BACKGROUND:Multiple observational studies have suggested a potential association between telomere length and musculoskeletal diseases.However,the underlying mechanisms remain unclear. OBJECTIVE:To investigate the genetic causal relationship between telomere length and musculoskeletal diseases using two-sample Mendelian randomization analysis. METHODS:Genome-wide association study summary data of telomere length were obtained from the UK Biobank.Genome-wide association study summary data of 10 common musculoskeletal diseases(osteonecrosis,osteomyelitis,osteoporosis,rheumatoid arthritis,low back pain,spinal stenosis,gout,scapulohumeral periarthritis,ankylosing spondylitis and deep venous thrombosis of lower limbs)were obtained from the FinnGen consortium.Inverse variance weighting,Mendelian randomization-Egger and weighted median methods were used to evaluate the causal relationship between telomere length and 10 musculoskeletal diseases.Inverse variance weighting was the primary Mendelian randomization analysis method,and sensitivity analysis was performed to explore the robustness of the results. RESULTS AND CONCLUSION:(1)Inverse variance-weighted results indicated a negative causal relationship between genetically predicted telomere length and rheumatoid arthritis(odds ratio=0.78,95%confidence interval:0.64-0.95,P=0.015)and osteonecrosis(odds ratio=0.56,95%confidence interval:0.36-0.90,P=0.016).No causal relationship was found between telomere length and the other eight musculoskeletal diseases(all P>0.05).(2)Sensitivity analysis affirmed the robustness of these causal relationships,and Mendelian randomization-Egger intercept analysis found no evidence of potential horizontal pleiotropy(all P>0.05).(3)This Mendelian randomized study supports that telomere length has protective effects against rheumatoid arthritis and osteonecrosis.However,more basic and clinical research will be needed to support our findings in the future.

Objective To investigate the nutritional quality characteristics of vitamin D3-fortified yogurt and explore its improving effect on vitamin D metabolism in the body under simulated weightlessness,thereby providing a theoretical basis for the development of functional foods.Methods Using reconstituted milk as the matrix and Vitamin D3(VD3)microcapsule powder as the fortifier,VD3-fortified yogurt was prepared.A systematic study was conducted to investigate the effects of different gradients(1.25 μg/100 mL,2.50 μg/100 mL,3.75 μg/100 mL,5.00 μg/100 mL,6.25 μg/100 mL)of VD3 microcapsule addition on its quality characteristics(titratable acidity,solid content,water-holding capacity,syneresis).In vivo assessments were conducted using a Sprague-Dawley(SD)rat tail-suspension model to simulate weightlessness.Levels in serum 25(OH)D3,1,25-(OH)2D3,calcium(Ca),and phosphorus(P)were detected using the enzyme-linked immunosorbent assay(ELISA)to evaluate its metabolic capacity.Results During fermentation(3 h),titratable acidity of VD?-fortified yogurt initially increased,then decreased,and eventually stabilized with rising microcapsule dosage,while total solid content remained consistent.WHC exhibited an initial increase followed by a decline,whereas syneresis showed an inverse trend.At an optimal dosage of 3.75 μg/100 mL,the yogurt displayed a dense and uniform network structure,characterized by non-Newtonian fluid behavior with shear-thinning properties.This formulation demonstrated robust structural stability under high-frequency mechanical stress,alongside desirable textural,flavor,and sensory attributes.Animal experiments revealed that the serum concentrations of 25(OH)D3,1,25-(OH)2D3,calcium,and phosphorus in the vitamin D?-fortified yogurt intervention group were significantly higher than those in the tail-suspended control group(P<0.05).Conclusion VD? microencapsulation technology effectively preserves and enhances the nutritional quality characteristics of yogurt and mitigates vitamin D metabolic dysregulation under simulated weightlessness.

Objective To evaluate the efficacy and safety of enteric-coated metformin hydrochloride capsules(Junlida?)in patients with T2DM and poor glycemic control under lifestyle interventions.Methods In this study,419 patients with T2DM were recruited from 15 research centers from July 2020 to March 2022,and randomly divided into observation(Obs)group(n=209)and control group(Con,n=210)using a multicenter,randomized,double-blind,non-inferiority trial design.Patients in the Obs group were treated with enteric-coated Metformin hydrochloride capsules(Junlida?),and patients in the Con group were treated with Metformin hydrochloride tablets(Glucophage?).The optimal effective dose of 2 g/d was achieved within 4 weeks,and the reasonable dose was maintained until the end of treatment.The treatment period was 24 weeks.HbA1c and its compliance rate,FPG,and body weight were compared between the two groups in full analysis set(FAS)and protocol set(PPS).Safety and adverse events(AE)were evaluated in safety set(SS).Results A total of 414 participants were randomized(207 cases in Obs group and 207 cases in Con group).414 cases in FAS population(207 cases in Obs group and 207 cases in Con group),and 328 cases in PPS population(164 cases in Obs group and 164 cases in Con group),and 414 cases in SS population(207 cases in Obs group and 207 cases in Con group).After treatment,HbA1c,FPG and body weight were lower in both groups(P<0.05)in FAS and PPS.HbA1c compliance rate was not significantly different between the two groups in FAS and PPS(P>0.05).The results of non-inferiority test showed that the lower limit was>-0.4%in both FAS(-0.154,95%CI-0.384～0.069)and PPS(-0.139,95%CI-0.390～0.112),and the Obs group reached non-inferiority end point.The achievement rate,compliance rate,safety index and incidence of AE were not significantly different between the two groups(P>0.05).Conclusions Junlida? demonstrated non-inferiority to Glucophage? in glycemic control and can be safely and effectively used in patients with diabetes.

Objective To evaluate the efficacy and safety of enteric-coated metformin hydrochloride capsules(Junlida?)in patients with T2DM and poor glycemic control under lifestyle interventions.Methods In this study,419 patients with T2DM were recruited from 15 research centers from July 2020 to March 2022,and randomly divided into observation(Obs)group(n=209)and control group(Con,n=210)using a multicenter,randomized,double-blind,non-inferiority trial design.Patients in the Obs group were treated with enteric-coated Metformin hydrochloride capsules(Junlida?),and patients in the Con group were treated with Metformin hydrochloride tablets(Glucophage?).The optimal effective dose of 2 g/d was achieved within 4 weeks,and the reasonable dose was maintained until the end of treatment.The treatment period was 24 weeks.HbA1c and its compliance rate,FPG,and body weight were compared between the two groups in full analysis set(FAS)and protocol set(PPS).Safety and adverse events(AE)were evaluated in safety set(SS).Results A total of 414 participants were randomized(207 cases in Obs group and 207 cases in Con group).414 cases in FAS population(207 cases in Obs group and 207 cases in Con group),and 328 cases in PPS population(164 cases in Obs group and 164 cases in Con group),and 414 cases in SS population(207 cases in Obs group and 207 cases in Con group).After treatment,HbA1c,FPG and body weight were lower in both groups(P<0.05)in FAS and PPS.HbA1c compliance rate was not significantly different between the two groups in FAS and PPS(P>0.05).The results of non-inferiority test showed that the lower limit was>-0.4%in both FAS(-0.154,95%CI-0.384～0.069)and PPS(-0.139,95%CI-0.390～0.112),and the Obs group reached non-inferiority end point.The achievement rate,compliance rate,safety index and incidence of AE were not significantly different between the two groups(P>0.05).Conclusions Junlida? demonstrated non-inferiority to Glucophage? in glycemic control and can be safely and effectively used in patients with diabetes.

OBJECTIVE To prepare and characterize curcumin nanomicelles （hereinafter referred to as Cur/mPEG-PBLA micelles）， and to evaluate the in vitro hepatoprotective activity against alcohol liver disease （ALD）. METHODS Cur/mPEG-PBLA micelles were prepared with the dialysis method using methoxy-poly（ethylene glycol）-poly（β-benzyl-L-aspartate） （mPEG-PLGA） as the carrier. The appearance and microscopic morphology of Cur/mPEG-PBLA micelles were observed， and particle size， polydispersity index， Zeta potential， encapsulation efficiency and drug loading content were all detected. The in vitro release， pH stability， thermal stability， dilution stability， storage stability， plasma stability tests， and hemolysis experiments were all performed. The cell model of ALD was established with anhydrous ethanol intervention using human liver cancer cells and normal liver cells as objects， Cur reference solution as reference， to evaluate in vitro preventive and ameliorative effects of Cur/mPEG- PBLA micelles on ALD. RESULTS The prepared Cur/mPEG-PBLA micelles exhibited a pale-yellow milky light， with a spherical shape and uniform distribution. The average particle size was about 140 nm， and the polydispersity index was less than 0.3. Zeta potential was （－8.15±0.05） mV； the encapsulation efficiency was （73.26±3.16）%， and the drug loading content was （4.87± 0.42）%. The cumulative release of Cur reference substance was close to 80% at 10 h； the cumulative release of Cur/mPEG-PBLA micelles at 8 h was 28.94% and only 48.25% at 48 h. pH stability and thermal stability of Cur/mPEG-PBLA micelles were better than those of Cur reference solution； Cur/mPEG-PBLA micelles showed good dilution stability， storage stability and plasma stability， and would not cause hemolysis. Cur reference solution and Cur/mPEG-PBLA micelles had varying degrees of in vitro preventive and ameliorative effects on ALD in two types of cells； after 48 h of application， the above effects of Cur/mPEG-PBLA micelles were significantly better than those of Cur reference solution at the same mass concentration （P＜0.05）. CONCLUSIONS Cur/mPEG-PBLA micelles can improve pH stability and thermal stability of Cur， delayits degradation rate， and have better in vitro hepatoprotective activity against ALD.

Objective: To investigate the protective effect and potential mechanism of tanshinol borneol ester (TBE) on homocysteine(Hcy) induced rat bone marrow mesenchymal stem cells (BMSCs) damage. Methods: BMSCs were isolated and cultured in vitro by density gradient centrifugation and adherent culture method. BMSCs were divided into the control (normal isolation and culture), TBE-1(10 μmol/L TBE-1 solution with 100 μl), TBE-2 (10 μmol/L TBE-2 solution with 100 μl), Hcy (0.5 mmol/L Hcy solution with 100 μl), Hcy + TBE-1(0.5 mmol/L Hcy solution with 100 μl, and 10 μmol/L TBE-1 solution with 100 μl), Hcy + TBE-2 (0.5 mmol/L Hcy solution with 100 μl, and 10 μmol/L TBE-2 solution with 100 μl), Hcy+ TBE-1+ inhibitor group(0.5 mmol/L Hcy solution with 100 μl, 10 μmol/L TBE-1 solution with 100 μl, and 25 μmol/L LY294002(specific blocker of phosphatidylinositol 3 kinase) solution with 100 μl), Hcy+ TBE-2+ inhibitor group(0.5 mmol/L Hcy solution with 100 μl, 10 μmol/L TBE-2 solution with 100 μl, and 25 μmol/L LY294002 solution with 100 μl). Cell proliferation activity was detected by MTT assay. The T-SOD activity and malonaldehyde level of cells were measured by anthineoxidase method and TBA method, respectively, to evaluate cell oxidative and antioxidative activities. The ultrastructure of cells was observed under transmission electron microscope. The expression level of PKB and NF-κB of cells in various groups were detected with the immunocytochemical method. Results: (1)Cell proliferation activity in TBE-1 group and TBE-2 group was significantly increased compared with the control group (both P<0.01), and was similar between TBE-1 group and TBE-2 groups after 1, 12, 24 and 48 hours treatment.(2)The T-SOD activity in TBE-1 group and TBE-2 group was significantly higher than in control group (both P<0.01), while it was significantly lower in Hcy group, Hcy+ TBE-1 group, and Hcy+ TBE-2 group than in control group(all P<0.01), and was similar between control group, Hcy+ TBE-1+ inhibitor group, and Hcy+ TBE-2+ inhibitor group(all P>0.05). The T-SOD activity was higher in Hcy+ TBE-1 group and Hcy+ TBE-2 group than in Hcy group(both P<0.01), and was higher in Hcy+ TBE-1+ inhibitor group than in Hcy+ TBE-1 group(P<0.05) and was higher in Hcy+ TBE-2+ inhibitor group than in Hcy+ TBE-2 group(P<0.05). The malonaldehyde level was lower in TBE-1 group and TBE-2 group than in control group(both P<0.01), was higher in Hcy group, Hcy+ TBE-1 group, Hcy+ TBE-2 group, Hcy+ TBE-1+ inhibitor group, and Hcy+ TBE-2+ inhibitor group than in control group(all P<0.01), was lower in Hcy+ TBE-1 group and Hcy+ TBE-2 group than in Hcy group(both P<0.01), was higher in Hcy+ TBE-1+ inhibitor group than in Hcy+ TBE-1 group(P<0.05), was higher in Hcy+ TBE-2+ inhibitor group than in Hcy+ TBE-2 group(P<0.05). (3)Under electron microscope, BMSCs showed profound swelling, senescence and apoptosis of cells increased significantly in Hcy group, Hcy+ TBE-1+ inhibitor group, and Hcy+ TBE-2+ inhibitor group when compared with control group. BMSCs in the TBE-1 and TBE-2 groups presented with abundant rough endoplasmic reticulum, and very active cell metabolism signs. Compared with Hcy group, BMSCs edema, the number of aging and apoptotic cells, and cell injury severity were significantly less in TBE-1+ Hcy group and TBE-2+ Hcy. (4)The PKB level was higher in TBE-1 group and TBE-2 group than in control group(both P<0.01), was lower in Hcy group, Hcy+ TBE-2 group, Hcy+ TBE-1+ inhibitor group, and Hcy+ TBE-2+ inhibitor group than in control group(all P<0.01), was similar between control group and Hcy+ TBE-1 group(P>0.05), was higher in Hcy+ TBE-1 group and Hcy+ TBE-2 group than in Hcy group(both P<0.05), was lower in Hcy+ TBE-1+ inhibitor group than in Hcy+ TBE-1 group(P<0.05), and was lower in Hcy+ TBE-2+ inhibitor group than in Hcy+ TBE-2 group(P<0.05). The NF-κB level was higher in TBE-1 group and TBE-2 group than in control group(both P<0.01), was lower in Hcy group, Hcy+ TBE-1 group, Hcy+ TBE-2 group, Hcy+ TBE-1+ inhibitor group, and Hcy+ TBE-2+ inhibitor group than in control group(P<0.01 or 0.05), was higher in Hcy+ TBE-1 group and Hcy+ TBE-2 group than in Hcy group(both P<0.05), was lower in Hcy+ TBE-1+ inhibitor group than in Hcy+ TBE-1 group(P<0.05) and was lower in Hcy+ TBE-2+ inhibitor group than in Hcy+ TBE-2 group(P<0.05). Conclusion Tanshinol borneol ester can promote the proliferation of BMSC, and attenuate the homocysteine induced rat BMSCs damage possibly through activation of phosphatidylinositol 3 kinase/PKB signal transduction and its downstream signal pathway protein NF-κB.

Objective To observe the effects of adenosine preconditioning on the intestinal inflammatory response,the damaged mucosal tissue and apoptosis of intestinal epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A had 0.9％ sodium chloride solution immersion + caudal vein injection of sterilization water (3 mg/kg).The animals in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg) and the animals in group C were given seawater immersion + caudal vein injection of adenosine pretreatment (3 mg/kg).All animals were sacrificed 6 hours after immersion.Pathological changes in intestinal mucosa were closely observed by histopathology.Levels of TNF-α and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA).Caspase-3 protein was detected by immunohistochemistry.Apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The intestinal pathological scores of TNF-α and IL-6 for the animals in group B(3.98 ±0.41)were significantly higher than those in group A (2.46 ±0.39) (P ＜0.01).The TNF-α and IL-6 levels for the animals in group B [(2.38 ±0.39) μg/L and(883.11 ±34.22) ng/L] were significantly increased,as compared with those in group A [(1.01 ± 0.06) μg/L and (258.09 ± 6.52) ng/L] (P ＜ 0.01).The TNF-α and IL-6 levels for the animals in group C[(1.88 ± 0.21)pg/L and (582.13 ±19.44)ng/L] were significantly decreased,as compared with those in group B (P ＜ 0.01).The level of Caspase-3 and percentage of apoptotic cells in the intestinal mucosa of the animals in group B [(27.9 ± 4.3) ％ and (24.5 ± 3.1) ％]were significantly higher than those of the animals in group A [(13.8 ± 2.6) ％ and (16.4 ± 2.3) ％] (P ＜0.01),and the expression level of Caspase-3 and percentage of apoptotic cells of the animals in group C [(20.2 ± 3.4) ％ and (19.9 ± 2.9) ％] were significantly lower than those of the animals in group B (P ＜ 0.01).Conclusions Adenosine pretreatment could significantly improve intestinal mucosal inflammatory response in seawater immersion rats coupled with open abdominal open injury,alleviate the destruction of intestinal epithelial structure,and reduce apoptosis of intestinal mucosal epithelial cells.

Objective To observe the effects of adenosine preconditioning on gastric mucosal tissue destruction,inflammatory response and apoptosis of epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A were treated with abdominal open injury + caudal vein injection of sterile water (3 mg/kg).The animals with abdominal open injury in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg),and the animals with abdominal open injury in group C were given seawater immersion + caudal vein injection of adenosine (3 mg/kg).All the animals were treated either with caudal vein injection of sterile water or adenosine at a dosage of 3 mg/kg 60 minutes before surgery,and were sacrificed 6 hours after immersion.Gastric mucosal ulcer index (UI) was calculated in the animals of all the groups.Pathological changes in gastric mucosa were closely observed under light microscopy.The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the gastric mucosa of various groups were detected by enzyme-linked immunosorbent assay (ELISA),the expression levels of Caspase-3 in gastric mucosa were detected by immunohistochemistry,and apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The UI,the levels of TNF-α and IL-6,and the pathological damage of gastric mucosa in group B were all significantly higher than those in group A (P＜0.01) and group C (P ＜0.05).The expression level of Caspase-3 (25.2％ ±3.6％) and the percentage of apoptosis cells (27.3％ ± 2.4％) in group B were significantly higher than those in group A (10.3％ ±1.4％ and 9.4％ ± 1.8％) (P ＜0.01),and the expression level of Caspase-3 of group C (19.4％ ±2.6％ and 21.9％ ± 2.6％) were signficantly lower than those of group B (P ＜0.05).Conclusions Adenosine pretreatment could effectively protect gastric mucosal epithelial inflammatory response in seawater immersion rats coupled with open abdominal injury,inhibit the secretion of inflammatory factors,alleviate gastric mucosal inflammatory response and reduce apoptosis of gastric mucosal epithelial cells.

Objective To observe the effects of adenosine preconditioning on the intestinal inflammatory response,the damaged mucosal tissue and apoptosis of intestinal epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A had 0.9％ sodium chloride solution immersion + caudal vein injection of sterilization water (3 mg/kg).The animals in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg) and the animals in group C were given seawater immersion + caudal vein injection of adenosine pretreatment (3 mg/kg).All animals were sacrificed 6 hours after immersion.Pathological changes in intestinal mucosa were closely observed by histopathology.Levels of TNF-α and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA).Caspase-3 protein was detected by immunohistochemistry.Apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The intestinal pathological scores of TNF-α and IL-6 for the animals in group B(3.98 ±0.41)were significantly higher than those in group A (2.46 ±0.39) (P ＜0.01).The TNF-α and IL-6 levels for the animals in group B [(2.38 ±0.39) μg/L and(883.11 ±34.22) ng/L] were significantly increased,as compared with those in group A [(1.01 ± 0.06) μg/L and (258.09 ± 6.52) ng/L] (P ＜ 0.01).The TNF-α and IL-6 levels for the animals in group C[(1.88 ± 0.21)pg/L and (582.13 ±19.44)ng/L] were significantly decreased,as compared with those in group B (P ＜ 0.01).The level of Caspase-3 and percentage of apoptotic cells in the intestinal mucosa of the animals in group B [(27.9 ± 4.3) ％ and (24.5 ± 3.1) ％]were significantly higher than those of the animals in group A [(13.8 ± 2.6) ％ and (16.4 ± 2.3) ％] (P ＜0.01),and the expression level of Caspase-3 and percentage of apoptotic cells of the animals in group C [(20.2 ± 3.4) ％ and (19.9 ± 2.9) ％] were significantly lower than those of the animals in group B (P ＜ 0.01).Conclusions Adenosine pretreatment could significantly improve intestinal mucosal inflammatory response in seawater immersion rats coupled with open abdominal open injury,alleviate the destruction of intestinal epithelial structure,and reduce apoptosis of intestinal mucosal epithelial cells.

Objective To observe the effects of adenosine preconditioning on gastric mucosal tissue destruction,inflammatory response and apoptosis of epithelial cells in rats with abdominal open injury coupled with seawater immersion.Methods Sixty male Wistar rats with abdominal open injury were randomly divided into 3 groups,each consisting of 20 animals.The animals in group A were treated with abdominal open injury + caudal vein injection of sterile water (3 mg/kg).The animals with abdominal open injury in group B received seawater immersion + caudal vein injection of sterile water (3 mg/kg),and the animals with abdominal open injury in group C were given seawater immersion + caudal vein injection of adenosine (3 mg/kg).All the animals were treated either with caudal vein injection of sterile water or adenosine at a dosage of 3 mg/kg 60 minutes before surgery,and were sacrificed 6 hours after immersion.Gastric mucosal ulcer index (UI) was calculated in the animals of all the groups.Pathological changes in gastric mucosa were closely observed under light microscopy.The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the gastric mucosa of various groups were detected by enzyme-linked immunosorbent assay (ELISA),the expression levels of Caspase-3 in gastric mucosa were detected by immunohistochemistry,and apoptosis of the cells in intestinal mucosa were monitored by TUNEL method.Results The UI,the levels of TNF-α and IL-6,and the pathological damage of gastric mucosa in group B were all significantly higher than those in group A (P＜0.01) and group C (P ＜0.05).The expression level of Caspase-3 (25.2％ ±3.6％) and the percentage of apoptosis cells (27.3％ ± 2.4％) in group B were significantly higher than those in group A (10.3％ ±1.4％ and 9.4％ ± 1.8％) (P ＜0.01),and the expression level of Caspase-3 of group C (19.4％ ±2.6％ and 21.9％ ± 2.6％) were signficantly lower than those of group B (P ＜0.05).Conclusions Adenosine pretreatment could effectively protect gastric mucosal epithelial inflammatory response in seawater immersion rats coupled with open abdominal injury,inhibit the secretion of inflammatory factors,alleviate gastric mucosal inflammatory response and reduce apoptosis of gastric mucosal epithelial cells.