencing factors for prognosis in early gastric cancer. All 1 011 patients were followed up for 43(range, 0-135)months, and the 3-year overall survival rate was 97.32%. Results of multivariate analysis showed that age >60 years and lymph node metastasis were independent risk factors influencing prognosis in early gastric cancer ( hazard ratio=9.50, 2.20, 95% confidence interval as 3.31-27.29, 1.00-4.87, P<0.05). Results of further analysis showed that the 3-year overall survival rate was 99.37% and 94.66% in patient with age >60 years and ≤60 years, respectively, showing a significant difference between them ( χ2=25.33, P<0.05). The 3-year overall survival rate was 95.42% and 97.92% in patients with and without lymph node metastasis, respectively, showing a significant difference between them ( χ2=5.69, P<0.05). Conclusions:The lymph node metastasis rate of early gastric cancer can reach 23.640%. Tumor diameter, tumor location, degree of tumor invasion, vascular thrombus, degree of tumor differentia-tion are independent factors influencing lymph node metastasis in early gastric cancer, age >60 years and lymph node metastasis are independent risk factors influencing prognosis.

Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2+endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3+endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1-CD62L+natural killer T cell subset may promote autoprotection through interferon-y-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.

Objective:To evaluate the influence of an additional roll test on the repositioning procedure by SRM-vertigo diagnosis system for horizontal canal benign paroxysmal positional vertigo（HC-BPPV）. Methods:A total of 713 patients diagnosed with HC-BPPV in Department of Otolaryngology Head and Neck Surgery，the First Affiliated Hospital of Xi'an Jiaotong University from Jan 2020 to Feb 2022 were enrolled. The patients were divided into two groups by hospital card numbers, in which the number is odd were considered as group A, and the number is even were considered as group B. The group A underwent two circles of Barbecue repositioning procedure by SRM-vertigo diagnosis system, while the group B first performed an additional roll test and then underwent two circles of Barbecue repositioning procedure by SRM-vertigo diagnosis system, to observe the cure rate and compare influence of HC-BPPV by an additional roll test. The quality of life and sleep of patients before and one-month after the treatment were assessed by the dizziness handicap inventory（DHI） and the pittsburgh sleep quality（PSQI）. Results:The cure rate of group A was 63.21%, and the cure rate of group B was 87.68%，the difference between the two groups was statistically significant（P<0.05）; The DHI score of patients after the repositioning was significantly lower than that before the repositioning（P<0.05）. The PSQI score after the repositioning was significantly lower than that before the repositioning（P<0.05）. The DHI and the PSQI scores after the repositioning were significantly lower than that before the repositioning, with a statistically significant difference （P< 0.05）. The total score of DHI in group B after treatment was lower than that in group A, with a statistically significant difference（P<0.05）. The total score of PSQI in group B after treatment was lower than that in group A, with non-statistically significant difference （P< 0.05）. Conclusion:An additional roll test before the repositioning procedure by SRM-vertigo diagnosis system can significantly improve the cure rate of HC-BPPV, relieve anxiety, and improve the quality of life.
Humans ; Benign Paroxysmal Positional Vertigo/diagnosis* ; Quality of Life ; Patient Positioning/methods* ; Dizziness ; Semicircular Canals

Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1β, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.