Ferroptosis of chondrocytes is a significant contributor to osteoarthritis (OA), for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis. Here, we screen for anti-ferroptotic drugs in Food and Drug Administration (FDA)-approved drug library via a high-throughput manner in chondrocytes. We identified a group of FDA-approved anti-ferroptotic drugs, among which vitamin K showed the most powerful protective effect. Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix (ECM) degradation in chondrocytes. Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus (DMM) mouse model. Mechanistically, transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6 (Gas6). Furthermore, exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase (AXL)/phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) axis. Together, we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis, indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in Food and Drug Administration(FDA)-approved drug library via a high-throughput manner in chondrocytes.We identified a group of FDA-approved anti-ferroptotic drugs,among which vitamin K showed the most powerful protective effect.Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix(ECM)degradation in chondrocytes.Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus(DMM)mouse model.Mechanistically,transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6(Gas6).Furthermore,exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase(AXL)/phosphatidylinositol 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)axis.Together,we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis,indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

Objective To predict the risk of in-hospital death in patients with chronic heart failure(CHF)complicated by lung infections using interpretable machine learning.Methods The clinical data of 1415 patients diagnosed with CHF complicated by lung infections were obtained from the MIMIC-IV database.According to the pathogen type,the patients were categorized into bacterial pneumonia and non-bacterial pneumonia groups,and their risks of in-hospital death were compared using Kaplan-Meier survival curves.Univariate analysis and LASSO regression were used to select the features for constructing LR,AdaBoost,XGBoost,and LightGBM models,and their performance was compared in terms of accuracy,precision,F1 value,and AUC.External validation of the models was performed using the data from eICU-CRD database.SHAP algorithm was applied for interpretive analysis of XGBoost model.Results Among the 4 constructed models,the XGBoost model showed the highest accuracy and F1 value for predicting the risk of in-hospital death in CHF patients with lung infections in the training set.In the external test set,the XGBoost model had an AUC of 0.691(95%CI:0.654-0.720)in bacterial pneumonia group and an AUC of 0.725(95%CI:0.577-0.782)in non-bacterial pneumonia group,and showed better predictive ability and stability than the other models.Conclusion The overall performance of the XGBoost model is superior to the other 3 models for predicting the risk of in-hospital death in CHF patients with lung infections.The SHAP algorithm provides a clear interpretation of the model to facilitate decision-making in clinical settings.

BACKGROUND:Glucocorticoids can inhibit the expression of hub genes in the parathyroid hormone type Ⅰ receptor(PTH1R)/protein kinase A(PKA)signaling axis and interfere with the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells,leading to the disruption of blood supply in bone and bone tissue structures.Previous studies of the research team showed that Gubitongxiao granules can induce blood vessel formation and inhibit osteoblast apoptosis,which has a certain effect on the prevention and treatment of steroid-induced femoral head necrosis. OBJECTIVE:To observe the therapeutic effect of Gubitongxiao granules in a mouse model of steroid-induced femoral head necrosis,and to explore its mechanism from the PTH1R/PKA signaling axis. METHODS:An animal model of steroid-induced necrosis of the femoral head was established by intraperitoneal injection of lipopolysaccharide and gluteal muscle injection of prednisolone acetate.After identification by nuclear magnetic resonance method,60 mice that were successfully modeled were divided into model group,Gubitongxiao granule group and Tongluo Shenggu capsule group,with 20 mice in each group.Another 12 normal mice were used as control group.The corresponding groups were intragastrically given the corresponding drugs for 12 weeks,and then the samples were taken under anesthesia.Histomorphology of femoral head samples was observed by hematoxylin-eosin staining.Enzyme-linked immunosorbent assay was used to detect the serum levels of bone alkaline phosphatase,type Ⅰ amino-terminal extension peptide,parathyroid hormone,osteocalcin and alkaline phosphatase.Western blot and RT-qPCR were used to detect PTH1R,PKA,myocyte enhancer factor 2,sclerostin and guanylate-binding protein activity-stimulating peptide at protein and gene expression levels,respectively. RESULTS AND CONCLUSION:Gubitongxiao granules may reduce the serum PTH level in mice,inhibit the activation of the PTH1R/PKA signal axis,further up-regulate the protein expressions of sclerostin and myocyte enhancer factor 2,and increase the levels of bone alkaline phosphatase,type Ⅰ amino-terminal extension peptide,osteocalcin and alkaline phosphatase in mice,thus improving femoral head necrosis,which is comparable to the intervention effect of Tongluo Shenggu capsules.It is speculated that Gubitongxiao granules may prevent and treating hormonal femoral head necrosis by regulating the PTH1R/PKA signaling axis.

Objective To predict the risk of in-hospital death in patients with chronic heart failure(CHF)complicated by lung infections using interpretable machine learning.Methods The clinical data of 1415 patients diagnosed with CHF complicated by lung infections were obtained from the MIMIC-IV database.According to the pathogen type,the patients were categorized into bacterial pneumonia and non-bacterial pneumonia groups,and their risks of in-hospital death were compared using Kaplan-Meier survival curves.Univariate analysis and LASSO regression were used to select the features for constructing LR,AdaBoost,XGBoost,and LightGBM models,and their performance was compared in terms of accuracy,precision,F1 value,and AUC.External validation of the models was performed using the data from eICU-CRD database.SHAP algorithm was applied for interpretive analysis of XGBoost model.Results Among the 4 constructed models,the XGBoost model showed the highest accuracy and F1 value for predicting the risk of in-hospital death in CHF patients with lung infections in the training set.In the external test set,the XGBoost model had an AUC of 0.691(95%CI:0.654-0.720)in bacterial pneumonia group and an AUC of 0.725(95%CI:0.577-0.782)in non-bacterial pneumonia group,and showed better predictive ability and stability than the other models.Conclusion The overall performance of the XGBoost model is superior to the other 3 models for predicting the risk of in-hospital death in CHF patients with lung infections.The SHAP algorithm provides a clear interpretation of the model to facilitate decision-making in clinical settings.

Objective To investigate the protective effect of Gubi Tongxiao granules on steroid-induced necrosis of femoral head(SANFH).Methods Femoral head and bone marrow tissues of patients with SANFH and femoral neck fracture(FNF)undergoing hip replacement were collected and studied.The expression levels of phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT),FoxOl and cholesterol regulatory binding protein(SREBP)were detected in bone tissue.Human bone marrow mesenchymal stem cells(hBMSCs)were isolated and cultured.The effect of the drug-containing serum of Gubitongxiao granule on the proliferation of hBMSCs was detected by CCK-8 method.Oil red O and alizarin red staining were used to observe the adipogenic and osteogenic differentiation of cells.The expression of peroxisome proliferator-activated receptor γ(PPARy),CCATT enhancer binding protein α(C/EBPα),Runt-associated transcription factor 2(Runx2),alkaline phosphatase(ALP)mRNA and pathway protein were analyzed by RT-qPCR and Western blot.Results Western blot results showed that the expression of PI3K,AKT and SREBP protein in femoral head tissue of SANFH patients was significantly increased compared with that of normal group,while FoxOl expression was significantly decreased(P＜0.05);Different volume fractions of Gubi Tongxiao granules could promote the proliferation of hBMSCs,especially in 5％group after 48h.Compared with the model group,5％drug-containing serum could significantly reduce the lipid droplet coloring in the cytoplasm and increase the orange-red mineralized nodules in the calcium salt deposit,down-regulate the mRNA expression levels of PPARγ and C/EBPα,and up-regulate the mRNA expression levels of Runx2 and ALP(P＜0.05).In addition,after the intervention of drug-containing serum,the expression of FoxO1 protein in cells was significantly increased,and the expression of AKT,p-FoxO1 and SREBP protein was decreased(P＜0.05).Conclusion After the intervention of Gubi Tongxiao granules,the lipid differentiation of hBMSCs decreased and the osteogenic differentiation increased,which can effectively improve the lipid deposition in glucocorticoid environment,and the mechanism may be related to the regulation of PI3K/AKT/FoxO1 signaling pathway.

Objective To investigate the protective effect of Gubi Tongxiao granules on steroid-induced necrosis of femoral head(SANFH).Methods Femoral head and bone marrow tissues of patients with SANFH and femoral neck fracture(FNF)undergoing hip replacement were collected and studied.The expression levels of phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT),FoxOl and cholesterol regulatory binding protein(SREBP)were detected in bone tissue.Human bone marrow mesenchymal stem cells(hBMSCs)were isolated and cultured.The effect of the drug-containing serum of Gubitongxiao granule on the proliferation of hBMSCs was detected by CCK-8 method.Oil red O and alizarin red staining were used to observe the adipogenic and osteogenic differentiation of cells.The expression of peroxisome proliferator-activated receptor γ(PPARy),CCATT enhancer binding protein α(C/EBPα),Runt-associated transcription factor 2(Runx2),alkaline phosphatase(ALP)mRNA and pathway protein were analyzed by RT-qPCR and Western blot.Results Western blot results showed that the expression of PI3K,AKT and SREBP protein in femoral head tissue of SANFH patients was significantly increased compared with that of normal group,while FoxOl expression was significantly decreased(P＜0.05);Different volume fractions of Gubi Tongxiao granules could promote the proliferation of hBMSCs,especially in 5％group after 48h.Compared with the model group,5％drug-containing serum could significantly reduce the lipid droplet coloring in the cytoplasm and increase the orange-red mineralized nodules in the calcium salt deposit,down-regulate the mRNA expression levels of PPARγ and C/EBPα,and up-regulate the mRNA expression levels of Runx2 and ALP(P＜0.05).In addition,after the intervention of drug-containing serum,the expression of FoxO1 protein in cells was significantly increased,and the expression of AKT,p-FoxO1 and SREBP protein was decreased(P＜0.05).Conclusion After the intervention of Gubi Tongxiao granules,the lipid differentiation of hBMSCs decreased and the osteogenic differentiation increased,which can effectively improve the lipid deposition in glucocorticoid environment,and the mechanism may be related to the regulation of PI3K/AKT/FoxO1 signaling pathway.

Objective:To analyze the clinical characteristics and prognosis of patients infected with novel coronavirus Omicron variant in Shanghai, as to provide a reference for epidemic prevention, clinical diagnosis, and treatment.Methods:Altogether 4 264 novel coronavirus Omicron variant-infected patients with positive results of nucleic acid admitted to Shanghai New International Expo Center N3 Mobile Cabin Hospital from April 2 to May 7, 2022, were included. The demographic and baseline clinical characteristics, treatment strategy, prognosis, and different factors affecting the length of hospital stay were analyzed.Results:A total of 4 264 novel coronavirus variant Omicron-infected cases were collected, including 3 111 cases (73.0%) asymptomatic infections and 1 153 cases (27.0%) mild infections. The overall median age was 45 (33, 55) years old with a range from 2 years old to 81 years old. The male to female ratio was 1.37∶1. Altogether 3 305 cases (77.5%) had been vaccinated, of which 3 166 cases completed more than 2 doses. The upper respiratory tract symptoms such as cough and expectoration were the most common clinical manifestations of these infected patients. During the course of the disease, patients with asymptomatic infection were mainly treated with traditional Chinese medicine (TCM, 55.1%) and clinical observation (36.8%), and those with mild infection were mainly treated with TCM (42.2%) or integrated Chinese and Western medicine (30.4%). All patients were cured and discharged. The overall median length of hospital stay and the negative conversion time of nucleic acid were 9 (6, 10) days and 8 (5, 9) days, respectively. Compared with the asymptomatic infected patients, the hospitalization duration and the nucleic acid negative conversion time of the mildly infected patients were slightly longer [days: 10 (8, 11) vs. 9 (5, 10); 8 (6, 10) vs. 7 (4, 9), both P < 0.001]. Multiple linear regression analysis showed that the increasing age and mild infection were associated with longer hospitalization duration, and the treatment of TCM or integrated Chinese and Western medicine was associated with shortened length of hospital stay (all P < 0.05). Conclusions:The current novel coronavirus Omicron variant epidemic in Shanghai mainly caused asymptomatic and mild infections. The young and middle-aged population had a relatively high infection rate. The upper respiratory tract symptoms such as cough and expectoration were the most common clinical symptoms. Elderly and confirmed patients had prolonged hospitalization duration, while for patients receiving TCM treatment, the hospitalization duration was shortened.

Objective:To study the curative effect of hydrotalcite combined with omeprazole in the treatment of gastric ulcer with gastric bleeding. Methods:Seventy-six patients with gastric ulcer and bleeding in the stomach were selected and randomly divided into two groups. Thirty-two patients in the control group were treated with omeprazole alone while 44 patients in the observation group were treated with hydrotalcite combined with omeprazole. The therapeutic effects were compared between the two groups. Results:The total effective rate in the observation group was 100% while that was 87. 5% in the control group,and the difference between the two groups was statistically significant(P<0. 05). The comprehensive score of symptoms of the patients in the observation group was(4. 2 ± 1. 2)while that was(6. 2 ± 1. 4)in the control group,and the difference was significant(P<0. 01). The abdominal pain,abdominal distention and belching remission time in the observation group were slightly shorter than those in the control group(P<0. 05)and the time of hematemesis and hemafecia remission was significantly shorter than that in the control group(P<0. 05). After the 3-month treatment,the re-bleeding rate in the observation group was 6. 82%,which was slightly better than that in the control group,and the difference had no statistical significance(P<0. 05). The incidence of adverse reactions in the observation group was 9. 09% while that was 6. 25% in the control group,and there was no significant difference between the two groups(P>0. 05). Conclusion:Hydro-talcite combined with omeprazole in the treatment of gastric ulcer with gastric bleeding is effective and safe.