Objective To explore the mechanism of Quhan Zhufeng Mixture on proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocyte(RA-FLS)based on NDRG2/JAK2/STAT3 signaling pathway.Methods RA-FLS cells were cultured in vitro,and were divided into ① blank serum group,methotrexate group,Quhan Zhufeng Mixture low-,medium-and high-dosage groups;② blank serum group,AG490 group,Quhan Zhufeng Mixture low-,medium-and high-dosage groups.Different concentrations of drug-containing serum were used to intervene cells.Cell proliferation was detected by CCK-8 method,apoptosis was detected by flow cytometry,and mRNA expressions of Bax,Bcl-2,Caspace-3,Caspace-9,N-myc downstream regulatory gene 2(NDRG2),Janus kinase 2(JAK2)and signal transduction and transcription activator 3(STAT3)were detected by RT-qPCR,Western blot was used to detect the protein expressions of Bax,Bcl-2,Caspace-3,Caspace-9,NDRG2,JAK2,STAT3,p-JAK2 and p-STAT3 in cells.Results Compared with the blank serum group,cell survival rate in methotrexate group,Quhan Zhufeng Mixture all dosage groups significantly decreased(P<0.01),the apoptosis rate significantly increased(P<0.01),the mRNA and protein expressions of Bax and Caspase-9 significantly increased(P<0.05,P<0.01),while the mRNA and protein expression of Bcl-2 significantly decreased(P<0.01),and Caspase-3 mRNA and protein expression in methotrexate group and Quhan Zhufeng Mixture medium-and high-dosage groups significantly increased(P<0.01).Compared with the blank serum group,the mRNA and protein expression of NDRG2 significantly increased in Quhan Zhufeng Mixture all dosage groups(P<0.05,P<0.01),the mRNA and protein expressions of JAK2 and STAT3 were significantly reduced in AG490 group and Quhan Zhufeng Mixture medium-and high-dosage groups(P<0.05,P<0.01),and the expressions of p-JAK2 and p-STAT3 proteins were significantly reduced(P<0.01).Conclusion Quhan Zhufeng Mixture can regulate the proliferation and apoptosis of RA-FLS by regulating the activity of NDRG2/JAK2/STAT3 signaling pathway,playing a role in treating rheumatoid arthritis.

BACKGROUND:Small intestinal submucosal acellular matrix has been proven by clinical and basic studies to be useful for urethral repair and reconstruction.However,when applied alone,it has problems such as slow growth of host cells,difficulty in survival due to insufficient stent vascularization,and obstruction of reconstructed urethral stricture,and is only suitable for short urethral stricture.OBJECTIVE:To investigate the feasibility of constructing tissue engineered urethra with acellular matrix combined with exosomes in small intestinal submucosa.METHODS:Exosomes were isolated from rabbit bone marrow mesenchymal stem cells.The porcine small intestinal submucosal acellular matrix was prepared,and exosomes were loaded on the porcine small intestinal submucosal acellular matrix.The extracellular stroma-exosome(PKH26 dye labeled)complex of small intestinal submucosa was co-cultured with umbilical vein endothelial cells for 12 hours to observe the uptake of exosomes.The umbilical vein endothelial cells with good growth status were selected and cultured in three groups:the blank group was cultured routinely.The control group was added with small intestinal submucosal acellular matrix,and the experimental group was added with small intestinal submucosal acellular stromat-exosome complex.The angiogenesis was evaluated by scratch test,tube formation test,and angiogenic factor secretion test.Thirty New Zealand white rabbits were selected to establish a long(3 cm)urethral defect model,and the intervention was divided into three groups by random number table method(n=10).The single material group was implanted with small intestinal submucosal acellular matrix.The control group was implanted with small intestinal submucosal acellular matrix-bone marrow mesenchymal stem cell complex.The experimental group was implanted with small intestinal submucosal acellular matrix-exosome complex.Urethrography,urodynamic examination,and pathological observation of reconstructed urethral sections were performed 12 weeks after implantation.RESULTS AND CONCLUSION:(1)Exosomes in the acellular matrix of small intestinal submucosa could be taken up by umbilical vein endothelial cells under the fluorescence microscope.(2)Compared with the blank group and the control group,the experimental group could promote the migration of umbilical vein endothelial cells,angiogenesis ability,and the secretion of angiogenic factors vascular endothelial growth factor,hepatocyte growth factor,and interleukin 8(P<0.05).(3)Urethrography results showed that all 10 rabbits in the single material group had urethral stenosis;2 out of 10 rabbits in the control group had urethral stenosis,and none of the 10 rabbits in the experimental group had urethral stenosis.The results of urodynamic examination showed that the maximum urethral pressure at 12 weeks after implantation was higher in the single material group than before surgery(P<0.05),and the maximum urethral pressure at 12 weeks after implantation was lower in the control group and the experimental group than in the blank group(P<0.05).Hematoxylin-eosin,Masson and immunohistochemical staining showed that in the single material group,there were obvious regenerated epidermis,a small amount of subcutaneous smooth muscle and blood vessels,mainly fibrous tissue hyperplasia,accompanied by obvious inflammatory cell infiltration.In the control group,there were more complete regenerated epithelium and a small amount of collagen,a large number of subcutaneous blood vessels and smooth muscle,accompanied by inflammatory cell infiltration.The experimental group showed complete regenerated epidermis,a large number of subcutaneous blood vessels and smooth muscle,and no obvious inflammatory cell infiltration.The positive expressions of AE1/AE3,alpha smooth muscle actin,and CD31 in the experimental group were higher than those in the single material group and the control group(P<0.05).(4)The results show that the small intestinal submucosal acellular matrix-exosome tissue engineered urethra can repair the urethral defect by promoting angiogenesis.

Synovium is the target organ of rheumatoid arthritis.The excessive proliferation of synovial cells and insufficient apoptosis lead to synovial hyperplasia,which in turn causes damage to the surrounding tissues of the joint and bone destruction."Yang transforming qi and yin forming elements"is derived from Su Wen and is a highly summarized description of the functions of yin and yang,which runs through the entire course of the disease.This article elucidated the theoretical connotation of"yang transforming qi and yin forming elements"and its connection with synovial hyperplasia,proposing that the insufficiency of"yang transforming qi"is the root of synovial hyperplasia,while the excess of"yin forming elements"is the manifestation of synovial hyperplasia.Based on this,it put forward that"assisting yang qi as the priority,and according to the bias of pathogenic factors of yin,supplementing the method of reducing yin forming elements"is an important principle for treating this disease,which could provide new ideas for the treatment of the disease.

Objective To explore the mechanism of Quhan Zhufeng Mixture on proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocyte(RA-FLS)based on NDRG2/JAK2/STAT3 signaling pathway.Methods RA-FLS cells were cultured in vitro,and were divided into ① blank serum group,methotrexate group,Quhan Zhufeng Mixture low-,medium-and high-dosage groups;② blank serum group,AG490 group,Quhan Zhufeng Mixture low-,medium-and high-dosage groups.Different concentrations of drug-containing serum were used to intervene cells.Cell proliferation was detected by CCK-8 method,apoptosis was detected by flow cytometry,and mRNA expressions of Bax,Bcl-2,Caspace-3,Caspace-9,N-myc downstream regulatory gene 2(NDRG2),Janus kinase 2(JAK2)and signal transduction and transcription activator 3(STAT3)were detected by RT-qPCR,Western blot was used to detect the protein expressions of Bax,Bcl-2,Caspace-3,Caspace-9,NDRG2,JAK2,STAT3,p-JAK2 and p-STAT3 in cells.Results Compared with the blank serum group,cell survival rate in methotrexate group,Quhan Zhufeng Mixture all dosage groups significantly decreased(P<0.01),the apoptosis rate significantly increased(P<0.01),the mRNA and protein expressions of Bax and Caspase-9 significantly increased(P<0.05,P<0.01),while the mRNA and protein expression of Bcl-2 significantly decreased(P<0.01),and Caspase-3 mRNA and protein expression in methotrexate group and Quhan Zhufeng Mixture medium-and high-dosage groups significantly increased(P<0.01).Compared with the blank serum group,the mRNA and protein expression of NDRG2 significantly increased in Quhan Zhufeng Mixture all dosage groups(P<0.05,P<0.01),the mRNA and protein expressions of JAK2 and STAT3 were significantly reduced in AG490 group and Quhan Zhufeng Mixture medium-and high-dosage groups(P<0.05,P<0.01),and the expressions of p-JAK2 and p-STAT3 proteins were significantly reduced(P<0.01).Conclusion Quhan Zhufeng Mixture can regulate the proliferation and apoptosis of RA-FLS by regulating the activity of NDRG2/JAK2/STAT3 signaling pathway,playing a role in treating rheumatoid arthritis.

BACKGROUND:Small intestinal submucosal acellular matrix has been proven by clinical and basic studies to be useful for urethral repair and reconstruction.However,when applied alone,it has problems such as slow growth of host cells,difficulty in survival due to insufficient stent vascularization,and obstruction of reconstructed urethral stricture,and is only suitable for short urethral stricture.OBJECTIVE:To investigate the feasibility of constructing tissue engineered urethra with acellular matrix combined with exosomes in small intestinal submucosa.METHODS:Exosomes were isolated from rabbit bone marrow mesenchymal stem cells.The porcine small intestinal submucosal acellular matrix was prepared,and exosomes were loaded on the porcine small intestinal submucosal acellular matrix.The extracellular stroma-exosome(PKH26 dye labeled)complex of small intestinal submucosa was co-cultured with umbilical vein endothelial cells for 12 hours to observe the uptake of exosomes.The umbilical vein endothelial cells with good growth status were selected and cultured in three groups:the blank group was cultured routinely.The control group was added with small intestinal submucosal acellular matrix,and the experimental group was added with small intestinal submucosal acellular stromat-exosome complex.The angiogenesis was evaluated by scratch test,tube formation test,and angiogenic factor secretion test.Thirty New Zealand white rabbits were selected to establish a long(3 cm)urethral defect model,and the intervention was divided into three groups by random number table method(n=10).The single material group was implanted with small intestinal submucosal acellular matrix.The control group was implanted with small intestinal submucosal acellular matrix-bone marrow mesenchymal stem cell complex.The experimental group was implanted with small intestinal submucosal acellular matrix-exosome complex.Urethrography,urodynamic examination,and pathological observation of reconstructed urethral sections were performed 12 weeks after implantation.RESULTS AND CONCLUSION:(1)Exosomes in the acellular matrix of small intestinal submucosa could be taken up by umbilical vein endothelial cells under the fluorescence microscope.(2)Compared with the blank group and the control group,the experimental group could promote the migration of umbilical vein endothelial cells,angiogenesis ability,and the secretion of angiogenic factors vascular endothelial growth factor,hepatocyte growth factor,and interleukin 8(P<0.05).(3)Urethrography results showed that all 10 rabbits in the single material group had urethral stenosis;2 out of 10 rabbits in the control group had urethral stenosis,and none of the 10 rabbits in the experimental group had urethral stenosis.The results of urodynamic examination showed that the maximum urethral pressure at 12 weeks after implantation was higher in the single material group than before surgery(P<0.05),and the maximum urethral pressure at 12 weeks after implantation was lower in the control group and the experimental group than in the blank group(P<0.05).Hematoxylin-eosin,Masson and immunohistochemical staining showed that in the single material group,there were obvious regenerated epidermis,a small amount of subcutaneous smooth muscle and blood vessels,mainly fibrous tissue hyperplasia,accompanied by obvious inflammatory cell infiltration.In the control group,there were more complete regenerated epithelium and a small amount of collagen,a large number of subcutaneous blood vessels and smooth muscle,accompanied by inflammatory cell infiltration.The experimental group showed complete regenerated epidermis,a large number of subcutaneous blood vessels and smooth muscle,and no obvious inflammatory cell infiltration.The positive expressions of AE1/AE3,alpha smooth muscle actin,and CD31 in the experimental group were higher than those in the single material group and the control group(P<0.05).(4)The results show that the small intestinal submucosal acellular matrix-exosome tissue engineered urethra can repair the urethral defect by promoting angiogenesis.

Objective To investigate the relationship between serum F2-isoprostaglandin(F2IP),homocysteine(Hcy),cytoplasmic phospholipase A2(cPLA2)and male erectile dysfunction.Methods A total of 198 patients with erectile dysfunction who were admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2020 to April 2025 were selected as the case group.Meanwhile,198 physical examinees with normal reproductive and sexual functions who underwent physical examinations in our hospital during the same period were selected as the control group.The levels of serum F2IP,Hcy,cPLA2,sex hormones,and the score of the international index of erectile function(IIEF)were measured and recorded in the two groups.Subsequently,the diagnostic value of serum F2IP,Hcy,and cPLA2 for male erectile dysfunction was analyzed.Based on the IIEF score,the patients with erectile dysfunction were classified into the severe group(45 cases),the moderate group(88 cases),and the mild group(65 cases).The levels of serum F2IP,Hcy,cPLA2,and sex hormones were compared among the three groups,and the correlation between the levels of serum F2IP,Hcy,cPLA2,sex hormones,and the IIEF score in patients with erectile dysfunction was analyzed.Results The levels of serum F2-isoprostane(F2IP),homocysteine(Hcy),cytosolic phospholipase A2(cPLA2),follicle-stimulating hormone(FSH),and luteinizing hormone(LH)in the case group were significantly higher than those in the control group,while the serum testosterone level and International Index of Erectile Function(IIEF)score were significantly lower than those in the control group(P<0.05).The area under the curve(AUC)of the combined detection of serum F2IP,Hcy,and cPLA2 in the diagnosis of erectile dysfunction was higher than that of each biomarker alone(P<0.05),with the sensitivity and specificity being 88.38%and 84.34%,respectively.In the mild,moderate,and severe groups,the levels of serum F2IP,Hcy,cPLA2,FSH,and LH exhibited an increasing trend,whereas the serum testosterone level showed a decreasing trend(P<0.05).The levels of serum F2IP,Hcy,and cPLA2 in patients with erectile dysfunction were negatively correlated with the serum testosterone level and IIEF score(r=-0.573,-0.618,-0.549,-0.516,-0.553,-0.581;P<0.05)and positively correlated with the levels of serum FSH and LH(r=0.571,0.650,0.650,0.511,0.648,0.547;P<0.05).Conclusions The occurrence of erectile dysfunction can lead to an increase in the levels of serum F2IP,Hcy,and cPLA2,as well as an abnormality in the levels of serum sex hormones.Moreover,the combination of serum F2IP,Hcy,and cPLA2 can enhance the diagnostic value of erectile dysfunction.Meanwhile,there is a significant correlation between the levels of serum F2IP,Hcy,and cPLA2,the levels of serum sex hormones,and the severity of the disease.

Objective To investigate the relationship between soluble CD73(sCD73) and miRNA(miR)-124a expression level and the severity of acute septic shock and its predictive value for 28 days. Methods A prospective analysis was conducted on 109 patients with acute septic shock admitted to the Third People's Hospital of Chengdu from June 2021 to December 2023. These patients were divided into a survival group (n=87) and a death group (n=22) based on their 28-day prognosis. The clinical data,serum sCD73,miR-124a levels of the two groups were compared,Pearson correlation analysis was used to analyze the relationship between sCD73,miR-124a and acute physiology and chronic health evaluation system Ⅱ (APACHE Ⅱ),sequential organ failure assessment (SOFA),C-reactive protein (CRP) and procalcitonin (PCT). The predictive value of sCD73 and miR-124a for prognosis was analyzed using receiver operating characteristic (ROC) curve analysis,and the interaction between sCD73 and miR-124a in the prognosis of patients with acute septic shock was analyzed using the interaction coefficient γ. Results The age,APACHE Ⅱ,SOFA score,CRP and PCT levels of the death group were higher than that of the survival group(t=4.485～14.147),and the duration of mechanical ventilation was longer than that of the survival group(t=7.215),with statistically significant differences (all P<0.001),respectively. Serum sCD73(3.69±1.12 μg/L) levels were lower in the death group than in the survival group(6.42±2.38 μg/L),and miR-124a (3.31±0.70) was higher than in the survival group(2.63±0.52),and the differences were statistically significant (t=5.222,5.089,all P<0.001). Serum sCD73 and APACHE Ⅱ,SOFA score,CRP and PCT was negatively correlated (r=-0.712～-0.649,all P<0.001),miR-124a and APACHE Ⅱ,SOFA score,CRP and PCT was positively correlated (r=0.643～0.728,all P<0.001). Serum sCD73,miR-124a was significantly correlated with the prognosis of patients with acute septic shock after 28 days of treatment (partial correlation coefficient-0.882,0.896,all P<0.001). The AUC(95％CI) of serum sCD73 and miR-124a for predicting the prognosis of 28-day treatment were 0.765 (0.674～0.841) and 0.754 (0.662～0.831),respectively. The AUC(95％CI) of the combined prediction of 28-day treatment prognosis was 0.916 (0.847～0.960),which was greater than that of the single indicator,and the differences were statistically significant (Z=4.352,4.221,all P<0.001). Low expression of sCD73 and high expression of miR-124a showed a positive interaction in the 28-day mortality risk of patients with acute septic shock (OR=6.668,95％CI:1.245～35.714,γ=1.133,P<0.024). Conclusion Low sCD73 expression and high miR-124a expression positively interacted with each other in the risk of death at 28-day in patients with acute septic shock,and the combined assay is informative for prognostic prediction.

Objective We aimed to evaluate the efficacy and safety of Shengxuebao Mixture in the treatment of cancer-related anemia(CRA)presenting with syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood.Methods A randomized,double-blind,placebo-controlled,multicenter clinical trial was conducted.Eligible patients with malignant tumors meeting the inclusion and exclusion criteria were enrolled from 26 hospitals,including Dongzhimen Hospital,Beijing University of Chinese Medicine,Xiaogan Central Hospital,and Yangzhou Hospital of Traditional Chinese Medicine,from June 1,2022,to September 30,2024.Patients were allocated 1:1 to either the experimental group receiving Shengxuebao Mixture or the control group receiving its simulator(placebo)using a block randomization method under double-blind conditions.Both groups received 15 mL orally three times daily for 28 consecutive days.The primary efficacy indicators included the hemoglobin(Hb)improvement rate(RHb)and the traditional Chinese medicine(TCM)syndrome improvement rate(RTCM)at week 4 of treatment.The secondary efficacy indicators encompassed Hb and red blood cell(RBC)count,Karnofsky Performance Status(KPS)score,TCM syndrome score,individual TCM symptom scores,and changes in each of these indicators compared to the baseline period at weeks 2,4,and 6 of treatment.Safety evaluations were conducted at week 4 of treatment.Results A total of 239 patients were enrolled,with 225 cases included in the Full Analysis Set(FAS)(109 in the experimental group vs.116 control group),163 in the Per Protocol Set(PPS)(77 vs.86),and 225 in the Safety Set(SS)(109 vs.116).Baseline characteristics between groups showed no significant differences.Significant differences were observed between the experimental and control groups in RHb at week 4(FAS:49.51%vs.35.24%,P<0.05;PPS:53.25%vs.36.05%,P<0.05)and RTCM at week 4(FAS:61.54%vs.39.62%,P<0.01;PPS:64.94%vs.40.70%,P<0.01).At weeks 2,4,and 6,the experimental group showed greater improvements in Hb and RBC counts than the control group.Additionally,the TCM syndrome scores were lower in the experimental group than in the control group at these time points.Except for week 2 in PPS,the KPS improvement was better in the experimental group than in the control group(P<0.05).The experimental group also demonstrated a greater reduction in scores for individual TCM symptoms such as spiritlessness and weakness,poor appetite and reduced food intake at weeks 4 and 6 compared to the control group(P<0.05,P<0.01).Furthermore,the reduction in vertigo score was more pronounced in the experimental group at week 6(P<0.01).For the score of pale and lusterless complexion,only in the PPS was the reduction from baseline more significant in the experimental group than in the control group at weeks 4 and 6(P<0.05).No significant differences were observed between the experimental and control groups in the incidence of all adverse events or drug-related adverse reactions.Conclusion Shengxuebao Mixture demonstrates significant efficacy in patients with CRA presenting syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood,effectively increasing Hb levels,ameliorating TCM syndromes,alleviating clinical symptoms,and enhancing functional status,with no significant difference in adverse drug reactions compared to the placebo.

Objective We aimed to evaluate the efficacy and safety of Shengxuebao Mixture in the treatment of cancer-related anemia(CRA)presenting with syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood.Methods A randomized,double-blind,placebo-controlled,multicenter clinical trial was conducted.Eligible patients with malignant tumors meeting the inclusion and exclusion criteria were enrolled from 26 hospitals,including Dongzhimen Hospital,Beijing University of Chinese Medicine,Xiaogan Central Hospital,and Yangzhou Hospital of Traditional Chinese Medicine,from June 1,2022,to September 30,2024.Patients were allocated 1:1 to either the experimental group receiving Shengxuebao Mixture or the control group receiving its simulator(placebo)using a block randomization method under double-blind conditions.Both groups received 15 mL orally three times daily for 28 consecutive days.The primary efficacy indicators included the hemoglobin(Hb)improvement rate(RHb)and the traditional Chinese medicine(TCM)syndrome improvement rate(RTCM)at week 4 of treatment.The secondary efficacy indicators encompassed Hb and red blood cell(RBC)count,Karnofsky Performance Status(KPS)score,TCM syndrome score,individual TCM symptom scores,and changes in each of these indicators compared to the baseline period at weeks 2,4,and 6 of treatment.Safety evaluations were conducted at week 4 of treatment.Results A total of 239 patients were enrolled,with 225 cases included in the Full Analysis Set(FAS)(109 in the experimental group vs.116 control group),163 in the Per Protocol Set(PPS)(77 vs.86),and 225 in the Safety Set(SS)(109 vs.116).Baseline characteristics between groups showed no significant differences.Significant differences were observed between the experimental and control groups in RHb at week 4(FAS:49.51%vs.35.24%,P<0.05;PPS:53.25%vs.36.05%,P<0.05)and RTCM at week 4(FAS:61.54%vs.39.62%,P<0.01;PPS:64.94%vs.40.70%,P<0.01).At weeks 2,4,and 6,the experimental group showed greater improvements in Hb and RBC counts than the control group.Additionally,the TCM syndrome scores were lower in the experimental group than in the control group at these time points.Except for week 2 in PPS,the KPS improvement was better in the experimental group than in the control group(P<0.05).The experimental group also demonstrated a greater reduction in scores for individual TCM symptoms such as spiritlessness and weakness,poor appetite and reduced food intake at weeks 4 and 6 compared to the control group(P<0.05,P<0.01).Furthermore,the reduction in vertigo score was more pronounced in the experimental group at week 6(P<0.01).For the score of pale and lusterless complexion,only in the PPS was the reduction from baseline more significant in the experimental group than in the control group at weeks 4 and 6(P<0.05).No significant differences were observed between the experimental and control groups in the incidence of all adverse events or drug-related adverse reactions.Conclusion Shengxuebao Mixture demonstrates significant efficacy in patients with CRA presenting syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood,effectively increasing Hb levels,ameliorating TCM syndromes,alleviating clinical symptoms,and enhancing functional status,with no significant difference in adverse drug reactions compared to the placebo.

During the career life cycle, workers may face various health problems such as occupational injuries, occupational diseases, and work-related diseases. How to comprehensively protect the health of workers is a crucial scientific issue that needs to be solved urgently. Workers show the characteristics of co-exposure to multiple occupational risks or co-existence of multiple health conditions in their occupational activities. Occupational injuries are closely related to occupational diseases and work-related diseases. To carry out prevention and control of occupational injuries in the context of "big health", we should further strengthen the systematic approach and highlight the concept of "overall process" and "all-round". That is to establish an occupational injury surveillance system covering the whole process of surveillance-assessment-intervention and the evaluation of intervention effects, and to set up the joint prevention and control strategy of occupational injuries, occupational diseases, and work-related diseases. This will promote the implementation of efficient and intensive health management at government, society, employers, workers and other levels to achieve all-round protection of workers' health. When exploring the possible effects of job burnout, occupational stress, comorbidity, and other factors on occupational injuries, the introduction of machine learning methods provides a new approach to identifying and analyzing the influencing factors of occupational injuries and to exploring potential underlying mechanisms.