OBJECTIVE: To assess the risk of aristolochic acid (AA)-associated cancer in patients with AA nephropathy (AAN). METHODS: A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014. Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer. The primary endpoint was the incidence of liver cancer, and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014. RESULTS: A total of 337 patients diagnosed with AAN were included in this study. From the initiation of taking AA to the termination of follow-up, 39 patients were diagnosed with cancer. No cases of liver cancer were observed throughout the entire follow-up period, with urinary cancer being the predominant type (34/39, 87.17%). Logistic regression analysis showed that age, follow-up period, and diabetes were potential risk factors, however, the dosage of the drug was not significantly associated with urinary cancer. CONCLUSIONS No cases of liver cancer were observed at the end of follow-up. However, a high prevalence of urinary cancer was observed in AAN patients. Establishing a direct causality between AA and HCC is challenging.
Humans ; Retrospective Studies ; Incidence ; Carcinoma, Hepatocellular ; Liver Neoplasms/epidemiology* ; Kidney Diseases/chemically induced* ; Aristolochic Acids/adverse effects*

Aim To explore the effects of Lycium berry seed oil on Nrf2/ARE pathway and oxidative damage in testis of subacute aging rats. Methods Fifty out of 60 male SD rats, aged 8 weeks, were subcutaneously injected with 125 mg • kg"D-galactosidase in the neck for 8 weeks to establish a subacute senescent rat model. The presence of senescent cells was observed using P-galactosidase ((3-gal), while testicular morphology was examined using HE staining. Serum levels of testosterone (testosterone, T), follicle-stimulating hormone ( follicle stimulating hormone, FSH ) , luteinizing hormone ( luteinizing hormone, LH ) , superoxide dis-mutase ( superoxide dismutase, SOD ) , glutathione ( glutathione, GSH) and malondialdehyde ( malondial-dehyde, MDA) were measured through ELISA, and the expressions of factors related to aging, oxidative damage, and the Nrf2/ARE pathway were assessed via immunohistochemical analysis and Western blotting. Results After successfully identifying the model, the morphology of the testis was improved and the intervention of Lycium seed oil led to a down-regulation in the expression of [3-gal and -yH2AX. The serum levels of SOD, GSH, T, and FSH increased while MDA and LH decreased (P 0. 05) . Additionally, there was an up-regulated expression of Nrf2, GCLC, NQOl, and SOD2 proteins in testicular tissue ( P 0. 05 ) and nuclear expression of Nrf2 in sertoli cells. Conclusion Lycium barbarum seed oil may reduce oxidative damage in testes of subacute senescent rats by activating the Nrf2/ARE signaling pathway.

Cerebral ischemia-reperfusion injury （CIRI） has a very high incidence， disability， and mortality rates， which seriously affects human life and health. In recent years， modern medicine has made some progress in the diagnosis and treatment of CIRI， but there are still problems such as difficulties in postoperative rehabilitation and adverse drug reactions， and new therapeutic drugs for CIRI are urgently needed. As an important class of active ingredients in traditional Chinese medicine， flavonoids can play antioxidant， apoptosis inhibition， anti-inflammatory， and other pharmacological effects to improve brain tissue damage， which is important for improving the quality of life of CIRI patients and slowing down the aging of the social population. Numerous studies have found that flavonoids in traditional Chinese medicine can regulate cell surface receptors Toll-like receptor 4/nuclear factor-kappaB （TLR4/NF-κB）， phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt）， adenylate-activated protein kinase/mammalian target of rapamycin protein （AMPK/mTOR）， Ras homologous gene family member A/Rho-associated coiled-coil protein kinase （RhoA/ROCK）， nuclear factor E₂-associated factor 2/Kelch-like epoxychloropropane-associated protein-1/haemoglobin oxygenase 1 （Nrf2/Keap1/ HO-1）， Notch， and other signaling pathways， so as to regulate the transcription and expression of related proteins after CIRI， alleviate brain tissue injury， and improve CIRI. This paper analyzed the relevant literature in China and abroad in recent years， reviewed the mechanism of action and related pathways of flavonoids in traditional Chinese medicine to improve CIRI， and explored the new therapeutic direction of CIRI at the metabolic level， with a view to providing a basis for the further development and application of flavonoids in traditional Chinese medicine.

In the past few decades, microbubbles were widely used as ultrasound contrast agents in the field of tumor imaging. With the development of research, ultrasound targeted microbubble destruction technology combined with drug-loaded microbubbles can achieve precise drug release and play a therapeutic role. As a micron-scale carrier, microbubbles are difficult to penetrate the endothelial cell space of tumors, and nano-scale drug delivery system—nanobubbles came into being. The structure of the two is similar, but the difference in size highlights the unique advantages of nanobubbles in drug delivery. Based on the classification principle of shell materials, this review summarized micro/nanobubbles used for ultrasound diagnosis or treatment and discussed the possible development directions, providing references for the subsequent development.

ObjectiveTo decipher the mechanism of Wenxiao powder in alleviating corticosterone-induced depression-like behaviors in mice. MethodMale ICR mice were randomized into normal， model， paroxetine （20 mg·kg^-1）， and low- and high-dose （3.27， 6.54 g·kg^-1， respectively） Wenxiao powder groups. The mice in normal and model groups received equal volume of saline. Other groups except the normal group were injected with corticosterone subcutaneously 0.5 h after gavage to induce depression. Mice were tested for depression-like behaviors after drug administration. Enzyme-linked immunosorbent assay （ELISA） was performed to measure the corticosterone content in the serum. Nissl staining was performed to observe the damage of hippocampal neurons. Immunofluorescence staining was employed to observe the expression of double cortin （DCX） in the dentate gyrus （DG） of the hippocampus. Western blot was employed to determine the expression of proteins in the brain-derived neurotrophic factor （BDNF）/tyrosine kinase receptor B （TrkB）/extracellular signal-regulated kinase （ERK）/cAMP-response element-binding protein （CREB） pathway in the hippocampus. ResultCompared with the normal group， the model group showed decreased sucrose preference rate， increased immobility time in the tail suspension test （P<0.01）， and reduced residence time in the central area of the open field and the total movement distance （P<0.05， P<0.01）. In addition， the modeling elevated the corticosterone level in the serum （P<0.01）， decreased the volume and intensified the nuclear staining of hippocampal neurons in the DG area， reduced the expression of DCX in the DG area， and down-regulated the protein levels of BDNF， phosphorylated （p）-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. Compared with the model group， low-dose Wenxiao powder improved the mouse behavivors in the sucrose preference， open field， and tail suspension tests （P<0.05， P<0.01）， and high-dose Wenxiao powder improved the behaviors in the sucrose preference and open field tests （P<0.05， P<0.01）. In addition， Wenxiao powder lowered the serum corticosterone level （P<0.01） and recovered the structure and morphology of neurons with obvious nuclei and presence of Nissl bodies in the DG area of the hippocampus. Moreover， Wenxiao powder at both doses promoted the expression of DCX in the DG area， and high-dose Wenxiao powder up-regulated the protein levels of BDNF， p-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. ConclusionWenxiao powder can alleviate corticosterone-induced depression-like behaviors and promote neurogenesis in mice possibly by activating the BDNF/TrkB/ERK/CREB signaling pathway.

ObjectiveThe traditional Chinese medicine Strychnos nux-vomica L. (SN) has the clinical effect of reducing swelling and relieving pain; however, SN is toxic due to its alkaloid components. Little is known about the endogenous metabolic changes induced by SN toxicity in rats and their potential effects on the metabolic dysregulation of intestinal microbiota. Therefore, toxicological investigation of SN is of great significance to its safety assessment. In this study, the toxic mechanisms of SN were explored using a combination of metabonomics and 16S rRNA gene sequencing. MethodsThe toxic dose, intensity, and target organ of SN were determined in rats using acute, cumulative, and subacute toxicity tests. UHPLC-MS was used to analyze the serum, liver, and renal samples of rats after intragastric SN administration. The decision tree and K Nearest Neighbor (KNN) model were established based on the bootstrap aggregation (bagging) algorithm to classify the omics data. After samples were extracted from rat feces, the high-throughput sequencing platform was used to analyze the 16S rRNA V3-V4 region of bacteria. ResultsThe bagging algorithm improved the accuracy of sample classification. Twelve biomarkers were identified, where their metabolic dysregulation may be responsible for SN toxicity in vivo. Several types of bacteria such as Bacteroidetes, Anaerostipes, Oscillospira and Bilophila, were demonstrated to be closely related to physiological indices of renal and liver function, indicating that SN-induced liver and kidney damage may be related to the disturbance of these intestinal bacteria. ConclusionThe toxicity mechanism of SN was revealed in vivo, which provides a scientific basis for the safe and rational clinical use of SN.

ObjectiveTo explore the protective effect of polysaccharide from Inonotus obliquus （IOP） on lipopolysaccharide （LPS）-induced acute lung injury （ALI） in mice. MethodA total of 40 male C57BL/6 mice were randomly divided into normal group， model group， dexamethasone group， and high-dose and low-dose IOP groups， with eight mice in each group. The high-dose and low-dose IOP groups were administered intragastrically with IOP at 20 and 10 mg·kg^-1， respectively. The normal group and the model group were intragastrically administered with normal saline in equal volumes， and the dexamethasone group was intraperitoneally injected with dexamethasone phosphate injection of 30 mg·kg^-1 for 21 days. An ALI mouse model induced by LPS was constructed， and hematoxylin-eosin （HE） staining， immunofluorescence staining， and blood routine were used to detect pathological damage of lung tissue and blood cell content. Enzyme-linked immunosorbent assay （ELISA） and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） were used to detect the expression levels of various inflammatory factors. Changes in gut microbiota and plasma differential metabolites in mice were detected using 16S rRNA sequencing and ultra-high performance liquid chromatography-quadrupole-time of flight tandem mass spectrometry （UPLC-Q-TOF-MS）. ResultCompared with the model group， the lung tissue lesions of ALI mice were significantly improved after IOP administration， and the spleen and thymus index were dramatically increased （P<0.05， P<0.01）. The ratio of wet-to-dry weight of lung tissue was sensibly decreased （P<0.05， P<0.01）， and the number of lymphocytes was substantially increased （P<0.05， P<0.01）. The number of neutrophils was markedly decreased （P<0.01）. The expression level of interleukin-6 （IL-6）， interleukin-8 （IL-8）， interleukin-1β （IL-1β）， nuclear factor-κB（NF-κB）， and nucleotide-binding oligomerization domain-like receptor 3 （NLRP3） decreased prominently （P<0.05， P<0.01） and the expression level of interleukin-10 （IL-10） increased memorably （P<0.01）. The 16S rRNA sequencing results show that IOP can regulate and improve intestinal microbial disorders. The UPLC-Q-TOF-MS results indicate that the treatment of ALI mice with IOP may involve pathways related to mitochondrial， sugar， and amino acid metabolism， such as nucleotide sugar metabolism， histidine metabolism， ubiquinone， and other terpenoid compound-quinone biosynthesis， as well as starch and sucrose metabolism. ConclusionThe improvement of lung tissue lesions and inflammatory response by IOP in ALI mice may be related to maintaining intestinal microbiota balance， regulating mitochondrial electron oxidation respiratory chain， as well as sugar and amino acid metabolism pathways， and affecting the production of related microbial metabolites and tricarboxylic acid cycle metabolites.

Objective To evaluate the value of miniprobe endoscopic ultrasound(EUS)in guiding endoscopic treatment of small-diameter(maximum diameter less than 1 cm)and low-grade(G1 grade)rectum neuroendocrine neoplasm(R-NEN),and to provide evidence and clues for its clinical application and further research.Methods The clinical data of 85 cases of low-grade(G1 grade)R-NEN with a maximum diameter of less than 1 cm who underwent endoscopic treatment in our center from January 2014 to December 2020 were retrospectively analyzed.The patients were divided into the EUS group(37 cases)and control group(48 cases)according to whether EUS was performed before endoscopic treatment.The positive rate of incision margin,the incidence of complications,the recurrence rate,the hospital stay,the cost of hospitalization and endoscopic therapy were compared between the two groups.Results The positive rate of incision margin in the EUS group was significantly lower than that in control group(P<0.05).There was no significant difference in the incidence of complications,tumor recurrence rate,hospital stay or hospital costs between the two groups(P>0.05).There was statistically significant difference in the endoscopic therapy between the two groups(P<0.05).Conclusion Evaluating the lesion depth of small-diameter and low-grade(G1 grade)R-NEN before surgery by miniprobe EUS and selecting endoscopic surgery according to its results of can significantly reduce the residual risk of resection margin tumors.

Objective:Utilizing a seven-year panel data set of a targeted admission medical student cohort,this study aims to examine their career development and provide insights for retaining healthcare talent in township health centers and village clinics in the central and western rural areas of China.Method:Starting from 2015,cohorts of targeted and general clinical graduates from four medical colleges in central and western China were selected and tracked for their career progression.Results:The targeted graduates'standardized residency training and medical licensing examination pass rates were similar to those of general clinical graduates.They advanced more quickly in professional titles and positions,with 82.5%becoming attending physicians and 16.2%obtaining positions in the seventh year after graduation.However,their monthly income was significantly lower than that of general clinical graduates,and this income discrepancy expanded annually.As of December 2022,among the 493 targeted graduates who completed their contracts,38.5%stayed in grassroots positions.Of those who left,60%moved to county-level or higher public hospitals,7.9%pursued further studies,and 27.7%were unemployed.Conclusion:Targeted graduates are well-trained and advance rapidly in their careers,but their lower income significantly impacts their willingness to remain at the grassroots level.After completing their service period,about one-third of the targeted graduates choose to stay in grassroots positions.

Objective:To provide a basis for improving the design and implementation of policies for ensuring the supply of pediatric drugs in China.Method:Based on the perspective of pharmaceutical enterprises,reviewed literature and conducts questionnaire surveys to identify the constraints in the development of pediatrict drugs throughout the entire drug lifecycle,and analyzes the constraints'concentration and urgency.Result:The main constraints include:difficulty in conducting clinical trials for children;the current registration and approval rules lack consideration for the specificity of pediatric drugs and specific requirements for application materials;lack of implementation rules and measures in the implementation process of incentive policies for pediatric drug production;The market interest mechanism of pediatric drugs is not yet perfect.Among them,research and development and payment for use are currently relatively concentrated issues.Discussion and suggestions:It is recommended that China fully utilize existing clinical trial data of pediatric and broaden sources,take multiple measures to increase investment in pediatric drug R&D;Develop special guidelines for pediatric drug application and encourage adult drug registration to submit pediatric research plans;Explore the optimization path of pediatrict drug production and supply based on typical cases;Provide more space for pediatric drugs in the rules of drug use and payment.