Objective: To explore the longitudinal associations between dietary macronutrients and lung function in schoolaged children, so as to provide the nutritional research evidence for promoting children s lung health. Methods: In November 2021, two primary schools located in Chengdu, Sichuan Province were selected from the Southwest China Childhood Nutrition and Growth (SCCNG) cohort by a stratified cluster random sampling method, enrolling a total of 1 112 school aged children aged 8 to 13 years. At baseline, the dietary and sociodemographic characteristics of the children were assessed. One year later, the forced vital capacity (FVC) of the children was measured and converted into Z scores (FVC- Z ), while the vital capacity index (VCI) was also calculated. Generalized linear regression analysis was employed to examine the associations between dietary macronutrients and lung function, considering interactions with gender and age, followed by stratified analysis. Results: After adjusting for confounding factors, the analysis results of the generalized linear regression model showed that the carbohydrate energy ratio was negatively correlated with FVC- Z ( β =-0.02) and VCI ( β =-0.16), while the fat energy ratio showed a positive correlation with FVC- Z ( β =0.03) and VCI ( β =0.23) ( P <0.05). The protein energy ratio was positively correlated with FVC- Z ( β =0.09) and VCI ( β =0.60) specifically in girls ( P <0.05). Additionally, there was an interaction effect of age on the associations between macronutrients and lung function ( P <0.01); in children aged 8-9 and 10-11, the carbohydrate energy supply ratio was negatively correlated with FVC- Z ( β =-0.04, -0.03) and VCI ( β =-0.29, -0.21), and fat energy supply ratio was positively correlated with FVC- Z ( β =0.07, 0.05) and VCI ( β =0.46, 0.32) ( P <0.05). Conclusions There are age and sex differences in the association of dietary macronutrients with lung function, with a low carbohydrate, high fat diet promoting lung function in children. Additionally, protein intake appears to have a positive influence on the lung function of girls. The early school age period may represent a critical window for dietary interventions aimed at promoting lung health.

Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

Objective To study the effect of cobalt-60 gamma-ray (⁶⁰Co-γ) radiation on the structure of Nialamide, compare the anti-inflammatory activity of irradiation products, and explore the mechanism of action. Methods After ⁶⁰Co-γ irradiation of nialamide at a dose of 50 kGy, five known compounds were obtained (2-6). The viability of RAW 264.7 (mouse mononuclear macrophage leukemia) cells treated with these compounds was determined by CCK-8 assay. The secretion of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE₂) and the content of nitric oxide (NO) were measured using enzyme-linked immunosorbent assay and Griess method. The production of reactive oxygen species (ROS) was detected using DCFH-DA fluorescent probe. The expression levels of cell-induced nitric oxide synthase (iNOS), cyclooxygenase (COX-2), nuclear transcription factor-κB (NF-κB), and IκB were detected using Western blot. Results The products of nialamide after irradiation did not significantly affect RAW264.7 cell viability (P > 0.05) but showed a strong anti-inflammatory effect (P < 0.01). Compared with nialamide, compounds 2, 3, 4, 6 significantly reduced NO content in LPS-induced RAW 264.7 cells (P < 0.01), and compound 4 had the most significant effect. Moreover, compound 4 significantly reduced the content of IL-6, TNF-α, PGE₂, and ROS (P < 0.05) as well as the expression of iNOS, COX-2, NF-κB, and IκB (P < 0.05) in LPS-induced RAW 264.7 cells. Conclusion The chemical structure of nialamide is changed after irradiation with ⁶⁰Co-γ, and its product compound 4 shows strong anti-inflammatory activity, which may be related to inhibiting the activation of NF-κB signaling pathway and reducing the release of inflammatory factors. Radiation technology can provide new insights into the changes of molecular structures and physiological properties of natural products.

The angiogenic microenvironment is a new blood vessel with different molecular and functional characteristics that sprouts on the original blood vessels through different mechanisms,which directly affects the process of tumor cell growth,proliferation,and migration and has an important impact on the occurrence and development of precancerous lesions of gastric cancer.Correa mode has shown that precancerous lesions of gastric cancer is the key pathological stage before the occurrence of gastric cancer,and it is of great significance to advance the prevention and treatment strategy to this stage.TCM believes that qi deficiency and blood stasis is the key pathogenesis of precancerous lesions of gastric cancer,and its basic treatment is to replenish qi and remove blood stasis,and based on the syndrome differentiation,drugs with the efficacy of nourishing yin and tonifying stomach,soothing the liver and regulating qi,resolving phlegm and dispersing lumps,and clearing heat and dampness for treatment.This article discussed the correlation between precancerous lesions of gastric cancer and angiogenic microenvironment and its regulatory pathways,and summarized the methods and mechanisms of TCM in the treatment of precancerous lesions of gastric cancer from the perspective of regulating angiogenic microenvironment-related pathways,in order to provide a reference for the treatment of precancerous lesions of gastric cancer with TCM.

Objective To investigate the associations between thyroid hormone sensitivity indices in euthyroid patients with hypertension and the risk of ischemic stroke,as well as gender difference in this association.Methods We selected 760 hypertensive patients admitted to the Geriatric Neurology Department and outpatient clinic in The Second Affiliated Hospital of Xi'an Jiaotong University between April 2021 and May 2022.We collected their basic characteristics,blood biochemical parameters,thyroid indices,and brain magnetic resonance imaging information.All the patients were divided into two groups based on the clinical manifestations and brain magnetic resonance imaging:hypertension combined with ischemic stroke(n=526)and control(n=234)groups.Independent sample t-tests or non-parametric tests were used to compare the differences in thyroid hormone sensitivity indicators between the two groups.Spearman correlation analysis was used to analyze the correlation between serum thyroid indices and ischemic stroke.Multivariate conditional Logistic regression analysis was made to estimate odds ratios(ORs)and 95％confidence intervals(CIs)for thyroid indices and ischemic stroke.Results There were statistically significant differences between the two groups in terms of age,gender,TC,LDL-c,HDL-c,systolic blood pressure,FT3/FT4,TFQI,and PTFQI(all P＜0.05).However,there was no statistically significant difference between the two groups in weight,smoking,drinking,history of diabetes,TG,FBG,diastolic blood pressure,TSHI,or TT4RI(all P＞0.05).The results of Spearman correlation analysis showed a negative correlation between FT3/FT4 and ischemic stroke(P＜0.05),but a positive correlation of TFQI and PTFQI with ischemic stroke(P＜0.05)in euthyroid patients with hypertension.Logistic regression analysis showed that FT3/FT4 was significantly associated with ischemic stroke in euthyroid patients with hypertension(P=0.001),with OR(95％CI)of 0.001(0.000,0.058).After stratifying by gender,Logistic regression analysis found that FT3/FT4,TFQI,and PTFQI were associated with an increased risk of ischemic stroke in female patients,with OR(95％CI)of 0.000(0.000,0.001),3.132(1.415,6.930),and 3.010(1.406,6.445),respectively.Conclusion Lower serum FT3/FT4 ratio is associated with an increased risk of ischemic stroke in euthyroid patients with hypertension,and the significant association of TFQI and PTFQI with the risk of ischemic stroke is found in females.

Background and purpose:Esophageal carcinoma(ESCA)is one of the malignant tumors with high mortality rate,and the underlying mechanism of its development is largely unknown.CDC20 plays an important role in tumorigenesis,and its dysregulated expression is closely related to tumor occurrence and development.The expression of CDC20 is increased in a variety of tumors,and knocking down CDC20 can inhibit tumor cell proliferation.NLRP3 is the main component of the inflammasome,and inflammasome is also closely related to tumor occurrence and development.Here,our study aimed to investigate whether CDC20 promotes the proliferation of ESCA cells through NLRP3 and its regulatory mechanism.Methods:The expression levels of CDC20 and NLRP3 genes in ESCA patients were analyzed using The Cancer Genome Atlas(TCGA)detabase and GTEx public database.We collected clinical and pathological data and tissues from 80 ESCA patients at the First Affiliated Hospital of Xinxiang Medical College,and detected the protein expression of NLRP3 in ESCA patients through immunohistochemistry staining.This study was approved by the Ethics Committee of the First Affiliated Hospital of Xinxiang Medical College(Number:EC-021-137).We studied the effects of knocking down CDC20 and NLRP3 gene on the proliferation ability of esophageal squamous cell carcinoma cells EC9706 and KYSE150 using short hairpin RNA(shRNA)technology.Co-immunoprecipitation(Co-IP),proteasome inhibitors and ubiquitination experiments were used to detect whether CDC20 interacts with NLRP3,and to elucidate whether CDC20 regulates NLRP3 expression through the ubiquitination pathway.This study was approved by the Ethics Committee of the First Affiliated Hospital of Xinxiang Medical College(Number:EC-021-137).Results:The TCGA database analysis showed that the expression levels of CDC20 and NLRP3 mRNA were significantly higher in the cancer tissues of ESCA patients than in the adjacent tissues.The immunohistochemistry results further showed that compared with adjacent tissues,the protein expression levels of CDC20 and NLRP3 were increased in ESCA tissues.Knocking down CDC20 and NLRP3 genes inhibited the proliferation of ESCA cells.Co-IP,proteasome inhibitors and ubiquitination experiments confirmed that CDC20 interacted with NLRP3 through its leucine-rich repeat(LRR),and CDC20 stabilized its expression by promoting NLRP3 ubiquitination.Conclusion:CDC20 and NLRP3 are upregulated in ESCA tissues,and CDC20 stabilizes their expression through ubiquitination of NLRP3,promoting ESCA cell proliferation.This suggests that CDC20 and NLRP3 may be potential diagnostic targets for ESCA.

Objective To explore the correlation between thyroid antibody levels and early renal injury in patients with type 2 diabetes mellitus(T2DM)combined with Hashimoto's thyroiditis(HT).Methods A total of 375 T2DM patients hospitalized in The Affiliated Hospital of Xuzhou Medical University from January 2018 to December 2022 were selectedas the study subjects,and 197 healthy people were selected as the control subjects.The patients with T2DM were divided into simple T2DM group(n=191)and T2DM combined with HT group(HT,n=184).According to the urinary albumin/creatinine ratio(UACR)level,T2DM patients with HT were divided into microalbuminuria subgroup(MUAlb,30≤UACR≤300 mg/g,n=70)and normal albuminuria subgroup(NUAlb,UACR<30 mg/g,n=114).According to whether the thyroid antibody was positive,they were divided into thyroid peroxides antibody[TPOAb(+)]subgroup(n=56),thyroglobulin antibody[TGAb(+)]subgroup(n=40)and TGAb and TPOAb double antibody positive subgroup(n=88).Results Compared with the NC group,the smoking,drinking,urinary creatinine,alpha 1-microglobulin,UACR,FPG,HbA1c,LDL-C,TC,and TG in the HT and T2DM groups increased(P<0.05),while HDL-C decreased(P<0.05).Compared with the NUAlb subgroup,the MUAlb subgroup showed age,DM duration,FPG,HbA1c,TGAb,TPOAb,thyroid stimulating hormone(TSH)increased(P<0.05),while FT3 and eGFR decreased(P<0.05).Spearman correlation analysis showed that UACR was positively correlated with age,HbA1c,TPOAb,TGAb,TSH(P<0.01),and negatively correlated with FT3(P<0.01).The UACR of the TGAb(+)+TPOAb(+)subgroup was higher than that of the TGAb(+)and TPOAb(+)subgroups(P<0.05).Logistic regression analysis showed that TSH,TGAb,TPOAb,and HbA1c were risk factors for MUAlb,while FT3 was a protective factor for MUAlb.Conclusions In T2DM with HT patients with normal thyroid function,TPOAb and TGAb are closely related to the occurrence of early renal injury.

Objective:To explore the clinical characteristics of pregnancy complicated by primary Sj?gren's syndrome (pSS) and the related factors of adverse outcomes in pregnant women with pSS.Methods:A retrospective analysis was conducted on the clinical data of 32 pregnancies complicated by pSS treated in the Department of Obstetrics at the Third Affiliated Hospital of Guangzhou Medical University from February 2017 to August 2022. The patients were divided into two groups according to whether they had perinatal adverse outcomes: an adverse outcome group ( n=20) and a favorable outcome group ( n=12). The clinical characteristics of the two groups were compared with two independant sample t-test, Mann-Whitney U test, and Fisher's exact test, and multivariate logistic regression analysis was used to analyze the related factors of adverse outcomes in pregnant women with pSS. Results:(1) The average maternal age of the 32 pSS pregnancies was (32.9±4.6) years, the pre-pregnancy body mass index was (21.1±3.8) kg/m 2, and the median gestational age at delivery was 37.8 (35.4-38.5) weeks. There were 18 women (56.3%, 18/32) were diagnosed before pregnancy and 14 women (43.7%, 14/32) during pregnancy. Out of the 32 pregnancies, 25 (79.1%, 25/32) received therapy with glucocorticoids and/or hydroxychloroquine during pregnancy, whereas seven (21.9%, 7/32) had no medication during pregnancy. (2) The main adverse maternal outcomes included oligohydramnios (25%, 8/32), hypertensive disorder of pregnancy (18.8%, 6/32), preterm birth (18.8%, 6/32), fetal growth restriction (15.6%, 5/32), miscarriage (12.5%, 4/32), gestational diabetes mellitus (9.4%, 3/32), and postpartum hemorrhage (3.1%, 1/32). (3) Adverse neonatal outcomes included low birth weight infants in seven cases (25.0%, 7/28), neonatal asphyxia in seven cases (25.0%, 7/28), and two cases of congenital heart block (7.1%, 2/28). (4) The rate of diagnosis before pregnancy in the favorable outcome group was higher than the adverse outcome group [10/12 vs. 40.0%(8/20), Fisher's exact test, P=0.028]. There were no significant differences between the two groups concerning maternal age, pre-pregnancy BMI, weight gain during pregnancy, parity, rates of positivity for autoantibodies (antinuclear antibody, Sj?gren-specific antibody A, Sj?gren-specific antibody B, anti-Ro-52), and proportion of drug treatment (glucocorticoids, hydroxychloroquine) (all P>0.05). (5) Multivariate logistic regression analysis showed that diagnosis before pregnancy ( OR=0.02, 95% CI: 0.00-0.62, P=0.024) and positive Sj?gren-specific antibody B ( OR=0.01,95% CI: 0.00-0.75, P=0.038) were the protective factors. Conclusions:The clinical manifestations of pSS among pregnant women are varied and atypical,often with insidious onset. For pregnant women with pSS, being diagnosed before pregnancy, positive Sj?gren-specific antibody B may reduce adverse outcomes. It is important to address pre-pregnancy examination, early diagnosis and timely intervention to reduce the occurrence of adverse outcomes in pregnant women with pSS.

ObjectiveTo evaluate the effect of Tripterygium wilfordii polyglycoside tablets （TWPT） combined with conventional synthetic disease-modifying antirheumatic drugs （csDMARDs） including methotrexate （MTX） and/or leflunomide （LEF） on autoantibodies in rheumatoid arthritis （RA） patients. MethodPubMed， EMBASE， Web of Science， Cochrane Library， China National Knowledge Infrastructure （CNKI）， VIP， Wanfang Data， and China Biomedical Literature Service System （SinoMed） were searched for randomized controlled trials （RCTs） of TWPT combined with MTX and/or LEF in the treatment of RA patients from database inception to December 1， 2021. Primary outcome indicators included rheumatoid factor （RF） and anti-citrullinated protein antibody （ACPA）， and secondary outcome indicators included immunoglobulin （IgA， IgG， and IgM） and adverse drug events （ADE）. ResultThirty-one RCTs， involving 2 643 adult patients， were included， including 20 RCTs of TWPT combined with MTX， 10 of TWPT combined with LEF， and one of TWPT combined with MTX and TWPT. The follow-up time ranged from two weeks to 13 months. Compared with csDMARDs alone， TWPT combined with other drugs significantly improved serum RF of RA patients ［SMD=-2.45， 95% CI ［-2.97， -1.93］， P<0.000 01］， anti-CCP ［SMD=-1.41， 95% CI （-2.35， -0.48）， P=0.003］， IgM ［SMD=-1.90， 95% CI （-3.03， -0.76）， P=0.001］， and IgA ［SMD=-1.18， 95% CI （-2.23， -0.12）， P=0.03］. There were no significant effects on IgG ［SMD=-1.02， 95% CI （-2.04， 0.01）， P=0.05］ and ADE ［RR=0.87， 95% CI （0.66， 1.15）， P=0.32］. ConclusionThe results of this study show that compared with csDMARDs alone， TWPT combined with csDMARDs can effectively improve the levels of autoantibodies in RA patients without increasing the incidence of ADE. However， due to the limited quality and quantity of the included RCTs， the relevant conclusions are only used as a reference for the clinical diagnosis and treatment of RA， and more high-quality studies are still needed to further confirm their efficacy.

Flagella are the main motility structure of Clostridioides difficile that affects the adhesion, colonization, and virulence of C. difficile in the human gastrointestinal tract. The FliL protein is a single transmembrane protein bound to the flagellar matrix. This study aimed to investigate the effect of the FliL encoding gene flagellar basal body-associated FliL family protein (fliL) on the phenotype of C. difficile. The fliL gene deletion mutant (ΔfliL) and its corresponding complementary strains (: : fliL) were constructed using allele-coupled exchange (ACE) and the standard molecular clone method. The differences in physiological properties such as growth profile, antibiotic sensitivity, pH resistance, motility, and spore production ability between the mutant and wild-type strains (CD630) were investigated. The ΔfliL mutant and the : : fliL complementary strain were successfully constructed. After comparing the phenotypes of strains CD630, ΔfliL, and : : fliL, the results showed that the growth rate and maximum biomass of ΔfliL mutant decreased than that of CD630. The ΔfliL mutant showed increased sensitivity to amoxicillin, ampicillin, and norfloxacin. Its sensitivity to kanamycin and tetracycline antibiotics decreased, and the antibiotic sensitivity partially returned to the level of CD630 strain in the : : fliL strain. Moreover, the motility was significantly reduced in the ΔfliL mutant. Interestingly, the motility of the : : fliL strain significantly increased even when compared to that of the CD630 strain. Furthermore, the pH tolerance of the ΔfliL mutant significantly increased or decreased at pH 5 or 9, respectively. Finally, the sporulation ability of ΔfliL mutant reduced considerably compared to the CD630 strain and recovered in the : : fliL strain. We conclude that the deletion of the fliL gene significantly reduced the swimming motility of C. difficile, suggesting that the fliL gene is essential for the motility of C. difficile. The fliL gene deletion significantly reduced spore production, cell growth rate, tolerance to different antibiotics, acidity, and alkalinity environments of C. difficile. These physiological characteristics are closely related to the survival advantage in the host intestine, which is correlated with its pathogenicity. Thus, we suggested that the function of the fliL gene is closely related to its motility, colonization, environmental tolerance, and spore production ability, which consequently affects the pathogenicity of C. difficile.
Humans ; Clostridioides/metabolism* ; Clostridioides difficile/metabolism* ; Bacterial Proteins/metabolism* ; Virulence ; Anti-Bacterial Agents/metabolism*