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.

Acute lung injury(ALI)is a common critical illness caused by intrapulmonary or extra-pulmonary factors,which is accompanied by ex-tremely high morbidity and mortality.Its pathogen-esis is extremely complex and difficult to treat.Src homology 2 domain-containing protein tyrosine phosphatase(Shp2),a key cellular signal transduc-tion molecule,plays a pivotal role in the pathophys-iological processes of diverse diseases.Notably,in the context of pathogen infection,Shp2 regulates the functionality of cellular immunity,lung epitheli-al cells,and vascular endothelial cells.This review article highlights the significant role of Shp2 in the onset and progression of ALI,emphasizing its regu-lation of inflammatory response,apoptosis,and ox-idative stress.Shp2 could emerge as a novel thera-peutic target for ALI,offering valuable insights for the development of innovative drug candidates to treat this debilitating condition.

AIM:To investigate the potential mechanisms by which cell division cycle protein 42(Cdc42)regulates endothelial-mesenchymal transition(EndMT)in pulmonary hypertension(PH).METHODS:The pulmonary hypertension(PH)model was established using Sugen-5416 combined with hypoxia.Twenty-four C57BL/6 mice were ran-domly divided into four groups:normoxia control(CON)group,normoxia+ML141(CON+ML141)group,Sugen-5416+hypoxia(SuHx)group,and SuHx+ML141 group,with 6 mice in each group.After 4 weeks,right ventricular systolic pressure(RVSP)and cardiac ultrasound parameters were measured,and lung tissues were collected for immunofluores-cence staining.Pulmonary microvascular endothelial cells(PMVECs)were isolated using magnetic bead sorting.Calcium imaging was performed to assess Ca2+signaling,and Western blot was used to detect EndMT-related proteins as well as stromal interaction molecule 1(STIM1)and Orai1 expression.RESULTS:In the SuHx group,mice exhibited signifi-cantly increased RVSP,Fulton index(right ventricle/left ventricle+septum),end-diastolic right ventricular free wall thick-ness(RVEDWT),and end-systolic right ventricular free wall thickness(RVESWT)(P<0.01).Conversely,pulmonary artery acceleration time/pulmonary artery ejection time(PAT/PET)and tricuspid annulus plane systolic excursion(TAPSE)were significantly reduced(P<0.01).The Cdc42 inhibitor ML141 ameliorated these changes.The SuHx group exhibited a significant decrease in CD31 fluorescence intensity in pulmonary vascular endothelial cells(P<0.01),a marked increase in α-smooth muscle actin(α-SMA)fluorescence intensity in smooth muscle cells(P<0.01),and the emergence of CD31/α-SMA co-localization.These alterations were reversed by ML141.Hypoxia induced EndMT in PM-VECs,characterized by decreased CD31 and vascular endothelial cadherin(VE-cadherin)along with increased α-SMA and vimentin(P<0.01),which was suppressed by ML141(P<0.01).Hypoxia activated store-operated calcium entry(SOCE),enhancing intracellular Ca2? release,extracellular Ca2? influx,and basal Ca2? levels(P<0.01),while upregulat-ing STIM1 and Orai1 expression(P<0.01).These changes were reversed by ML141.Furthermore,both ML141 and STIM1 knockdown inhibited the upregulation of EndMT-related transcription factors Snail and Twist(P<0.05).CON-CLUSION:Cdc42 may participate in EndMT in PH by regulating store-operated calcium channels in pulmonary microvas-cular endothelial cells.

Objective To observe the correlations of lumbar bone mineral density(BMD)with serum uric acid(SUA),hepatic fat and abdominal fat based on quantitative CT(QCT).Methods A total of 522 subjects who underwent lumbar QCT were retrospectively enrolled.Subjects with different genders were divided into hyperuricemia(HUA)group and normal SUA group according to SUA levels,and QCT parameters were compared between groups.Meanwhile,subjects with different genders were also divided into normal bone mass group(normal group),osteopenia group and osteoporosis(OP)group,and SUA and QCT parameters were compared among groups.Pearson correlation analyses were performed to explore the correlations of lumbar BMD with age,SUA,visceral adipose tissue(VAT),subcutaneous adipose tissue(SAT)and liver fat content.Results There were 325 males,with 105 ones in HUA group and 220 ones in normal SUA group.There were 197 females,with 26 ones in HUA group and 171 ones in normal SUA group.VAT,SAT and percentage of liver fat content in HUA group of different genders were all higher than those in normal SUA group(all P＜0.05).Among 325 males,there were 196 ones in normal group,105 ones in osteopenia group and 24 ones in OP group among males,and VAT increased successively in the above groups(all P＜0.05).Among 197 females,there were 147 ones in normal group,30 ones in osteopenia group and 20 ones in OP group,and VAT and SAT increased successively in the above groups(all P＜0.05).Lumbar BMD was moderately and weakly negatively correlated with age and VAT in males(r=-0.618,-0.286,both P＜0.001),which was moderately,lowly and weakly negatively correlated with age,VAT and SAT in females,respectively(r=-0.772,-0.451,-0.273,all P＜0.001).Conclusion Increased SUA levels resulted in increased abdominal and liver fat content,and the latter was negatively correlated with lumbar BMD.

The intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is currently the first-line therapy for retinopathy of prematurity (ROP) in clinical practice.This therapy has several advantages, including ease of operation, rapid onset of action, and minimal adverse reactions.However, the high reactivation rate observed in clinical applications limits its utility.Understanding reactivation characteristics is crucial for patient management and clinical trial design.The International Classification of Retinopathy of Prematurity (Third edition) updated the definition of reactivation and related concepts.This article summarizes the clinical manifestations and mechanisms of ROP reactivation after anti-VEGF therapy in recent studies and analyzes high-risk factors associated with reactivation, including those related to the infant, the disease, and the medication.The goal is to provide guidance for the early identification, prevention, and intervention in clinical practice.Nevertheless, significant clinical controversies remain regarding the prevention and retreatment of ROP reactivation.Future research should accumulate more evidence-based medical data and conduct large-scale prospective studies to further standardize diagnostic and treatment processes.

Acute lung injury(ALI)is a common critical illness caused by intrapulmonary or extra-pulmonary factors,which is accompanied by ex-tremely high morbidity and mortality.Its pathogen-esis is extremely complex and difficult to treat.Src homology 2 domain-containing protein tyrosine phosphatase(Shp2),a key cellular signal transduc-tion molecule,plays a pivotal role in the pathophys-iological processes of diverse diseases.Notably,in the context of pathogen infection,Shp2 regulates the functionality of cellular immunity,lung epitheli-al cells,and vascular endothelial cells.This review article highlights the significant role of Shp2 in the onset and progression of ALI,emphasizing its regu-lation of inflammatory response,apoptosis,and ox-idative stress.Shp2 could emerge as a novel thera-peutic target for ALI,offering valuable insights for the development of innovative drug candidates to treat this debilitating condition.

The intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is currently the first-line therapy for retinopathy of prematurity (ROP) in clinical practice.This therapy has several advantages, including ease of operation, rapid onset of action, and minimal adverse reactions.However, the high reactivation rate observed in clinical applications limits its utility.Understanding reactivation characteristics is crucial for patient management and clinical trial design.The International Classification of Retinopathy of Prematurity (Third edition) updated the definition of reactivation and related concepts.This article summarizes the clinical manifestations and mechanisms of ROP reactivation after anti-VEGF therapy in recent studies and analyzes high-risk factors associated with reactivation, including those related to the infant, the disease, and the medication.The goal is to provide guidance for the early identification, prevention, and intervention in clinical practice.Nevertheless, significant clinical controversies remain regarding the prevention and retreatment of ROP reactivation.Future research should accumulate more evidence-based medical data and conduct large-scale prospective studies to further standardize diagnostic and treatment processes.

AIM:To investigate the potential mechanisms by which cell division cycle protein 42(Cdc42)regulates endothelial-mesenchymal transition(EndMT)in pulmonary hypertension(PH).METHODS:The pulmonary hypertension(PH)model was established using Sugen-5416 combined with hypoxia.Twenty-four C57BL/6 mice were ran-domly divided into four groups:normoxia control(CON)group,normoxia+ML141(CON+ML141)group,Sugen-5416+hypoxia(SuHx)group,and SuHx+ML141 group,with 6 mice in each group.After 4 weeks,right ventricular systolic pressure(RVSP)and cardiac ultrasound parameters were measured,and lung tissues were collected for immunofluores-cence staining.Pulmonary microvascular endothelial cells(PMVECs)were isolated using magnetic bead sorting.Calcium imaging was performed to assess Ca2+signaling,and Western blot was used to detect EndMT-related proteins as well as stromal interaction molecule 1(STIM1)and Orai1 expression.RESULTS:In the SuHx group,mice exhibited signifi-cantly increased RVSP,Fulton index(right ventricle/left ventricle+septum),end-diastolic right ventricular free wall thick-ness(RVEDWT),and end-systolic right ventricular free wall thickness(RVESWT)(P<0.01).Conversely,pulmonary artery acceleration time/pulmonary artery ejection time(PAT/PET)and tricuspid annulus plane systolic excursion(TAPSE)were significantly reduced(P<0.01).The Cdc42 inhibitor ML141 ameliorated these changes.The SuHx group exhibited a significant decrease in CD31 fluorescence intensity in pulmonary vascular endothelial cells(P<0.01),a marked increase in α-smooth muscle actin(α-SMA)fluorescence intensity in smooth muscle cells(P<0.01),and the emergence of CD31/α-SMA co-localization.These alterations were reversed by ML141.Hypoxia induced EndMT in PM-VECs,characterized by decreased CD31 and vascular endothelial cadherin(VE-cadherin)along with increased α-SMA and vimentin(P<0.01),which was suppressed by ML141(P<0.01).Hypoxia activated store-operated calcium entry(SOCE),enhancing intracellular Ca2? release,extracellular Ca2? influx,and basal Ca2? levels(P<0.01),while upregulat-ing STIM1 and Orai1 expression(P<0.01).These changes were reversed by ML141.Furthermore,both ML141 and STIM1 knockdown inhibited the upregulation of EndMT-related transcription factors Snail and Twist(P<0.05).CON-CLUSION:Cdc42 may participate in EndMT in PH by regulating store-operated calcium channels in pulmonary microvas-cular endothelial cells.

Objective To observe the correlations of lumbar bone mineral density(BMD)with serum uric acid(SUA),hepatic fat and abdominal fat based on quantitative CT(QCT).Methods A total of 522 subjects who underwent lumbar QCT were retrospectively enrolled.Subjects with different genders were divided into hyperuricemia(HUA)group and normal SUA group according to SUA levels,and QCT parameters were compared between groups.Meanwhile,subjects with different genders were also divided into normal bone mass group(normal group),osteopenia group and osteoporosis(OP)group,and SUA and QCT parameters were compared among groups.Pearson correlation analyses were performed to explore the correlations of lumbar BMD with age,SUA,visceral adipose tissue(VAT),subcutaneous adipose tissue(SAT)and liver fat content.Results There were 325 males,with 105 ones in HUA group and 220 ones in normal SUA group.There were 197 females,with 26 ones in HUA group and 171 ones in normal SUA group.VAT,SAT and percentage of liver fat content in HUA group of different genders were all higher than those in normal SUA group(all P＜0.05).Among 325 males,there were 196 ones in normal group,105 ones in osteopenia group and 24 ones in OP group among males,and VAT increased successively in the above groups(all P＜0.05).Among 197 females,there were 147 ones in normal group,30 ones in osteopenia group and 20 ones in OP group,and VAT and SAT increased successively in the above groups(all P＜0.05).Lumbar BMD was moderately and weakly negatively correlated with age and VAT in males(r=-0.618,-0.286,both P＜0.001),which was moderately,lowly and weakly negatively correlated with age,VAT and SAT in females,respectively(r=-0.772,-0.451,-0.273,all P＜0.001).Conclusion Increased SUA levels resulted in increased abdominal and liver fat content,and the latter was negatively correlated with lumbar BMD.

Malignant tumors represent a significant health challenge, critically impacting human well-being. Malignant tumors have become one of the leading causes of death worldwide. According to statistics from the World Health Organization, nearly one-sixth of global deaths in 2020 were caused by malignant tumors. The burden of malignant tumors in our country is also increasing. In recent years, with population aging and changes in lifestyle, the incidence and mortality rates of malignant tumors in China have been steadily rising, malignant tumors have gradually become one of the main causes of death in China. Developing effective diagnostic and treatment methods is of great significance in reducing the burden of malignant tumors in our country. Historically, the focus has been on leveraging the biochemical cues of tumors for both diagnosis and treatment. While valuable, this strategy does not recapitulate the full complexity of tumor diagnosis and management. Recently, the integration of biomechanics and mechanobiology with oncology has highlighted the importance of mechanical cues, which have emerged as new hallmarks of tumors, regulating tumor initiation and development are expected to open potential novel routes for cancer diagnosis and therapeutic interventions. Despite the advances, a thorough literature review suggests a pronounced gap in our understanding of the mechanical properties of tumors. The clinical community has not yet completely recognized the diagnostic and therapeutic relevance of the mechanical cues of tumors. To bridge this knowledge gap, we propose and introduce the paradigm of "Tumor Mechanomedicine". We provide a comprehensive overview of the multi-scale mechanical characteristics of tumors, exploring their influence on tumor biology, from the aspects of tumor biomechanics, tumor mechanobiology, tumor mechanodiagnostics, and tumor mechanotherapeutics. By elucidating the diagnostic and therapeutic potential of these mechanical cues, we aim to furnish the oncology community with fresh insights, paving the way for innovative solutions to persistent clinical conundrums.