OBJECTIVE To investigate the mechanisms of rutin in alleviating depressive symptoms associated with premenstrual dysphoric disorder （PMDD） characterized by liver qi stagnation syndrome. METHODS Network pharmacology was employed to identify the intersecting targets of action between PMDD and rutin. A protein-protein interaction network was constructed to screen core targets， followed by gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis. Molecular docking simulations validated rutin’s binding affinity to core targets. The bilateral ovaries of female Wistar rats were removed， followed by artificial hormone induction. The rats were then randomly divided into normal group （10 rats） and modeling group （50 rats）. PMDD rat model with liver qi stagnation syndrome was established via restraint stress. The successfully modeled rats were further divided into model group， fluoxetine group （positive control） and rutin group， with 12 rats in each group. The corresponding drug solutions or water were administered by gavage at 9：00 a.m. every day， continuing for two estrous cycles. The open-field test， forced swimming test and Y-maze test were utilized to evaluate the effects of rutin on the behavioral indexes of model rats. Additionally， the density of neuronal dendritic spines in the hippocampal tissues of the rats was observed. Serum brain-derived neurotrophic factor （BDNF） levels and the expressions of BDNF， tyrosine kinase receptor type B （TrkB）， synuclein （Syn）， and postsynaptic density protein 95 （PSD95） in hippocampal tissues were quantified， respectively. RESULTS Network pharmacology and molecular docking revealed the core targets through which rutin ameliorated PMDD characterized by liver qi stagnation syndrome included BDNF， TrkB， PSD65， Syn， etc. The results of experimental validation demonstrated that rutin significantly increased the spontaneous alternation behavior scores of PMDD model rats with liver qi stagnation syndrome during the non-receptive phase， shortened their immobility time during the forced swimming test， and enhanced the density of neuronal dendritic spines in the hippocampal tissues. Additionally， rutin upregulated the levels of serum BDNF and the protein expressions of BDNF， TrkB and Syn in the hippocampal tissues （P＜0.05）. However， it had no significant effect on the above indexes in model rats during the receptive phase （P＞0.05）. CONCLUSIONS Rutin ameliorates depressive symptoms， enhances spatial memory capabilities， and reduces neuronal damage in PMDD model rats with liver qi stagnation syndrome. These effects may be associated with the activation of BDNF/TrkB signaling pathway and upregulation of Syn protein expression.

OBJECTIVE To explore the characteristics and regulations of adverse drug reactions （ADR） caused by apatinib， and to provide a reference for the safe use of apatinib in clinic. METHODS Case and group reports on ADR and safety evaluation of apatinib were retrieved from Chinese and English databases such as CNKI， Wanfang medical network， VIP and PubMed since its listing in 2014， literature data were extracted and statistically analyzed after screening. RESULTS Totally 101 cases were included， involving 221 ADR. In the above cases， the male-to-female ratio was 1.24∶1， with the highest proportion of patients aged 51 to 70 years， most of the patients were given a dose of 500 mg or more， and the patients given low dose of apatinib combined with other antitumor drugs were also likely to have ADR. One to two types of adverse reaction were the most common， while the types could reach up to six. Most ADR occurred within 30 days after medication， and the systems/organs involved were mainly the cardiovascular system damage，skin and its accessories damage， gastrointestinal system damage and urinary system damage； the main clinical manifestations were hypertension/aggravation，hand-foot syndrome，abdominal pain diarrhea and albuminuria， etc. Hypertension/aggravation， hand-foot syndrome and myelosuppression were the most common serious ADR. Most ADR could be improved/cured by suspension of administration， dose downregulation and symptomatic treatment. All 4 patients who died had underlying diseases， and their ECOG scores all ≥2 points. Special ADR （such as reversible posterior encephalopathy syndrome， psychiatric disorders， and cognitive impairment） were mostly caused by apatinib itself， or may be caused by apatinib in combination with the primary or underlying disease. CONCLUSIONS Advanced age， large dose， combination medication， underlying diseases and poor physical condition might be the high risks for ADR caused by apatinib. It is recommended to monitor the blood pressure，urine protein and skin of hands and feet of all patients with medication on a daily basis，pay attention to the occurrence of special ADR， and timely detect abnormal states and give effective intervention，so as to avoid the aggravation of ADR and other secondary ADR.

BACKGROUND:Gingival thickness is an important indicator to determine gingival phenotype.The correct evaluation of gingival phenotype is helpful for the smooth going of periodontal surgery,implant implantation and orthodontic treatment.The search for a comfortable,accurate and convenient method of measuring gingival thickness has always been a research hotspot in this field. OBJECTIVE:To analyze the gingival thickness in different dental positions and to study the consistency of cone-beam computed tomography(CBCT)image and digital intraoral scanners and cone-beam computed tomography(DIS-CBCT)superimposition image for measuring gingival thickness and determining whether the gingiva is thick or thin. METHODS:Twenty volunteers(10 males and 10 females)with complete maxillary dentition were recruited.The thickness of the gingiva 2 mm below the buccal gingival margin of 160 teeth was measured by CBCT image and DIS-CBCT digital superimposition image.Gingival thickness was used to determine whether the gingiva was thick or thin.Paired t-test was used to analyze the differences in gingival thickness measured by the two methods.Pearson correlation analysis was used to evaluate the correlation between the gingival thickness results of the two methods.The intraclass correlation coefficient(ICC)and Bland-AItman chart were used to analyze the repeatability and consistency in measuring gingival thickness using the two methods.Kappa value was used to analyze the consistency in determining whether the gingiva was thick or thin using the two methods. RESULTS AND CONCLUSION:The gingival thickness measured by CBCT image and DIS-CBCT digital superimposition image was(1.47±0.39)and(1.42±0.36)mm,respectively(t=5.673,P＜0.05).Pearson correlation analysis showed that the gingival thickness measured by the two methods was positively correlated(r=0.968,P＜0.001).In the CBCT group,the values of intraobserver and interobserver ICC were 0.980-0.982 and 0.984,respectively;in the DIS-CBCT group,the values of intraobserver and interobserver ICC were 0.941-0.984 and 0.964,respectively(P＜0.001).The intergroup ICC value of gingival thickness measured by the two methods was 0.967(P＜0.001).Bland-AItman analysis showed that 4.37%(7/160)of the points measured by both methods for gingival thickness was outside the 95%limits of agreement.There were 71 cases of thick-gingiva and 89 cases of thin-gingiva measured by CBCT imaging,and 59 cases of thick-gingiva and 101 cases of thin-gingiva measured by DIS-CBCT digital superimposition image.The Kappa value of the two groups was 0.845(P＜0.001).These findings indicate that there is a significant difference in the thickness measurement of the gingiva 2 mm below the gingival margin between the CBCT group and the DIS-CBCT group,but the correlation is very strong.The repeatability and consistency of gingival thickness measurement are both high,and there is a good consistency between the two methods when used to determine whether the gingiva is thick or thin.

Objective To observe the value of nomogram model based on clinical and ultrasonic characteristics for diagnosing lymphoma.Methods Data of 176 patients with suspected lymphoma due to enlarged superficial lymph nodes were retrospective analyzed.The patients were divided into lymphoma group(n=90,invasive subgroup[n=40]and non-invasive subgroup[n=50])or non-lymphoma group(n=86)based on pathological results.Clinical and ultrasonic data were compared between groups and subgroups.Multivariate logistic regression was used to screen the independent risk factors of lymphoma,and then a nomogram was constructed.Receiver operating characteristic curves were drawn to evaluate the efficacy of conventional ultrasound,conventional contrast-enhanced ultrasound(C-CEUS),high-frame-rate contrast-enhanced ultrasound(H-CEUS)and nomogram for diagnosing lymphoma.Results Multivariate logistic regression analysis revealed that age＞59 years,cortical stripe/reticular hyperecho of lymph nodes and"centrifugal firework"enhancement pattern showed with H-CEUS were all independent risk factors of lymphoma(all P＜0.05).Taken 59 years as the best cut-off value of patients'age,the sensitivity,specificity,accuracy and the area under the curve(AUC)for diagnosing lymphoma was 67.78%,58.10%,63.06%and 0.630,respectively.The sensitivity,specificity,accuracy and AUC of cortical stripe/reticular hyperecho of lymph nodes for diagnosing lymphoma was 73.33%,58.10%,65.91%and 0.657,respectively,while of"centrifugal firework"pattern enhancement in H-CEUS was 77.78%,69.80%,73.86%and 0.738,respectively.AUC of conventional ultrasound,C-CEUS,H-CEUS and nomogram for diagnosing lymphoma was 0.657,0.540,0.738 and 0.844,respectively.Conclusion Nomogram model based on clinical and ultrasonic characteristics had good diagnostic efficacy for lymphoma,and"centrifugal firework"pattern enhancement in H-CEUS could be regarded as the specific characteristic of lymphoma.

OBJECTIVE To study the correlation between penetration enhancement effect and transepidermal water loss(TEWL)values of essential oils(EOs)from traditional Chinese medicine(TCM).METHODS The amount of 3 kinds of glycosides(geniposide,gentiopicroside,paeoniflorin)and their oil-water partition coefficient were determined by HPLC.The penetration enhancement effect of the five EOs from Gaoliangjiang(Alpiniae Officinarum Rhizoma,AOR),Ganjiang(Zingiberis Rhizoma,ZR),Bohe(Menthae Haploca-lycis Herba,MHH),Hujiao(Piperis Fructus,PF)and Wuzhuyu(Euodiae Fructus,EF)on geniposide,gentiopicroside,and paeoniflor-in were performed by the modified Franz diffusion cell method with the abdominal skin of rats.The TEWL values were measured to evalu-ate the effect of the five EOs on the skin barrier function of rats.The correlation between penetration enhancement effect of EOs and their effect on skin barrier function was investigated by correlation analysis.RESULTS AOR oil,ZR oil,MHH oil,and PF oil could im-prove the absorption of the three glycosides and reduce skin barrier function of rats.The results of correlation analysis showed that the penetration enhancement effect of EOs was significantly related to TEWL values following dermal administration of EOs.CONCLUSION TEWL measurement technology provides a more convenient method for the selection of penetration enhancers.

Objective:To evaluate the accuracy of continuous photoplethysmography algorithms for atrial fibrillation diagnosis and atrial fibrillation burden evaluation via wearable devices.Methods:This study was a self-controlled prospective cohort study. A total of 254 consecutive inpatients were recruited from the Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University from September 2022 to November 2022. All participants were required to wear two devices at the same time: (1) an electrocardiogram (ECG) watch for acquisition of photoplethysmography (watch-recorded-photoplethysmography, W-PPG) and electrocardiogram (watch-recorded-electrocardiogram, W-ECG); (2) an ECG patch for acquisition of electrocardiogram (patch-recorded-electrocardiogram, P-ECG). The results were measured in 30 s data segments and individual participants, separately, which were calculated for sensitivity and specificity by comparing them with the results of expert-read ECG according to the receiver operating characteristic curve. Four groups were separated according to the proportion of the atrial fibrillation burden, and the difference of atrial fibrillation burden from algorithm and expert-read ECG was calculated.Results:All 254 subjects completed the study. The mean age of participants was (63.04±11.04) years old, 99 (38.98%) of them were female, and 97 (38.19%) patients had persistent atrial fibrillation. Expert-read ECG results were taken as standard criteria in all calculations. The P-ECG algorithm had a sensitivity of 94.86% (95% CI: 94.81%-94.91%) and a specificity of 99.30% (95% CI: 99.28%-99.31%) when measured in data segments. The W-PPG algorithm had a sensitivity of 96.07% (95% CI: 95.97%-96.18%) and a specificity of 98.62% (95% CI: 98.59%-98.65%). When measured in terms of individual participants, the P-ECG algorithm had a sensitivity of 92.55% (95% CI: 87.57%-95.71%) and a specificity of 96.39% (95% CI: 93.45%-98.09%), while the W-PPG algorithm had a sensitivity of 93.71% (95% CI: 88.75%-96.67%) and a specificity of 89.62% (95% CI: 85.61%-92.65%). When measured in terms of a single acquisition of W-ECG records, the W-ECG algorithm had a sensitivity of 92.04% (95% CI: 88.14%-94.78%) and a specificity of 96.19% (95% CI: 94.35%-97.47%). For atrial fibrillation burden assessment, the difference between the W-PPG analysis results and the expert-read ECG results was less than 2% in all burden distribution intervals. Conclusions:Continuous photoplethysmography algorithm applied to wearable devices to detect atrial fibrillation is a feasible strategy. Taking expert-read ECG results as standard, continuous monitoring of PPG by a smartwatch is highly accurate for atrial fibrillation diagnosis and can also be used to effectively complete atrial fibrillation burden assessment.

Acetaminophen (APAP) overdose is a major cause of liver injury. Neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases; however, its role in APAP-induced liver injury (AILI) is unclear. Thus, this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI. We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes. Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury, while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro. Additionally, hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1 (VDAC1) and increased VDAC1 oligomerization. Furthermore, VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency. Mechanistically, NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1. Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). This targeted liposome is prepared through a mature preparation process, and indoleamine-2,3-dioxygenase (IDO) inhibitor NLG919 was encapsulated into it. Moreover, mediated by the enhanced permeability and retention effect (EPR effect) and AUNP-12, NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues. At the same time, the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12, thus realizing the precise block of PD-1 signal pathway, and restoring the activity of T cells. The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

Organoid models are used to study kidney physiology, such as the assessment of nephrotoxicity and underlying disease processes. Personalized human pluripotent stem cell-derived kidney organoids are ideal models for compound toxicity studies, but there is a need to accelerate basic and translational research in the field. Here, we developed an automated continuous imaging setup with the "read-on-ski" law of control to maximize temporal resolution with minimum culture plate vibration. High-accuracy performance was achieved: organoid screening and imaging were performed at a spatial resolution of 1.1 μm for the entire multi-well plate under 3 min. We used the in-house developed multi-well spinning device and cisplatin-induced nephrotoxicity model to evaluate the toxicity in kidney organoids using this system. The acquired images were processed via machine learning-based classification and segmentation algorithms, and the toxicity in kidney organoids was determined with 95% accuracy. The results obtained by the automated "read-on-ski" imaging device, combined with label-free and non-invasive algorithms for detection, were verified using conventional biological procedures. Taking advantage of the close-to-in vivo-kidney organoid model, this new development opens the door for further application of scaled-up screening using organoids in basic research and drug discovery.
Humans ; Kidney ; Organoids ; Pluripotent Stem Cells

Objective To determine the oral health， related knowledge and behavior of 12-year-old children in Guoluo Prefecture， Qinghai Province， and provide scientific evidence for policy-making of oral health programs. Methods Six counties were selected by using a multi-stage and stratified sampling strategy. Oral health examination and survey questionnaire were performed according to the instructions of the Fourth National Oral Epidemiology Study. The oral health examination included dental caries and periodontal status. The questionnaire investigated oral health knowledge and behavior. Results The prevalence of caries was 71.6% （288/402）and their DMFT was 2.04±1.90. Approximately 1.2% of deciduous teeth were filled. In the children， 81.3% （327/402） had teeth brush every day， while only 42.0% （169/402） brushed twice or more per day. Moreover， 10.2% （41/402） used fluoride toothpaste； in contrast， 62.2% （250/402） did not use toothpaste appropriately. In addition， the survey on dietary habits showed that 41.3% of the children consumed sweetened food once or more per day. Conclusion Oral health education should be further strengthened to promote oral health in children.