Aim To investigate the role of ferrostatin-1(Fer-1)in adriamycin(ADR)induced podocyte inju-ry.Methods Western blot and RT-qPCR were used to detect the expression of the ferroptosis signaling pathway and podocyte injury-related proteins in podo-cytes treated with ADR and Fer-1.The therapeutic effect of Fer-1 on podocytes was screened by CCK-8;malondialdehyde(MDA),glutathione(GSH)and Fe2+kit were used to evaluate the lipid peroxidation level of podocytes.A mouse model of ADR nephropa-thy was constructed in vivo,and the expression of fer-roptosis related proteins in mouse glomerular podocytes was detected by Western blot and RT-qPCR.The fer-roptosis level of kidney was evaluated by immunohisto-chemistry staining of 4-HNE.Results The expression level of ACSL4,a marker related to ferroptosis,was significantly up-regulated.GPX4 and SLC7A11 were significantly down-regulated in podocytes under ADR stimulation.Compared with the ADR group,Fer-1 in-tervention could partially restore the anomalous change of ferroptosis related protein and improve the expression level of podocellular damage protein desmin.The re-sults of MDA,GSH and Fe2+showed that Fer-1 could improve the lipid peroxidation level of podocytes.The expression level of ACSL4 was significantly up-regula-ted and GPX4 and SLC7A11 were significantly up-reg-ulated in the ADR model group.IHC staining of 4-HNE increased in ADR model group.Conclusions Adriamycin promotes podocyte injury by induced ferrop-tosis,and inhibiting ferroptosis may be a potential strat-egy to prevent the progression of ADR nephropathy.

The 68 Center for Drug Evaluation recommend approved innovative drugs between 2019 and 2021 evaluation situation was summarized in this article,to analyzes the innovative drugs research and development trend and the influence of the drug evaluation and approval system reform.Meanwhile,after sorting out the clinical trials inspection report,to analyze the clinical trials on-site inspection of innovative drugs,and summarized the common defects,hope to provide reference and suggestions for subsequent innovative drug application and high-quality drug clinical trials.

Objective To explore the clinical value of anti-Müllerian hormone(AMH)to optimize endocrine therapy for peri-menopausal early breast cancer.Methods Two hundred and four patients of pre-menopausal breast cancer aged 45-55 years old between 2020 and 2023 were enrolled,and AMH≤0.1 ng/mL was considered as cut-off value for menopause.Switching from selective estrogen receptor modulator(SERM)to aromatase inhibitor aromatase inhibitor(AI)and initial endocrine therapy regimens were based on AMH,follicle-stimulating hormone(FSH)and estradiol(E2).Results Pre-chemotherapy AMH level was significantly negatively correlated with FSH level(P<0.001).Among 100 cases who were amenorrhea for one year during SERM treatment,42 cases did not have AMH testing.Fourteen out of the 42 cases switched to AI within one year,and ovarian function recovery(OFR)occurred in 2 cases after AI switching.Fifteen cases with AMH>0.1 ng/mL did not switch to AI within one year.Forty among 43 cases with AMH≤0.1 ng/mL switched to AI,after a significantly shorter median SERM treatment duration(3.15 months vs.8.14 months,P<0.001)and a significantly lower OFR rate(0 vs.12.5%,P=0.023)compared with those who did not test AMH but switched to AI.AMH≤0.1 ng/mL was an independent risk factor of transition to menopause shortly in peri-menopausal patients(OR=35.857,P<0.001).Among 104 cases with AMH tested before adjuvant chemotherapy,69 cases had AMH>0.1 ng/mL.Thirty-one out of the 69 cases were treated with ovarian function suppression(OFS)initially and 38 with SERM initially.Thirty-five cases with AMH≤0.1 ng/mL were all treated with SERM initially,with a higher rate of switching to AI(71.4%vs.23.7%,P<0.001)and a shorter SERM treatment duration(6.52 months vs.13.56 months,P=0.016)compared with the 38 cases(AMH>0.1 ng/mL)treated initially with SERM.After a median 30-month follow-up,no recurrence was observed in these thirty-five cases treated with SERM initially and AMH≤0.1 ng/mL,just like in OFS group.And they had a tendency of improved survival outcome compared with those treated with SERM initially and AMH>0.1 ng/mL(Log Rank P=0.076).Conclusion AMH could evaluate and predict menopause accurately,resulting in optimizing endocrine therapy for peri-menopausal patients effectively and safely.

Objective To construct and identify an organoid model of human placental site trophoblastic tumor(PSTT).Methods The tumor cells were obtained by digesting and separating the PSTT tissues and then embedded in Matrigel.The organoids were cultured in the specific organoid medium.The histological morphology of the organoid model was observed by HE staining and the expression levels of the PSTT specific markers[human placental prolactin(HPL),human leukocyte antigen-G(HLA-G)and placental alkaline phosphatase(PLAP)]were detected by immunohistochemistry and immunofluorescence,so as to evaluate the consistency between the organoid model and the PSTT tissue.Meanwhile,the morphology and forming efficiency of the constructed model were observed under a microscope after primary culture,passage generation and cryopreservation to evaluate its potential application as an organoid model in basic and clinical translational research of PSTT.Results The constructed organoid model could proliferate stably,growing from small microspheres into compact solid spheres or spheres with follicle-like structures,and could passage after fully grown in 7-10 days.The cell state remained stable after passage,frozen storage and recovery.HE staining showed that the morphology of the cells in the organoids was similar to that of the primary PSTT tumor cells,and immunofluorescence staining showed that the organoids highly expressed HLA-G and lowly expressed β-HCG,indicating that the constructed organoid model mainly contained intermediate trophoblast.Conclusion The adult-derived PSTT organoid(ADPO)models were successfully established.

With the in-depth study of molecular biology,non-small cell lung cancer(NSCLC)has opened the era of precision medicine based on mutation-based molecular targeting therapy.Epidermal growth factor receptor(EGFR)driver mutations are closely related to the progression of NSCLC,and EGFR-tyrosine kinase inhibitors(TKIs)developed based on this have achieved significant therapeutic effects,but acquired drug resistance is still one of the major factors limiting their long-term use.As resistance mechanisms are further investigated,in addition to secondary EGFR mutation,MET amplification,HER2 amplification,histologic transformation,etc.,receptor tyrosine kinase(RTK)fusion mutation have been shown to be a targetable mechanism of acquired resistance.Among the acquired RTK fusion mutations,rearranged during transfection(RET)fusion mutations are the accessible targets of our concern.As the RET molecule continues to be explored,drugs targeting RET fusions have been approved and marketed.There are different clinical strategies to deal with acquired RET fusion mutation mediating resistance to EGFR-TKIs treatment.In this review,the structure and function of RET,its relationship with EGFR-TKIs resistance,and treatment strategies are reviewed to further improve patient survival outcomes.

Objective:To observe the effects of early energy intake and early enteral nutrition on prognosis of patients during extracorporeal membrane oxygenation (ECMO).Methods:Patients who received ECMO treatment in the emergency intensive care unit (EICU) of the Jiangsu Provincial Hospital (First Affiliated Hospital of Nanjing Medical University) from January 2021 to June 2022 were selected as subjects to summarize the early energy intake of ECMO patients. Logistic regression analysis and restricted cubic spline (RCS) analysis were used to determine the relationship between early energy intake and prognosis of ECMO patients. According to the results of RCS analysis, the patients were divided into energy-deficient group and energy-sufficient group. And according to whether early enteral nutrition (EEN) was initiated, the patients were divided into EEN group and non-EEN group. The differences of clinical outcomes between energy-deficient group and energy-sufficient group, EEN group and non-EEN group were compared.Results:There was no significant difference in age, sex, BMI, primary disease and ECMO pattern between energy-deficient group and energy-sufficient group, EEN group and non-EEN group. The ECMO conversion time (days) and hospitalization time (days) in the energy-deficient group were significantly lower than those in the energy-sufficient group, and the survival rate in the energy-deficient group was significantly lower than that in the energy-sufficient group [43.2% (19/44) vs. 66.0% (31/47), P=0.029]. Kaplan-Meier survival analysis showed that the 28-day survival rate in the energy-deficient group was significantly lower than that in the energy-sufficient group, and the risk of death was 2.595 times higher than that in the energy-sufficient group. The conversion time (days), hospital stay (days) and average daily energy intake [kcal/(kg·d)] in the EEN group were higher than those in the non-EEN group ( P<0.05), and the survival rate in the non-EEN group was significantly higher than that in the non-EEN group [66.1% (41/62) vs. 31.0% (9/29), P<0.002]. Kaplan-Meier survival analysis showed that the 28-day survival rate in the non-EEN group was significantly lower than that in the EEN group, and the risk of death was 2.981 times higher than that in the EEN group ( P<0.001). Conclusions:The energy intake of patients with ECMO above 16.94 kcal/ (kg·d) is a protective factor for prognosis. EEN helps to increase early energy intake and improve prognosis in patients during ECMO.

OBJECTIVE: To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine. METHODS: Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients. RESULTS: Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes >60 months (OR=3.562, P=0.010), anemia (OR=4.176, P<0.001), hyperuricemia (OR=3.352, P<0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD. CONCLUSIONS Male, course of diabetes >60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).
Humans ; Male ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Hyperuricemia ; Kidney ; Proteinuria ; Renal Insufficiency, Chronic/complications*

Objective: To identify the main metals involved in cognitive impairment in the Chinese oldest old, and explore the association between these metal exposures and cognitive impairment. Methods: A cross-sectional study was conducted on 1 568 participants aged 80 years and older from Healthy Aging and Biomarkers Cohort Study (2017 to 2018). Fasting venous blood was collected to measure the levels of nine metals (selenium, lead, cadmium, arsenic, antimony, chromium, manganese, mercury, and nickel). The cognitive function of these participants was evaluated by using the Chinese version of the Mini-Mental State Examination (CMMSE). The random forest (RF) was applied to independently identify the main metals that affected cognitive impairment. The multivariate logistic regression model and restricted cubic splines (RCS) model were used to further verify the association of the main metals with cognitive impairment. Results: The age of 1 568 study subjects was (91.8±7.6) years old, including 912 females (58.2%) and 465 individuals (29.7%) with cognitive function impairment. Based on the RF model (the out-of-bag error rate was 22.9%), the importance ranking of variables was conducted and the feature screening of five times ten-fold cross-validation was carried out. It was found that selenium was the metal that affected cognitive function impairment, and the other eight metals were not included in the model. After adjusting for covariates, the multivariate logistic regression model showed that with every increase of 10 μg/L of blood selenium levels, the risk of cognitive impairment decreased (OR=0.921, 95%CI: 0.889-0.954). Compared with the lowest quartile(Q₁) of blood selenium, the ORs (95%CI) of Q₃ and Q₄ blood selenium were 0.452 (0.304-0.669) and 0.419 (0.281-0.622) respectively. The RCS showed a linear dose-response relationship between blood selenium and cognitive impairment (P_nonlinear>0.05). Conclusion: Blood selenium is negatively associated with cognitive impairment in the Chinese oldest old.
Aged, 80 and over ; Female ; Humans ; Selenium ; Cohort Studies ; Cross-Sectional Studies ; Metals/analysis* ; Cognitive Dysfunction/epidemiology* ; China/epidemiology*

Objective To investigate the effect of Danhuangsan on high glucose-induced vascular endothelial cell injury based on PINK 1/Parkin signaling pathway,and to explore its specific mechanism.Methods Human um-bilical vein endothelial cells were cultured in vitro and randomly divided into control group,growth factor group,Danhuangsan group,high glucose group,high glucose+growth factor group,high glucose+Danhuangsan group,with 3 cases in each group,treated for 48 hours.Cell scratch test was used to detect cell migration rate,and Transwell test was used to detect cell invasion rate.Immunofluorescence was used to detect the expression of anti-apoptotic protein Bcl-2,Beclin-1 and pro-apoptotic protein Bax.Western blot was used to detect the protein expression levels of PINK 1,Parkin and LC 3-Ⅱ.Results Cell scratch test and Transwell test showed that under normal environment and high glucose treatment,Danhuangsan could reduce the cell migration and invasion rate(P＜0.05).Immunofluorescence assay showed that under normal environment and high glucose treatment,Danhuang-san up-regulated the expression levels of Bcl-2 and Beclin-1 protein in cells(P＜0.05).Western blot results showed that under normal environment and high glucose treatment,Danhuangsan increased the protein expression levels of PINK 1,Parkin and LC 3-Ⅱ in cells and down-regulated the expression levels of Bax protein(P＜0.05),and the effects of Danhuang powder were significantly better than those of blank serum and growth factor(P＜0.05).Conclusion Danhuangsan can alleviate high glucose-induced endothelial cell injury by activating PINK 1/Parkin pathway,and the mechanism may be related to promoting mitophagy and enhancing the repair of damage.

Codonopsis Radix is a traditional tonic medicine commonly used in China, which has the effects of strengthening the spleen and tonifying the lung, as well as nourishing blood and engendering liquid. The chemical constituents of Codonopsis species are mainly polyacetylenes, alkaloids, phenylpropanoids, lignans, terpenoids and saponins, flavonoids, steroids, organic acids, saccharides, and so on. Modern pharmacological studies showed that Codonopsis Radix also has a variety of pharmacological effects such as enhancing body immunity, protecting gastrointestinal mucosa and resisting ulcers, promoting hematopoietic function, regulating blood sugar, and delaying aging. In this paper, the chemical constituents of Codonopsis species and the pharmacological effects of Codonopsis Radix were summarized, and on this basis, the quality markers of Codonopsis Radix were analyzed. It was predicted that lobetyolin, tangshenoside I, codonopyrrolidium A, and the oligosaccharides were the possible Q-markers of Codonopsis Radix. This paper will provide scientific references for the quality evaluation and profound research and the development of Codonopsis Radix.
Drugs, Chinese Herbal ; Codonopsis ; Alkaloids ; Medicine, Traditional ; Plant Roots