BACKGROUND:The formation of postoperative abdominal adhesions is a complicated process,and the prevention of postoperative adhesions is an urgent problem in clinic. OBJECTIVE:To analyze the mechanism of adhesion at cellular and molecular levels,and to provide theoretical basis for the prevention and treatment of adhesion by mesenchymal stem cell exosomes. METHODS:"Abdominal adhesion,pelvic adhesion,postoperative adhesion,epithelial mesenchymal transformation,mesenchymal stem cells,stem cell exosomes,mesenchymal stem cell exosomes"were selected as Chinese and English search terms.We searched PubMed,CNKI,and Chinese biomedical literature and screened relevant articles on postoperative abdominal adhesion and mesenchymal stem cell exosomal intervention published from inception to August 2023.After systematic analysis,54 articles were finally included for the review. RESULTS AND CONCLUSION:(1)Any pathological factors such as peritoneal inflammation,mechanical injury,tissue ischemia,and foreign body implantation cause peritoneal surface injury,resulting in postoperative abdominal adhesion.The formation process of adhesion includes the interaction of peritoneal mesothelial cell repair,inflammatory response,fibrinolytic system,coagulation pathway and other processes,involving a variety of cytokines and signaling pathways.Wnt/β-catenin pathway can induce fibrosis and angiogenesis,and cooperate with transforming growth factor-β/Smads signaling pathway to stimulate fibroblast proliferation and cause peritoneal fibrosis.Meanwhile,nuclear factor-κB signaling pathway up-regulates the expression of cellular inflammatory factors,promotes fibroblast proliferation,and plays a key role in the process of tissue fibrosis.(2)The paracrine function of stem cells is an important direction of molecular intervention in abdominal adhesions based on regenerative medicine.It can participate in a variety of complex cytokines and signaling pathways involved in abdominal adhesions.(3)Compared with traditional methods for treating abdominal adhesions,mesenchymal stem cell exosome has biological activity and is safe to use.Mesenchymal stem cell exosomes without special culture and expansion have lower immunogenicity,longer stability and other advantages,can guide a normal repair and healing through a variety of ways.(4)Mesenchymal stem cell exosome has been proven to be involved in regulating the above processes of adhesion formation in previous studies,showing potential application prospects in clinical studies.However,further clinical studies are needed to explore appropriate treatment options for mesenchymal stem cell exosomes to address the problem of clinical translation.

BACKGROUND:Osteoarthritis is now considered a metabolic disease.Previous studies have shown that glycolysis plays an important role in the occurrence and development of osteoarthritis.Compound 3k,as a novel small molecule inhibitor of glycolysis,has anti-inflammatory and anti-tumor effects.Therefore,it can target glycolysis and is expected to provide new ideas for the treatment of osteoarthritis. OBJECTIVE:To explore the role of Compound 3k in osteoarthritis caused by glycolytic overactivity based on the hypoxia-inducible factor 1 alpha(HIF-1α)/reactive oxygen species(ROS)pathway. METHODS:ATDC5 chondroblasts at logarithmic growth phase were taken to induce osteoarthritis in an in vitro cellular model by the action of 10 ng/mL interleukin-1β for 24 hours.The cytotoxicity of Compound 3k at different concentrations(0.25,0.5,1,2.5,5,10,15 μmol/L)was detected by cell counting kit-8 assay,and the appropriate concentrations were selected for the subsequent experiments.The chondrocytes were randomly divided into control,model and treatment groups.The model group was induced with 10 ng/mL interleukin 1β,and the treatment group was pre-stimulated with Compound 3k for 2 hours and then co-cultured with interleukin 1β.The proliferation of the cells in each group was detected by the cell counting kit-8 assay;the inflammatory level of the cells in each group was detected by the ELISA kit;the ROS,extracellular lactate and glucose contents were detected using the kit;qRT-PCR and western blot were used to detect the levels of related inflammatory factors,interleukin-6 and tumor necrosis factor-α,glycolysis-related genes glucose transporter protein-1,glyceraldehyde 3-phosphate dehydrogenase,monocarboxylate transporter protein-1 and HIF-1α. RESULTS AND CONCLUSION:Compared with the control group,the model group showed a decrease in cell proliferative activity,active glycolysis level,manifested by an increase in extracellular lactate content(P<0.001)and a decrease in glucose content(P<0.001),interleukin-6(P<0.000 1)and tumor necrosis factor-α(P<0.001).The expression levels of glycolysis-related genes glucose transporter protein-1(P<0.001),glyceraldehyde 3-phosphate dehydrogenase(P<0.001),monocarboxylic acid transporter protein-1(P<0.001)and HIF-1α(P<0.001)in the model group were all up-regulated,accompanied by oxidative stress and overproduction of ROS.Compared with the model group,Compound 3k treatment effectively increased cell proliferation activity and inhibited the level of overactive glycolysis(P<0.001),while suppressing the expression of genes related to inflammation(P<0.001)and glycolysis in osteoarthritic chondrocytes,inhibiting oxidative stress,downregulating the expression level of HIF-1α(P<0.000 1)and decreasing the content of ROS.To conclude,Compound 3k inhibits interleukin-1β induced chondrocyte inflammation,and its mechanism may be related to glycolysis and HIF-1α/ROS mediated oxidative stress.

BACKGROUND:Recent research indicates that disc degeneration is closely related to abnormal stress load,and mechanotransduction proteins play a key role in it. OBJECTIVE:To investigate the role and mechanism of mechanotransduction proteins in the mechanotransduction process induced by abnormal mechanical stimulation in disc degeneration,and to summarize the current treatment strategies targeting mechanotransduction to delay intervertebral disc degeneration. METHODS:Using"intervertebral disc,nucleus pulposus,annulus fibrosus,cartilaginous endplate,cell,mechanics,signal transduction,protein,biomechanics"as Chinese search terms,and"intervertebral disc,nucleus pulposus,annulus fibrosus,cartilaginous endplate,cell,mechanical stimulation,signal transduction,protein,biomechanics"as English search terms,relevant literature in the PubMed and CNKI databases was searched.A total of 88 articles were ultimately included for review. RESULTS AND CONCLUSION:Disc cells can sense external mechanical stimulation through various mechanotransduction proteins and convert it into biological responses within the cells.These transduction proteins mainly include collagen proteins in the extracellular matrix,cell membrane surface receptors(such as integrins and ion channels),and cytoskeleton structural proteins.Their regulation of mechanotransduction processes primarily involves the activation of multiple pathways,such as the PI3K/AKT signaling pathway,nuclear factor-kB signaling pathway,and Ca2+/Calpain2/Caspase3 pathway.Mechanotransduction proteins play a key role in the mechanotransduction of disc cells.Abnormal expression of these proteins or resulting changes in the extracellular matrix environment can disrupt the mechanical balance of disc cells,leading to disc degeneration.In-depth study of the expression and regulatory mechanisms of mechanotransduction proteins in disc cells,and identification of key pathological links and therapeutic targets,is of significant importance for developing treatment strategies for disc degeneration.Current strategies to delay intervertebral disc degeneration by targeting mechanotransduction mainly include regulation of transduction proteins and improvement of the extracellular matrix.However,research in this area is still in its early stages.As research continues,new breakthroughs are expected in the regulation of disc degeneration by mechanotransduction proteins.

BACKGROUND:Micro-abrasion,at-home whitening combined with infiltration resin have a good effect on dental fluorosis,but the effect of this method on micro-cracks in dental fluorosis is still unclear. OBJECTIVE:To explore the effect of micro-abrasion,at-home whitening combined with infiltration resin on micro-cracked dental fluorosis. METHODS:(1)Clinical research:A total of 23 patients with micro-cracked dental fluorosis,including 255 micro-cracked dental fluorosis,were selected from July 2020 to March 2021 in the Department of Prosthodontics,Stomatology Hospital,Tianjin Medical University.All of them received combined treatment of tooth micro-abrasion,at-home whitening and infiltration resin.The tooth color,tooth sensitivity,and tooth pain threshold were compared before treatment and 1 week and 1 month after treatment.(2)In vitro experiment:60 teeth with fluorosis with at least one crack on the tooth surface were collected and randomly divided into three groups for treatment.The control group was treated without any treatment.The whitening group was treated with micro-abrasion and at-home whitening,and the combined group was treated with micro-abrasion,at-home whitening,and infiltration resin,with 20 teeth in each group.The microhardness of the three groups of teeth samples after treatment was measured. RESULTS AND CONCLUSION:(1)Clinical study:6 months after treatment,among 255 teeth with micro-cracked dental fluorosis,whitening treatment for 207 teeth was significantly effective and whitening treatment for 48 teeth was effective,and the overall treatment efficiency was 100%.With the extension of treatment time,the proportion of moderate and severe dental sensitivity showed a decreasing trend.At 6 months after treatment,255 teeth with dental fluorosis had no severe sensitivity,15 with moderate sensitivity,125 with mild sensitivity,and 115 with no sensitivity,and the difference was significant compared with the sensitivity before treatment(P<0.05).There was no significant difference in the threshold of tooth pain before treatment and 1 week and 6 months after treatment(P>0.05).(2)In vitro experiment:The tooth microhardness of the whitening group was lower than that of the control group and the combined group(P<0.05),but there was no significant difference between the control group and the combined group(P>0.05).(3)The results show that the methods of micro-abrasion,at-home whitening combined with infiltration resin have good clinical efficacy in the treatment of micro-cracked dental fluorosis.

BACKGROUND:The capability of repairing articular cartilage damage is very limited,and tissue engineering technology provides new therapeutic options for repairing damaged cartilage,in which the interaction and induction between chondrocytes,bone marrow mesenchymal stem cells,and synovial mesenchymal stem cells is the basis of autologous healing of cartilage damage. OBJECTIVE:To construct the chondrocyte-bone marrow mesenchymal stem cell-synovial mesenchymal stem cell co-culture system to simulate the in vitro microenvironment of chondrocytes,and to explore the optimal cell inoculation ratio,meanwhile to observe the effects of icariin-containing serum on the proliferation of chondrocytes and the chondrogenic differentiation of stem cells in the system. METHODS:Rat knee chondrocytes,bone marrow mesenchymal stem cells and synovial mesenchymal stem cells were extracted,cultured and identified,and a chondrocyte-bone marrow mesenchymal stem cell-synovial mesenchymal stem cell non-contact co-culture system was constructed according to different cell inoculation ratios.After 72 hours of co-culturing,the chondrocyte proliferative activity and phenotypic ability were observed,and the co-culture system with the best overall effect was selected.New Zealand white rabbits were gavaged with icariin solution(0.25 mg/mL)to prepare icariin-containing serum,and cultured in conventional complete medium(high sugar DMEM culture medium containing 10%fetal bovine serum and 1%double antibody by volume)as the control group,while the experimental group was intervened by adding 10%icariin-containing serum by volume on the basis of above.The proliferative activity of chondrocytes and the expression of collagen type II were tested for the two groups after 24 and 48 hours.The differentiation of bone marrow mesenchymal stem cells and synovial mesenchymal stem cells into chondrocytes in the co-culture system was tested by immunofluorescence staining after 14 days. RESULTS AND CONCLUSION:(1)The three kinds of cells grew normally adherently to the wall in different ratios of co-culture,where chondrocytes showed the best proliferative activity and phenotypic ability in the co-culture system when chondrocytes:bone marrow mesenchymal stem cells:synovial mesenchymal stem cells=2:1:1.(2)Compared with the control group,the proliferative activity and type II collagen expression of chondrocytes in the experimental group were significantly increased after 24 hours(P<0.01),and the two groups still had difference after 48 hours(P<0.05).The two groups showed obvious chondrogenic differentiation of bone marrow mesenchymal stem cells and synovial mesenchymal stem cells after 14 days(P<0.01),and some of the cells appeared round or oval,and the cytoplasmic type II collagen immunofluorescence staining was positive.The fluorescence intensity of the experimental group was significantly higher than that of the control group(P<0.01).(3)The results showed that the chondrocyte-bone marrow mesenchymal stem cell-synovial mesenchymal stem cell co-culture system could be successfully established by the non-contact co-culture method,and the best chondrocyte proliferative activity and phenotypic ability could be obtained when the cell ratio was 2:1:1.Icariin-containing serum had the promoting effect on chondrocyte proliferation,and chondrogenic differentiation of bone marrow mesenchymal stem cells and synovial mesenchymal stem cells in the system.

Objective To investigate the features of non-motor symptoms and transcranial substantia nigra ultrasound in essential tremor （ET）. Methods General data were collected from 50 patients with ET and 50 healthy controls，and non-motor symptom scales and transcranial nigra sonography （TCS） were used for assessment. The t-test，the non-parametric test，and the chi-square test were used for comparison of general data，scale assessment results，and TCS findings between the two groups. Results There were significant differences between the ET group and the healthy control group in the total scores of NMSS，MoCA，HAMA，HAMD，PSQI，ESS，and FSS and the incidence rates of cognitive impairment，moderate or severe anxiety，poor sleep，and daytime sleepiness，while there were no significant differences in the incidence rates of moderate or severe depression and fatigue between the two groups. There were no significant differences between the two groups in terms of “hyperechoic area of the left side” “hyperechoic area of the right side” “hyperechoic area of both sides” “S/M value” “the number of cases with a hyperechoic area of >0.2 cm2 for at least one side” “the number of cases with an S/M ratio of >7%” and “the number of cases with positive TCS results”. Conclusion Compared with healthy controls，ET patients are more susceptible to cognitive impairment，anxiety，depression，poor sleep quality，daytime sleepiness，and fatigue，and the non-motor symptoms of ET should be taken seriously in clinical practice. TCS examination has a relatively low diagnostic value in ET patients and healthy individuals.

Ubiquitination is a crucial post-translational modification process that can degrade proteins within cells and plays a vital role in maintaining protein homeostasis and abundance.Deubiquitinating enzymes(DUBs)are important proteases in the ubiquitin system.They reverse the ubiquitination process by cleaving protein chains and recycling ubiquitin molecules to regulate protein stability.Abnormal deubiquitinating enzyme activity is related to the occurrence and development of many malignant tumors.JOSD2,a DUB,is a member of the Machado-Joseph disease protein domain protease(MJD)family and characterized by a single highly conserved catalytic Josephin domain.Increasing studies have revealed a connection between JOSD2 and malignant tumors.This article elaborates on the current research status of DUBs,particularly JOSD2,in malignant tumors.Results suggest that JOSD2 is a potential target for the treatment of malignant tumors.

Objective To explore the effects of four extralevator abdominoperineal excision(ELAPE)procedures on the biomechanics of female pelvic floor through finite element analysis.Methods Six finite element models of the female pelvic floor were established,including a normal model,an ELAPE model,and four individual models.The maximum stress in each model was measured under the same pressure,and the stress distribution was observed.Results The maximum stress of non-levator ani muscle tissues on the partially reserved side and totally removed side of the levator ani muscle were 3.101±0.133 and 4.868±0.123 MPa in individual model 1,respectively,which were lower than the maximum stress in the ELAPE model(5.111±0.081 MPa;both P<0.01).The maximum stress in the non-levator ani muscle tissue were 5.138±0.091 MPa on both sides in individual model 2,which were not significantly different from that in the ELAPE model(P>0.05).The maximum stress of non-levator ani muscle tissues were 4.700±0.105 and 3.653±0.156 MPa in individual models 3 and 4,respectively,which were lower than the maximum stress in the ELAPE model(both P<0.01).Conclusion Three ELAPE procedures,including ELAPE with unilateral levator ani muscle resection plane close to the rectum,and the bilateral pubococcygeal muscle lateral resection of levator ani muscle and levator ani muscle in front of the rectum preserved could decrease stress in the non-levator ani muscle tissue on both sides.The effect is evident on the levator ani muscle partially reserved side of ELAPE with unilateral levator ani muscle resection plane close to the rectum.ELAPE with unilateral levator ani muscle resection plane close to the pelvic wall has no significant reduction effect on the non-levator ani muscle tissue on either side.ELAPE模型(均P<0.01).

Objective To evaluate the pharmacokinetic characteristics and safety of single and multiple oral azvudine tablets in healthy young and elderly Chinese subjects.Methods This was a open-label and parallel-group study.The trial consisted of two groups:healthy young subjects group and healthy elderly subjects group,with 12 subjects in each group.Enrolled subjects were first given a single dose,fasting oral azvudine tablet 5 mg,after a 3-day cleansing period entered the multiple dose phase,fasting oral azvudine tablet 5 mg·d-1 for 7 days.Results After a single dose of azvudine 5 mg,Cmax and AUC0-∞ were(4.76±2.12)ng·mL-1,(6.53±2.20)ng·mL-1·h,and Tmax,t1/2 were 0.75,1.87 h in young subjects;Cmax and AUC0-∞ were(6.40±3.25)ng·mL-1,(9.50±3.70)ng·mL-1·h,and Tmax,t1/2 were 0.63,2.66 h in elderly subjects.After a multiple dose of azvudine 5 mg·d-1 for 7 d,Cmax and AUC0-∞ were(3.26±1.61)ng·mL-1,(5.38±2.19)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.88,2.13 h in young subjects;Cmax,ss and AUC0-∞,ss were(3.97±2.09)ng·mL-1,(6.71±3.26)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.75,2.56 h in elderly subjects.Elderly/young geometric mean ratios and 90％CIs were 128.37％(88.23％-186.76％),139.93％(105.42％-185.72％),140.03％(106.33％-184.41％)for azvudine Cmax,AUC0-t,AUC0-∞ after a single dose,and were 118.66％(80.83％-174.20％),118.41％(83.60％-167.69％),118.95％(84.78％-166.89％)for azvudine Cmax,AUC0-t,AUC0_∞ after a multiple dose of azvudine 5 mg·d-1 for 7 d.Conclusion After single and multiple oral administration of azvudine tablets,systemic exposure to azvudine was higher in healthy elderly subjects compared with healthy young subjects.After taking azvudine tablets,the types,severity and incidence of adverse events and adverse drug reactions in healthy elderly people were not significantly different from those in healthy young subjects.Azvudine was found to be safe and well tolerated in healthy elderly subjects.

Objective To explore the improvement effect of leonurine(LEO)on primary nephrotic syndrome(PNS)rats by regulating Ras homolog gene family member A(RhoA)/Rho associated coiled-coil containing protein kinase(ROCK)signaling pathway.Methods Rat glomerular mesangial cells HBZY-1 were cultured and randomly grouped into control group,proliferation group(100 ng·mL-1 LPS),low concentration experimental group(100 ng·mL-1 LPS+5 μmol·L-1 LEO),high concentration experimental group[100 ng·mL-1 lipopolysaccharide(LPS)+10 μmol·L-1LEO],and combined treatment group(100 ng·mL-1LPS+10 μmol·L-1 LEO+10 nmol·L-1 RhoA activator U46619).Cell counting kit-8 assay was applied to detect cell proliferation activity;flow cytometry was applied to detect apoptosis.Sixty SPF Wistar rats were randomly grouped into normal group,model group,low-dose experimental group(10 mg·kg-1 LEO),high-dose experimental group(20 mg·kg-1 LEO),and combination group(20 mg·kg-1 LEO+10 mmol·L-1 U46619),with 12 rats in each group.Except the normal group,the other groups were injected with adriamycin hydrochloride via tail vein to establish PNS rat model;coomassie brilliant blue method was applied to detect 24-hour urinary protein content in rats.Enzyme linked immunosorbent assay was used to detect the levels of inflammatory factors tumor necrosis factor-α(TNF-α),interleukin(IL)-4 in renal tissue.Western blot was used to detect RhoA and Rock1 protein expression in rat kidney.Results In the cell experiment,the proliferation activities(optical density value)of HBZY-1 cells in control group and hyperplasia group was 0.32±0.03 and 0.70±0.07;the apoptosis rate were(9.23±1.04)％and(1.64±0.22)％,with statistical significance(all P＜0.05).In animal experiments,24 h urinary protein content of normal group,model group,low-dose experimental group,high-dose experimental group and combination group were(21.45±2.28),(127.38±14.70),(120.85±13.34),(43.15±6.68)and(96.20±10.63)mg;TNF-α levels were(0.27±0.05),(1.58±0.16),(1.56±0.16),(0.44±0.05)and(1.03±0.10)ng·mL-1;IL-4 levels were(0.17±0.02),(1.24±0.12),(1.20±0.12),(0.29±0.03)and(0.87±0.09)ng·mL-1;RhoA protein expression levels were 0.27±0.03,0.78±0.08,0.76±0.07,0.34±0.03 and 0.72±0.07;the expression levels of ROCK1 protein were 0.22±0.02,0.85±0.09,0.83±0.08,0.41±0.04 and 0.75±0.08.The differences of above indexes were statistically significant between the high-dose experimental group and the combination group(all P＜0.05).Conclusion LEO may improve PNS in rats by down-regulating RhoA/ROCK signaling pathway.