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28 September 2024, Volume 28 Issue 27 Previous Issue    Next Issue

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Safety risk assessment of in vitro heart in antitumor drug development Zheng Shuangjia, Zhao Ting, Ren Cuixia, Wang Baoqiang, Chen Lanlan, Lin Moxu, Li Yingji, Zhang Xu 2024, 28 (27):  4265-4272.  doi: 10.12307/2024.560 Abstract ( 108 )   PDF (1570KB) ( 9 )   Save BACKGROUND: Tyrosine kinase inhibitors, as well as other types of small-molecule cancer drugs, can cause severe cardiotoxicity. OBJECTIVE: To perform a heart safety re-evaluation by observing the effects of antitumor drugs on isolated heart electrocardiograph, cardiac action potential and associated ion channels and cytotoxicity. METHODS: Extracorporeal cardiac perfusion was given to the isolated rabbit heart using Langendorff perfusion: Sunitinib (0.3, 3, 10 μmol/L), Crizotinib (0.3, 1, 3 μmol/L), and Doxorubicin (1, 30 μmol/L) were perfused sequentially for 120 minutes to record electrocardiograph and left ventricular pressure. A blank control group was set for comparison. Manual patch clamp was used to record the effects of Crizotinib, Sunitinib, Doxorubicin on hERG, Cav1.2, Nav1.5 channel currents and action potential in human induced pluripotent stem cell derived cardiomyocytes. Adenosine triphosphate level in human induced pluripotent stem cell derived cardiomyocytes was detected by CellTiter-Glo luminescent cell viability assay.  RESULTS AND CONCLUSION: Isolated rabbit heart using Langendorff perfusion: Compared with the blank ontrol group, Sunitinib and Crizotinib at ≥ 3 μmol/L decreased heart rate (P < 0.01) and prolonged QT/QTc interval (P < 0.01), and reduced left ventricular pressure to different extents. Manual patch clamp recording: Compared with the blank control group, Sunitinib and Crizotinib at 3 μmol/L inhibited the activities of hERG, Nav1.5 and Cav1.2 channels and significantly prolonged the duration of action potential (P < 0.01). According to the analysis of the test article, the difference between the labeled concentration and the measured concentration of the recovered solution was not significant. Cell viability assays: Compared with the blank control group, adenosine triphosphate content in human induced pluripotent stem cell derived cardiomyocytes significantly decreased after treatment with Sunitinib (IC50=4.64 μmol/L), Doxorubicin (IC50=4.21 μmol/L) and Crizotinib (IC50=2.87 μmol/L), indicating that cell viability significantly decreased (P < 0.01). To conclude, this study successfully established an early cardiac safety evaluation method for antitumor drugs, which provides good support and help for the subsequent development of antitumor drugs. Figures and Tables | References | Related Articles | Metrics

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Establishment and validation of the Sprague-Dawley rat model of osteoarthritis with kidney deficiency and blood stagnation Yang Cheng, Li Yusheng, Jiao Hongzhuo, Shang Man, Liu Qi, Li Linzhen, Fan Fangyang, Zhang Chenglong, Zhang Xiaoyu, Zhang Juntao 2024, 28 (27):  4273-4280.  doi: 10.12307/2024.548 Abstract ( 104 )   PDF (2183KB) ( 10 )   Save BACKGROUND: Kidney deficiency and blood stasis syndrome are common traditional Chinese medicine syndromes observed in knee osteoarthritis, which serve as fundamental pathogenesis factors. There exists a significant connection between the two. Previous studies have demonstrated that kidney deficiency and blood stasis syndrome effectively contribute to knee joint cartilage degeneration and the progression of knee osteoarthritis. However, the mechanisms underlying the promotion of knee joint cartilage damage remain unclear and require further investigation.  OBJECTIVE: To investigate the influence of kidney deficiency and blood stasis syndrome on the progression of knee osteoarthritis in Sprague-Dawley rats.  METHODS: Sixteen Sprague-Dawley rats were randomly divided into two groups: a model observation group and a control group, with eight rats in each group. Animal models of kidney deficiency were induced by ovary removal in the model observation group, while the control group was given a sham procedure for ovarian removal. Two months after modeling, both groups underwent modified HULTH surgery to induce knee osteoarthritis. One week after modified HULTH surgery, the model observation group was subcutaneously given adrenaline hydrochloride to make blood stasis models, while the control group was subcutaneously given normal saline. At the 5th week after modified HULTH surgery, blood rheology, coagulation parameters, triiodothyronine, tetraiodothyronine, and estradiol levels were measured. Knee joint X-ray images were taken, and knee joint sections were stained with safranin O-fast green, hematoxylin-eosin, and immunohistochemistry.  RESULTS AND CONCLUSION: Compared with the control group, the model observation group exhibited significant increases in whole blood viscosity at low, medium, and high shear rates, as well as increased plasma viscosity. Fibronectin levels in the coagulation parameters were significantly increased, while prothrombin time and activated partial thromboplastin time were significantly decreased. Triiodothyronine, tetraiodothyronine, and estradiol levels were all significantly decreased. Radiographic results showed that the model observation group exhibited more severe degree of knee joint space narrowing and surface roughness, with the appearance of high-density shadows. Hematoxylin-eosin and safranin O-fast green staining demonstrated more severe cartilage damage in the model observation group, with significantly higher OARSI and Mankin scores compared with the control group. Compared with the control group, immunohistochemistry results showed a significant reduction in the expression of extracellular matrix type II collagen and aggrecan protein in the cartilage of the model observation group rats. Moreover, there was a significant increase in the expression of matrix metalloproteinase 13 and aggrecanase 5, which are inflammatory factors. These results indicate that the Sprague-Dawley rat model of knee osteoarthritis with kidney deficiency and blood stasis was successfully established. Kidney deficiency and blood stasis syndrome further aggravate cartilage extracellular matrix degradation and cartilage degeneration by promoting the expression of inflammatory factors, thereby promoting the progression of knee osteoarthritis in rats. Figures and Tables | References | Related Articles | Metrics

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Effect of matrine on apoptosis of nucleus pulposus cells in rats with intervertebral disc degeneration Wang Chong, Kong Li, Cui Xuechao, Bao Tiezhou 2024, 28 (27):  4281-4287.  doi: 10.12307/2024.541 Abstract ( 98 )   PDF (1527KB) ( 15 )   Save BACKGROUND: Nucleus pulposus cell apoptosis is the main pathological basis for intervertebral disc degeneration, and inflammation and peroxidation are important factors leading to apoptosis in the nucleus pulposus. Studies have shown that matrine has antioxidant, senescent, inflammatory and apoptotic effects, and may be a potential drug for the treatment of disc degeneration. OBJECTIVE: To investigate the effect of matrine on apoptosis of nucleus pulposus cells in rats with intervertebral disc degeneration by regulating the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) signaling pathway.  METHODS: (1) Nucleus pulposus cells of rats at a logarithmic phase were randomly separated into a control group, a model group, a low-dose matrine group, a high-dose matrine group, an empty group, and a high-dose matrine+cGAS overexpression group. Except for the control group, cell models of intervertebral disc degeneration were established in the other groups through oxygen-glucose deprivation. At the same time of modeling, the low-dose and high-dose groups were treated with 0.4 and 0.8 mmol/L matrine, respectively, and the empty group was transfected with the empty plasmid, while the high-dose+cGAS overexpression group was treated with 0.8 mmol/L matrine with the transfection of the cGAS overexpression plasmid. After 24 hours of treatment, cell activity and apoptosis, intracellular levels of reactive oxygen species, superoxide dismutase, tumor necrosis factor α and interleukin 1β, and intracellular expression of apoptotic proteins and cGAS-STING pathway proteins were detected. (2) Sixty Sprague-Dawley rats were randomized into six groups (n=10 per group): control group, model group, low-dose matrine group, high-dose matrine group, empty group, and high-dose+cGAS overexpression group. After 12 weeks of modeling, 60 and 120 mg/kg matrine were given by gavage in the low-dose and high-dose matrine groups, respectively (once a day), and the empty plasmid was injected into the tail vein in the empty group (2 times/week), while the high-dose+cGAS overexpression group was given 120 mg/kg matrine by gavage and injected with cGAS overexpression plasmid to the tail vein. Treatment in each group was given consecutively for 3 weeks. Samples were taken after drug administration and assayed for apoptosis, levels of reactive oxygen species, superoxide dismutase, tumor necrosis factor α and interleukin 1β, as well as apoptotic protein and cGAS-STING pathway protein expression. RESULTS AND CONCLUSION: Compared with the control group, in the model group, cell activity and superoxide dismutase levels were decreased (P < 0.05), and apoptosis rate, levels of reactive oxygen species, tumor necrosis factor α and interleukin 1β, and the expression of cGAS, STING, cleaved caspase-3 and Bax proteins were elevated (P < 0.05). Matrine dose-dependently ameliorated the above changes in each index due to cellular modeling (P < 0.05), whereas cGAS overexpression partially antagonized the ameliorative effect of high-dose matrine. Similar results to the in vitro cellular experiments were obtained in animal experiments. These results indicate that matrine could inhibit inflammation and oxidative stress by blocking the cGAS-STING signaling, which in turn attenuates apoptosis and elevates the activity of nucleus pulposus cells in rats with intervertebral disc degeneration. Figures and Tables | References | Related Articles | Metrics

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Causal relationship between blood metabolites and sarcopenia-related traits: a Mendelian randomization study Chen Tianxin, Dong Tingting, Li Yan, Zhang Sheng, Zhang Lei 2024, 28 (27):  4288-4292.  doi: 10.12307/2024.572 Abstract ( 102 )   PDF (2462KB) ( 15 )   Save BACKGROUND: Clinical evidences have suggested a correlation between metabolic factors and sarcopenia. Blood metabolites have been found as biological factors underlying the mechanisms of musculoskeletal disorders. However, the causal relationship between blood metabolites and sarcopenia is unclear. OBJECTIVE: To explore the causal relationship between blood metabolites and sarcopenia-related traits through a two-sample Mendelian randomization analysis and to analyze their metabolic pathways. METHODS: A dataset of 486 blood metabolites and sarcopenia-related traits was obtained from public databases. The inverse variance weighting, MR-Egger and weighted median methods were used to assess the causal relationship of blood metabolites with muscle mass and strength across genders. Sensitivity analyses, including heterogeneity and gene pleiotropy, were performed to explore the robustness of the results. Metabolic pathway analysis of potential causal relationships was performed using the Metaboanayst 5.0 tool. RESULTS AND CONCLUSION: A total of 124 metabolites and sarcopenia-related traits were observed to have potential causal relationships (P < 0.05). Mannose and 1-arachidonoylglycerophosphocholine were significantly causally associated with an increased muscle mass in males (P < 1.03×10-4). Pentadecanoate and glycine were significantly causally associated with decreased muscle mass and muscle strength in females, respectively (P < 1.03×10-4). Metabolic pathway analysis identified eight metabolic pathways associated with altered levels of muscle mass and muscle strength in sarcopenia, including the “glyoxylate and dicarboxylate metabolism” and “Glycine, serine and threonine metabolism.” The identified metabolites are considered as useful circulating metabolic biomarkers for screening and prevention of sarcopenia in clinical practice, serving as candidate molecules for future mechanistic exploration and drug target selection. Figures and Tables | References | Related Articles | Metrics

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Bioinformatics identification of CA9 as a signature gene for cartilage-associated ferroptosis in steroid-induced osteonecrosis of the femoral head Yu Peng, Meng Dongfang, Li Huiying, Zhang Xiangbei 2024, 28 (27):  4293-4299.  doi: 10.12307/2024.520 Abstract ( 92 )   PDF (2191KB) ( 10 )   Save BACKGROUND: Disturbances in bone metabolism have a significant association with ferroptosis in steroid-induced osteonecrosis of the femoral head (SONFH). Furthermore, the pathologic process of SONFH is characterized by the presence of cartilage damage and degeneration. However, the specific regulatory targets and the relationship between ferroptosis and cartilage concerning SONFH remain unclear. OBJECTIVE: To employ bioinformatics and machine learning techniques to identify specific genes associated with ferroptosis that target cartilage and to investigate the correlation between ferroptosis and cartilage, thereby providing novel ideas and methodologies for the study and treatment of SONFH. METHODS: Disease datasets pertinent to the study and ferroptosis-related genes were retrieved from the GEO and FerrDb databases. Subsequently, the disease datasets were normalized and differential analysis using the R language to identify ferroptosis-related differential genes (Fe-DEGs). We conducted Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis of Fe-DEGs. Furthermore, ferroptosis-related signature genes were filtered based on the protein-protein interaction network of Fe-DEGs and machine learning methods. Finally, the rabbits were divided into normal and model groups. The normal group was given the same dose of saline to simulate the modeling drug, and the animal model of SONFH in rabbits was constructed by injection of modified horse serum combined with methylprednisolone. After successful modeling, the expression of signature gene was verified between different groups, and the phenotype of ferroptosis in cartilage was analyzed. RESULTS AND CONCLUSION: Through the normalization and differential analysis of the dataset, a total of 1 315 differentially expressed genes were identified. Additionally, 379 ferroptosis-related genes were obtained from the FerrDb database. After intersecting both gene sets, 19 Fe-DEGs were obtained. The GO analysis revealed that Fe-DEGs were mainly involved in biological processes such as cell migration and cellular response to oxidative stress, cellular components such as kinase complexes, amino acid complexes, and cytoplasmic membranes, as well as molecular functions such as kinase activity, receptor activity, and protein binding. The KEGG analysis revealed that Fe-DEGs were mainly enriched in the FoxO signaling pathway, vascular endothelial growth factor signaling pathway, and FcγR-mediated phagocytosis. Constructing a protein-protein interaction network and using machine learning, we identified the ferroptosis-related signature gene, CA9. The gene set enrichment analysis of the signature gene CA9 revealed an upregulated expression in biological processes such as fatty acid metabolism and O-GlcNAc glycosylation modification, while being inhibited in terms of neural activity and ligand-receptor interactions. RT-PCR and western blot results showed that compared with the normal group, the expressions of ACSL4 and CA9 at mRNA and protein levels were significantly higher in the model group (P < 0.05), while the expressions of SLC7A11 and GPX4 at mRNA and protein levels were significantly lower in the model group (P < 0.05), coinciding with the expression levels of the signature genes in the dataset. These findings indicate that the cartilage of SONFH is closely related to ferroptosis, and targeting the signature gene may provide certain ideas and directions for the study and treatment of SONFH. Figures and Tables | References | Related Articles | Metrics

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Medical ozone alleviates pain in temporomandibular joint osteoarthritis Lu Caixia, Zhang Simin, Nigeayi·Aihemaiti, Li Xueer, Chen Zeyuan, Maimaitituxun·Tuerdi 2024, 28 (27):  4300-4305.  doi: 10.12307/2024.542 Abstract ( 113 )   PDF (1260KB) ( 11 )   Save BACKGROUND: Temporomandibular joint osteoarthritis can cause severe pain, which significantly affects the patient’s quality of life and psychological health. Studies have found that medical ozone can effectively alleviate pain due to temporomandibular joint osteoarthritis, but its analgesic effect and mechanism are still unclear.  OBJECTIVE: To explore the effects of medical ozone on pain relief in temporomandibular joint osteoarthritis and the potential mechanisms. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into four groups (n=6 per group): control group, model group, air group, and medical ozone group. A sodium iodate-induced rat model of temporomandibular joint osteoarthritis was established in all groups except for the control group. After 1 week of modeling, rats in the air group and medical ozone group were injected with clean air and medical ozone, respectively, in the temporomandibular joint. The injection frequency for the air group and medical ozone group was once a week for three times in total. The von Frey mechanized pain measurement technique was used to assess the mechanical pain threshold of the temporomandibular joint in rats before and 28 days after modeling. ELISA was utilized to detect interleukin-1β in both serum and temporomandibular joint fluid at 28 days after modeling. Histopathologic changes of the temporomandibular joint were evaluated through hematoxylin-eosin staining. Additionally, the expression levels of hypoxia-inducible factor 1α and cyclooxygenase 2 in the temporomandibular joint were analyzed using immunohistochemistry. RESULTS AND CONCLUSION: Compared with the control group, the mechanical pain thresholds of the temporomandibular joint in the model group were decreased at 1, 3, 7, 14, 21, and 28 days after modeling (P < 0.01); and compared with the model and air groups, the mechanical pain thresholds of the temporomandibular joint in the medical ozone group were increased at 28 days after modeling (P < 0.01). Compared with the control group, the level of interleukin 1β in the serum and joint fluid of rats in the model group was elevated (P < 0.01); compared with the model and air groups, the level of interleukin 1β in the serum and joint fluid of rats in the medical ozone group was decreased (P < 0.01). Hematoxylin-eosin staining results showed derangement and degeneration of the cartilage structure in the model group and the air group, while the derangement of the cartilage structure in the medical ozone group was less than that in the model group and the air group. Immunohistochemical staining showed that the expression of hypoxia-inducible factor 1α and cyclooxygenase 2 in the temporomandibular joints of rats in the model group was elevated compared with that in the control group (P < 0.01); the expression of hypoxia-inducible factor 1α and cyclooxygenase 2 in the temporomandibular joints of rats in the medical ozone group was decreased compared with that in the model group and the air group (P < 0.01, P < 0.05). These findings suggest that medical ozone can alleviate the pain caused by osteoarthritis of the temporomandibular joints in Sprague-Dawley rats by reducing the expression of hypoxia-inducible factor 1α, interleukin 1β, and cyclooxygenase 2.  Figures and Tables | References | Related Articles | Metrics

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Research hotspots and trends in the field of articular cartilage repair: a visualization analysis Zhang Zhilong, Yang Shengping, Chen Tianxin, Zhu Yuqi 2024, 28 (27):  4306-4311.  doi: 10.12307/2024.547 Abstract ( 101 )   PDF (3047KB) ( 17 )   Save BACKGROUND: Due to the very limited ability of articular cartilage to repair itself, articular cartilage defects caused by natural degeneration or trauma often cannot be repaired on their own, which triggers or aggravates osteoarthritis and even leads to severe disability. Therefore, the repair treatment after articular cartilage injury has become an urgent clinical problem. OBJECTIVE: To summarize the hot research topics and development trends in the field of articular cartilage repair using bibliometric analysis. METHODS: Literature related to articular cartilage repair was searched from the Web of Science Core Collection from 2000 to 2023, and bibliometric and visualization analyses were carried out using VOSviewer, Citespeace and Bibliometrix R-package. RESULTS AND CONCLUSION: The annual publication volume in the field of articular cartilage repair shows an overall increasing trend, with the United States, China, and Germany being the top three countries in terms of publication volume, and the research institutions focus on universities and hospitals, with Harvard University, New York Hospital for Special Surgery, and Shanghai Jiao Tong University being the top three institutions in terms of publication volume. AMERICAN JOURNAL OF SPORTS MEDICINE is the journal that publishes the most research literature in the field, and BIOMATERIALS is the journal with the highest number of citations in the field. “Injectable hydrogels for cartilage and bone tissue engineering” is the most cited document published in the last decade, and the author with the most publications is Madry Henning, an active author in the field. The active authors in this field have formed a number of stable research teams with each other, and the cooperation between different teams needs to be further strengthened. Intra-articular injections, high tibial osteotomies, hydrogels, drug delivery, inflammation, cartilage regeneration, and scaffolds are the current hot topics of research in this field, and the application of 3D printing technology, bio-inks, silk proteins, injectable hydrogels, and exosomes in articular cartilage repair may be the frontier of research in this field. Integrating various innovative technologies and methods for more effective, durable and functional cartilage tissue regeneration and repair, and facilitating the clinical translation of the relevant technologies and methods by conducting more high-quality clinical studies may be the future research trend in this field. Figures and Tables | References | Related Articles | Metrics

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Expression of immune-related genes in rheumatoid arthritis and a two-sample Mendelian randomization study of immune cells Fan Yidong, Qin Gang, He Kaiyi, Gong Yufang, Li Weicai, Wu Guangtao 2024, 28 (27):  4312-4318.  doi: 10.12307/2024.571 Abstract ( 125 )   PDF (4334KB) ( 26 )   Save BACKGROUND: Rheumatoid arthritis is a chronic systemic autoimmune disease. It is important to study the immunological changes involved in it for diagnosis and treatment. OBJECTIVE: To identify immune-related biomarkers associated with rheumatoid arthritis utilizing bioinformatics techniques and examine alterations in immune cell infiltration as well as the relationship between immune cells and biomarkers. METHODS: Differential expression analysis was used to identify the immune-related genes that were up-regulated in rheumatoid arthritis based on the GEO and Immport databases. Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) enrichment analyses were used to investigate the possible function of these elevated genes. The immunological characteristic genes associated with rheumatoid arthritis were screened using least absolute shrinkage and selection operator (Lasso) and support vector machine recursive feature elimination (SVM-RFE). Independent datasets were used for difference validation, and the diagnostic performance was evaluated by plotting receiver operating characteristic curves for feature genes. Immune cell infiltration was used to analyze the differential profile of immune cells in rheumatoid arthritis and the correlation between the characterized genes and immune cells. In order to ascertain the causal relationship between monocytes and rheumatoid arthritis in immune cells, Mendelian randomization analysis was ultimately employed. RESULTS AND CONCLUSION: There were 39 upregulated differentially expressed genes in rheumatoid arthritis. The genes were primarily enriched in chemotaxis, cytokine activity, and immune receptor activity, according to GO enrichment analysis, while kEGG enrichment analysis revealed that the genes were considerably enriched in the tumor necrosis factor signaling pathway and peripheral leukocyte migration. Lasso and SVM-RFE identified five feature genes: CXCL13, SDC1, IGLC1, PLXNC1, and SLC29A3. Independent dataset validation of the feature genes found them to be similarly highly expressed in rheumatoid arthritis samples, with area under the curve values greater than 0.8 for all five feature genes in both datasets. Immune cell infiltration indicated that most immune cells, including natural killer cells and monocytes, exhibited increased levels of infiltration in rheumatoid arthritis samples. The correlation analysis revealed a significant positive correlation between memory B cells and immature B cells and these five feature genes. Correlation analysis showed that the five feature genes were positively correlated with memory B cells and immature B cells. The inverse variance weighting method revealed that monocytes were associated with the risk of developing rheumatoid arthritis. Figures and Tables | References | Related Articles | Metrics

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Association between obesity and osteoporosis: a two-sample Mendelian randomization analysis Zhan Qunzhang, Zhang Yuling, Han Yuxin, Lyu Jiazhen, Zheng Xiaoxia, Qu Chongzheng 2024, 28 (27):  4319-4324.  doi: 10.12307/2024.579 Abstract ( 142 )   PDF (2295KB) ( 13 )   Save BACKGROUND: Numerous clinical studies have suggested a close relationship between obesity and osteoporosis, but whether there is a genetic causal effect between obesity and osteoporosis remains unclear. OBJECTIVE: To explore the association between obesity and osteoporosis using summary data from a large-scale genome-wide association study (GWAS) through Mendelian randomization analysis. METHODS: Obesity data were derived from summary statistics of the Genetic Investigation of Anthropometric Traits (GIANT) and the UK Biobank (UKBB). Osteoporosis data were obtained from the Genetic Factors for Osteoporosis (GeFOS) consortium, including two bone density phenotypes: total body bone mineral density (BMD) and heel BMD. The inverse variance-weighted method was the primary analysis, with the Mendelian randomization method based on Egger regression (MR-Egger) and weighted median method as supplementary approaches to calculate the causal association between genetic variations related to obesity and osteoporosis. Sensitivity analyses were conducted to validate the reliability of the results. Heterogeneity was assessed using Cochran’s Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test. Leave-one-out analysis was performed to evaluate the potential influence of single nucleotide polymorphisms on the combined inverse variance-weighted estimates. RESULTS AND CONCLUSION: (1) Impact of obesity on osteoporosis: In addition to body mass index and forearm BMD, body mass index, waist-to-hip ratio, body mass index-adjusted waist-to-hip ratio, and whole-body body mass index, heel BMD, forearm BMD, lumbar spine BMD, and femoral neck BMD were causally related to each other. Further Meta-analysis revealed that obesity increased the risk of BMD  (odds ratio=1.07, 95% confidence interval: 1.03-1.12, P < 0.01). (2) Impact of osteoporosis on obesity: Apart from arm BMD and lumbar spine BMD as exposure factors showing causal relationships with obesity, other datasets indicated no causal effect between total body BMD, heel BMD, femoral neck BMD, and obesity. Additional meta-analysis demonstrated that BMD did not increase the risk of obesity (odds rate=0.99, 95% confidence interval: 0.98-1.01, P < 0.01 ). There is a causal relationship between obesity and osteoporosis, suggesting that obesity may be a risk factor for osteoporosis. However, no causal association is found between osteoporosis and obesity. Figures and Tables | References | Related Articles | Metrics

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Gut microbiota and drug-associated osteonecrosis: a two‑sample Mendelian randomization study Chai Jinlian, Li Shudong, Li Wei, Du Haitao, Dong Limin, Liang Xuezhen, Wang Ping 2024, 28 (27):  4325-4331.  doi: 10.12307/2024.559 Abstract ( 131 )   PDF (2134KB) ( 14 )   Save BACKGROUND: Osteonecrosis due to drugs is a serious adverse reaction occurring after the application of such drugs. Increasing evidence suggests that the gut microbiota composition is associated with osteonecrosis due to drugs. However, the causal relationship of the gut microbiota to osteonecrosis due to drugs is still unclear. OBJECTIVE: To evaluate the potential causal relationship between the gut microbiota and the risk of osteonecrosis due to drugs using the Mendelian randomization method. METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n=13 266) conducted by the MiBioGen consortium as well as the summary statistics of osteonecrosis due to drugs obtained from the FinnGen consortium R9 release data (264 cases and 377 013 controls). Inverse variance weighted, MR-Egger, weighted median, weighted model and simple model were used to examine the causal association between gut microbiota and osteonecrosis due to drugs. Sensitivity analysis was used to test whether the results of the Mendelian randomization analysis were reliable. Reverse Mendelian randomization analysis was performed on all the bacteria as an outcome for effect analysis and sensitivity analysis. RESULTS AND CONCLUSION: Inverse variance weighted estimates suggested that Lentisphaerae (phylum), Lentisphaeria (class), Melainabacteria (class), Gastranaerophilales (order), Rhodospirillales (order), Victivallales (order) and Bifidobacterium (genus) had protective causal effects on osteonecrosis due to drugs. Methanobacteria (class), Bacillales (order), Methanobacteriaceae (family), Lachnospiraceae (family), Methanobacteriales (order), Holdemania (genus), Holdemania (UCG010 group) (genus), Odoribacter (genus) and Tyzzerella3 (genus) had negative causal effects on osteonecrosis due to drugs. According to the results of reverse Mendelian randomization analysis, Clostridiaceae1 (family), Peptostreptococcaceae (family), Streptococcaceae (family), Clostridiumsensustricto1 (genus) and Streptococcus (genus) showed negative causal effects on osteonecrosis due to drugs. However, Eisenbergiella (genus) showed protective causal effects on osteonecrosis due to drugs. None of the bidirectional sensitivity analysis revealed heterogeneity or horizontal pleiotropy. When gut microbiota were used as exposure and osteonecrosis due to drugs as the outcome, Mendelian randomization analysis found that seven bacterial traits were positively correlated to osteonecrosis due to drugs, nine bacterial traits were negatively related to osteonecrosis due to drugs. When osteonecrosis due to drugs were used as exposure and gut microbiota as the outcome, reverse Mendelian randomization analysis found a negative correlated relationship with five bacterial traits and a positive causal relationship with one bacterial trait. By changing the diversity and composition of gut microbiota, it is expected to improve the incidence and prognosis of osteonecrosis due to drugs, providing new ideas for the study of orthopedic diseases. Figures and Tables | References | Related Articles | Metrics

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Effects of cumulative and continuous exercise of different intensities on intestinal mucosal permeability in insulin-resistant mice Liang Fei 2024, 28 (27):  4332-4339.  doi: 10.12307/2024.554 Abstract ( 103 )   PDF (1133KB) ( 10 )   Save BACKGROUND: The relationship between insulin resistance and intestinal mucosal permeability may be related to excess fat, inflammation and oxidative stress. At present, the influence of different kinds of exercise on this relationship has not been fully studied, and the relevant mechanism needs to be further studied. OBJECTIVE: To study the effects of continuous exercise and cumulative exercise on intestinal mucosal permeability of insulin-resistant mice induced by high fat diet, and to compare the effects of different intensities of exercise, thereby evaluating the health-promoting effects of cumulative exercise. METHODS: Four-week-old male C57BL/6J mice were fed high-fat diet to induce insulin resistance, and mice with successful modeling were randomly divided into five groups: high-fat insulin resistance group, general dietary insulin resistance group, moderate-intensity continuous exercise group, moderate-intensity cumulative exercise group, and high-intensity cumulative exercise group. Mice in the high-fat insulin resistance group received high-fat diet and mice in the other groups were fed normally. All the exercise groups received 8 weeks of different forms of treadmill training. Mice in the moderate-intensity sustained exercise group exercised for 50 minutes at a speed of 11 m/min. Mice in the moderate-intensity cumulative exercise group were subjected to 12.5 minutes of exercise, four times a day (3 hours between sessions), at a speed of 11 m/min. Mice in the high-intensity cumulative exercise group exercised for 7.5 minutes once, four times a day (3 hours between sessions), at a speed of 19 m/min. At 48 hours after the final session, the levels of lipopolysaccharide and D-lactic acid in serum of mice were detected, the pathological changes of ileal tissue were observed by hematoxylin-eosin staining, and the expression of intestinal compact linking protein was detected by western blot. The expression of interleukin-10, tumor necrosis factor αin blood and ileum and intestinal secreted immunoglobulin A were detected by ELISA. RESULTS AND CONCLUSION: High-fat diet-induced insulin resistance was associated with body mass gain. The serum levels of endotoxin and D-lactic acid significantly increased, and the levels of tumor necrosis factor-α in serum and small intestine were significantly increased. Long-term regular cumulative exercise and continuous exercise could reduce the body mass of insulin-resistant mice, significantly improve glucose metabolism, and correct or improve insulin resistance symptoms. Both long-term regular cumulative exercise and continuous exercise could increase the expression of zonula occludens protein 1 and increase the secretion of secreted immunoglobulin A in intestinal mucosal tissue, thereby improving intestinal mucosal permeability, enhancing intestinal immune function, reducing the content of lipopolysaccharide in serum, and reducing the expression of pro-inflammatory factors in circulating blood and intestinal tissue. Finally, it could protect the intestinal mucosal barrier of insulin-resistant mice. Compared with medium-intensity cumulative exercise and continuous exercise, high-intensity cumulative exercise had more obvious effects on reducing body mass, improving insulin resistance symptoms and protecting intestinal mucosal barrier in insulin-resistant mice. Figures and Tables | References | Related Articles | Metrics

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Relationship between statin drugs and bone density: a drug target-mediated Mendelian randomization study Ma Weiwei, Xiong Yong, Chen Honggu, Huang Wenzhuo, Huang Xin, Zhou Xiaohong 2024, 28 (27):  4340-4345.  doi: 10.12307/2024.555 Abstract ( 152 )   PDF (1265KB) ( 17 )   Save BACKGROUND: Observational studies have suggested that statin drugs may have a protective effect on bone density, making them a potential treatment option for osteoporosis. OBJECTIVE: To evaluate the causal relationship between drug target-mediated lipid phenotypes and bone mineral density (BMD) using Mendelian randomization methods.  METHODS: We obtained single nucleotide polymorphismsrelated to statin drugs and BMD data from the IEU Open GWAS database. The primary analysis method was the inverse variance weighted method, and we also used weighted median, simple median, weighted mode, and MR-Egger regression. We used β values and 95% confidence intervals (CI) to assess the causal relationship between statin drugs and BMD. Additionally, we conducted sensitivity analyses to validate the results, assessed heterogeneity using Cochran’s Q test, examined for horizontal pleiotropy using the MR-Egger intercept test, and performed leave-one-out analyses to determine if individual or multiplesingle nucleotide polymorphism influenced the results. RESULTS AND CONCLUSION: There was a significant association between the statin target of action, 3-hydroxy-3-methyl glutaryl coenzyme A reductase-mediated low-density lipoprotein cholesterol, and heel bone BMD (β=-0.086, 95% CI: -0.117 to -0.055, P=5.42×10-8) and whole-body BMD (β=-0.193, 95% CI: -0.288 to -0.098, P=7.35×10-5). The findings of this study support the protective effect of statin drugs on BMD. These findings not only deepen our understanding of the relationship between cholesterol-related genes and bone health but also reveal potential therapeutic targets for improving BMD. Figures and Tables | References | Related Articles | Metrics

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Yougui Pill in the treatment of lumbar disc herniation: network pharmacological analysis of active ingredients and potential targets Yang Jingyan, Ma She, Huang Renjun, Yang Xiaoxia, Tang Xiaochen, Yu Dong 2024, 28 (27):  4346-4352.  doi: 10.12307/2024.543 Abstract ( 136 )   PDF (1905KB) ( 17 )   Save BACKGROUND: Yougui Pill is a famous formula of the Chinese traditional medicine, which has good efficacy for lumbar disc herniation due to kidney yang insufficiency.  OBJECTIVE: To investigate the potential targets and mechanism of action of Yougui Pill in the treatment of lumbar disc herniation by using network pharmacology and molecular docking technology, and verified by animal experiments. METHODS: (1) Network pharmacological analysis: We obtained the active ingredients and targets of Yougui Pill from TCMSP and other databases, collected genes related to lumbar disc herniation from GeneCards database, and took the intersection of the two for the topological analysis to derive the main active ingredients and core therapeutic targets. Gene ontology function analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analysis were performed using R software. (2) Molecular docking: Autodock and Pymol software were utilized for the prediction of molecular binding energy of TCM active ingredients to core therapeutic targets. (3) Animal experiments: Eighteen Sprague-Dawley rats were randomly divided into a control group, a degeneration group and a Yougui Pill group, with 6 rats in each group. A rat model of intervertebral disc degeneration was prepared by fiber puncture method in the degeneration and Yougui Pill groups. At 2 weeks after modeling, Yougui Pill was given by gavage in the Yougui Pill group, once a day for 2 consecutive weeks. The level of tumor necrosis factor-α in serum was detected by the ELISA method, and morphological changes of the annulus fibrosus and nucleus pulposus cells were observed using hematoxylin-eosin staining. RESULTS AND CONCLUSION: There were 90 active ingredients and 64 targets, and the main active ingredients were found to be quercetin, kaempferol, β-carotene, soybean flavonoid, and 4'-O-methylnyasol. The core targets of Yougui Pill for the treatment of lumbar disc herniation were interleukin 6, tumor necrosis factor-α, AKT1, interleukin 1B, and vascular endothelial growth factor A. Enrichment analysis revealed that the intersecting genes might be expressed through the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, MAPK signaling pathway, PI3K-AKT signaling pathway, and other signaling pathways to improve intervertebral disc degeneration. The molecular docking test verified that quercetin, kaempferol, and β-carotene had strong binding ability to the core targets. Animal experiments showed that the level of serum tumor necrosis factor α in the degeneration group was higher than that in the control group (P < 0.05), and the level of serum tumor necrosis factor α in the Yougui Pill group was lower than that in the degeneration group (P < 0.05). Hematoxylin-eosin staining showed that the fibrous annulus of the intervertebral discs and the structure of the nucleus pulposus in the degeneration group were destroyed, and the number of nucleus pulposus cells was reduced; there was a tendency to reconstructing the fibrous annulus of the intervertebral discs in the Yougui Pill group, and the number of nucleus pulposus cells increased compared with the degeneration group. To conclude, Yougui Pill may treat lumbar disc herniation by improving disc degeneration through the effects of quercetin, kaempferol, beta-carotene and other key active ingredients on core targets such as tumor necrosis factor. Figures and Tables | References | Related Articles | Metrics

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Mechanisms underlying internal heat-type acupuncture in the treatment of steroid-induced osteonecrosis of the femoral head in rabbits Ma Liangchen, Tian Fubao, Xu Yujuan, Tian Xinbao, Tao Ying, Chen Mengying, Lian Jiawei, Lin Ruizhu, Zhu Ning 2024, 28 (27):  4353-4359.  doi: 10.12307/2024.549 Abstract ( 101 )   PDF (1899KB) ( 7 )   Save BACKGROUND: Internal heat-type acupuncture therapy is a new treatment technique that combines acupuncture therapy with hyperthermia. It has good clinical effects on steroid-induced osteonecrosis of the femoral head, but the mechanism of action is still not fully clear. OBJECTIVE: To explore the possible mechanism of internal heat-type acupuncture therapy in treating steroid-induced osteonecrosis of the femoral head in rabbits. METHODS: Thirty-two New Zealand rabbits were randomly divided into blank group, model group, internal heat-type acupuncture group and shock wave group using a random number table method, with 8 rabbits in each group. The model group, internal heat-type acupuncture group and shock wave group were modeled using methylprednisolone sodium succinate combined with Escherichia coli endotoxin. The internal heat-type acupuncture group received an internal heat-type acupuncture intervention on the buttocks of rabbits, once a week, for 20 minutes each time. The shock wave group received shock wave intervention on the buttocks of rabbits, once a week, with 2 000 beats per session. The blank group and model group were not given any treatment. After 4 weeks of intervention, blood samples and bilateral femoral head samples were collected from experimental rabbits. The levels of tumor necrosis factor-α and interleukin-6 in serum were detected by ELISA; the histomorphology of the femoral head was observed using hematoxylin-eosin staining and the rate of empty lacunae was calculated; the protein expressions of matrix metalloproteinase 2, matrix metalloproteinase 9, matrix metalloproteinase tissue inhibitor 1, and matrix metalloproteinase tissue inhibitor 2 were detected by immunohistochemistry and western blot. RESULTS AND CONCLUSION: Compared with the blank group, the model rabbits showed reduced food intake, mental fatigue, and decreased activity; compared with the model group, the above performance of the experimental rabbits was significantly improved after internal heat-type acupuncture and shock wave treatment. Compared with the blank group, the histomorphology of the femoral head in the model group deteriorated significantly and the rate of empty bone lacuna increased (P < 0.001), while the histomorphology of the femoral head in the internal heat-type acupuncture group and shock wave group was significantly improved compared with the model group, and the rate of empty bone lacuna was reduced (P < 0.001). The serum levels of tumor necrosis factor-α and interleukin-6 in the model group were significantly higher than those in the blank group (P < 0.05), while the serum levels of tumor necrosis factor-α and interleukin-6 in the internal heat-type acupuncture group and the shock wave group were significantly lower than those in the model group (P < 0.05). Compared with the blank group, the expression levels of matrix metalloproteinase 2 and matrix metalloproteinase 9 in the femoral head of the model group were significantly increased, while the expression levels of matrix metalloproteinase tissue inhibitor 1 and matrix metalloproteinase tissue inhibitor 2 were significantly decreased (P < 0.001); compared with the model group, the protein expression levels of matrix metalloproteinase 2 and matrix metalloproteinase 9 were significantly decreased, while the protein expression levels of matrix metalloproteinase tissue inhibitor 1 and matrix metalloproteinase tissue inhibitor 2 were significantly increased in the internal heat-type acupuncture group and the shock wave group (P < 0.001). Overall, these findings indicate that internal heat-type acupuncture may promote the repair of the necrotic femoral head by regulating the levels of matrix metalloproteinases/matrix metalloproteinase tissue inhibitors and serum inflammatory factors, thus treating early steroid-induced osteonecrosis of the femoral head. Figures and Tables | References | Related Articles | Metrics

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Effects of different strength of pressing massage on myofascial trigger points with chronic pain in rats Jiang Quanrui, Feng Xiang, Liu Dan, Ai Kun, Li Jiangshan, Liu Xiaowei, Li Wu 2024, 28 (27):  4360-4366.  doi: 10.12307/2024.552 Abstract ( 105 )   PDF (1263KB) ( 15 )   Save BACKGROUND: Pressing massage applied to myofascial trigger points (MTrPs) has shown clear effect in relieving pain. However, further research is needed to investigate the effects of different levels of pressure applied during the massage. OBJECTIVE: To investigate the different strength of pressing on MTrPs in rats with chronic pain.  METHODS: Sixty SPF-rated male Sprague-Dawley rats were randomly divided into a blank group of 10 rats not involved in MTrPs modeling and 50 rats involved in modeling. The MTrPs model was established in the left medial thigh muscle of rats by blunt strikes combined with centrifugal exercise and 40 rats that met the evaluation criteria after modeling were randomly divided into model group, light press group, medium press group and heavy press group, with 10 rats in each group. The rats in the blank group and the model group were not intervened, while the rats in the light press group, the medium press group and the heavy press group were intervened with a homemade press stimulator with light force (0.3 kg), medium force (0.5 kg) and heavy force (0.7 kg) to MTrPs. The intervention time was 7.5 minutes per session, with one session every other day, totaling seven sessions. Electromyogram, soft tissue tension and mechanical pain threshold were detected by electrophysiological instruments, soft tissue tension tester, and pressure painmeter, respectively. After the intervention, in the blank group, muscle tissue was taken from the inside of the left thigh, while in the other groups, MTrPs tissue was taken. The pathological morphology was observed by hematoxylin-eosin staining, while enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of cyclooxygenase-2, prostaglandin E2 and bradykinin.  RESULTS AND CONCLUSION: Compared with the blank group, the model group had lower mechanical pain thresholds, higher soft tissue tone, higher amplitude frequency of spontaneous electrical activity, significant pathomorphological changes, and increased levels of cyclooxygenase-2, prostaglandin E2 and bradykinin (P < 0.05). Compared with the model group, the medium press group and the heavy press group showed increased mechanical pain thresholds, decreased soft tissue tension, decreased spontaneous potential frequency amplitude, and decreased levels of cyclooxygenase-2, prostaglandin E2 and bradykinin (P < 0.05), and significant recovery on pathomorphological changes. No significant changes in the above indicators were observed in the light press group (P > 0.05). Compared with the medium press group, the heavy press group showed better improvement in the above indicators (P < 0.05). To conclude, moderate to heavy pressing is often required to alleviate MTrPs pain.  Figures and Tables | References | Related Articles | Metrics

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Association between interleukin-1B gene linkage disequilibrium and susceptibility to primary frozen shoulder Shen Chengkai, Liu Kun, Liu Weiliang, Lyu Chengyu, Zhao Haijun 2024, 28 (27):  4367-4372.  doi: 10.12307/2024.551 Abstract ( 86 )   PDF (940KB) ( 8 )   Save BACKGROUND: A large number of domestic and international documents have confirmed that elevated interleukin-1β is associated with primary frozen shoulder. Interleukin-1B gene polymorphisms can affect the transcription and protein expression of interleukin 1β-related genes, resulting in altered levels of cytokines in vivo, and thus altering the incidence of primary frozen shoulder. Through the study of interleukin-1B gene polymorphism and susceptibility to primary frozen shoulder, this study aimed to explore new breakthroughs in the pathogenesis of primary frozen shoulder from the perspective of molecular biology, and to search for susceptibility genes of primary frozen shoulder.  OBJECTIVE: To explore the association between linkage disequilibrium of three gene loci in interleukin-1B gene and susceptibility to primary frozen shoulder.  METHODS: A case-control study was conducted. There were two groups in this study. One group consisted of 184 patients with primary frozen shoulder, while the other group included 260 healthy controls. The genotypes of interleukin-1B gene loci -511C/T (rs16944), +3954C/T (rs1143634), and -31C/T (rs1143627) were detected by polymerase chain reaction and restriction fragment length polymorphism. The correlation between the probability of linkage disequilibrium and haplotypes and the risk of primary frozen shoulder disease was compared and analyzed. RESULTS AND CONCLUSION: Unconditional Logistic regression analysis showed that the proportion of CT genotypes at rs1143634 and rs1143627 sites increased significantly in the primary frozen shoulder. Linkage disequilibrium analysis showed that rs16944, rs1143634 and rs1143627 tended to be balanced in the control group (D’ value < 0.1), while there was a certain degree of linkage disequilibrium at rs1143627 and rs1143634 sites in the primary frozen shoulder group (D’ value=0.595). Haplotype TTT increased the risk of primary frozen shoulder by 6.66 times compared with CCT type (TTT, OR=6.66, 95% CI=1.59-27.88, P=0.009 7). To conclude, there is a certain degree of linkage disequilibrium between interleukin-1B gene loci rs1143627and rs1143634 in patients with primary frozen shoulder; haplotype TTT formed by these three gene loci may increase the risk of developing primary frozen shoulder. Figures and Tables | References | Related Articles | Metrics

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Oleanolic acid alleviates steroid-induced osteonecrosis of the femoral head in rats by regulating Wnt/beta-catenin signaling pathway#br# Gong Gaojin, Huang Haixun 2024, 28 (27):  4373-4377.  doi: 10.12307/2024.556 Abstract ( 123 )   PDF (1222KB) ( 7 )   Save BACKGROUND: Oleanolic acid can promote osteoblast proliferation and inhibit osteoclast proliferation, thereby improving steroid-induced osteonecrosis of the femoral head, but its specific mechanism of action is not yet fully understood. OBJECTIVE: To explore the mechanism by which oleanolic acid alleviates steroid-induced osteonecrosis of the femoral head in rats by regulating the Wnt/β-catenin signaling pathway.  METHODS: Forty Sprague-Dawley rats were randomized into control group, model group, oleanolic acid group and oleanolic acid+sFRP1 group. An animal model of steroid-induced osteonecrosis of the femoral head was established by injecting prednisolone acetate in the latter three groups. Rats in the oleanolic acid group were gavaged with 10 mg/kg/d oleanolic acid and intramuscularly injected with the corresponding saline; rats in the oleanolic acid+sFRP1 group were gavaged with 10 mg/kg/d oleanolic acid and intramuscularly injected with 1 mg/kg/d Wnt inhibitor-sFRP1; and rats in the control and model groups were administered by gavage and intramuscularly injected with equal volumes of saline for 6 weeks. The levels of serum calcium, phosphorus, transforming growth factor-β1, and alkaline phosphatase were detected. Micro-CT was applied to detect femoral morphology. The morphology of femoral tissue was detected by hematoxylin-eosin staining. Cell apoptosis was detected by TUNEL. The levels of Bcl-2, Bax, β-catenin, and Wnt proteins were determined by western blot.  RESULTS AND CONCLUSION: Compared with the control group, the trabeculae bone and femoral head of the model group were seriously injured, the serum levels of calcium, phosphorus, and transforming growth factor-β1 were significantly decreased, the levels of Bcl-2, Wnt, and β-catenin proteins in bone tissue were significantly reduced, and the serum alkaline phosphatase level, cell apoptosis rate, and Bax protein level were significantly increased (P < 0.05). Compared with the model group, the degree of trabecular thinning in the oleanolic acid group was significantly improved, and the degree of femoral head damage was significantly reduced, serum alkaline phosphatase level, cell apoptosis rate, and Bax protein level were significantly reduced, serum levels of calcium, phosphorus, and transforming growth factor-β1, and levels of Bcl-2, Wnt, and β-catenin proteins in bone tissue were significantly increased (P < 0.05). Compared with the oleanolic acid group, the oleanolic acid+sFRP1 group showed opposite changes in the above-mentioned indicators (P < 0.05). To conclude, oleanolic acid can improve bone metabolism indicators and trabecular structure and attenuate femoral head necrosis in rats with steroid-induced osteonecrosis of the femoral head, which can be achieved by activating the Wnt/β-catenin signaling pathway. Figures and Tables | References | Related Articles | Metrics

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Autophagy protects neurons against facial nerve injury in rats Duan Kunling, Fei Jing, Li Leiji 2024, 28 (27):  4378-4382.  doi: 10.12307/2024.508 Abstract ( 99 )   PDF (1231KB) ( 6 )   Save BACKGROUND: After peripheral facial nerve injury, glial cell-derived neurotrophic factor (GDNF) can play a protective role in facial neurons. It has been found that GDNF can regulate the level of autophagy through mammalian target of rapamycin (mTOR), but it is unclear whether it can regulate facial neurons through the adenylate-activated protein kinase/Unc-51-like kinase 1 (AMPK/ULK1) signaling pathway after facial nerve injury. OBJECTIVE: To establish a facial nerve injury model in Sprague-Dawley rats and explore the role of autophagy in facial nerve regeneration and the mechanism by which the GDNF/AMPK/ULK1 signaling pathway promotes facial nerve repair after injury.  METHODS: Seventy-two Sprague-Dawley rats were randomly divided into sham group, model group and autophagy inhibitor 3-methyladenine (3-MA) group, with 24 rats in each group. Only the main trunk of the facial nerve was exposed in the sham group, while the remaining two groups were modeled for the compression injury of the facial nerve trunk. After successful modeling, the model group was given intraperitoneal injection of normal saline (15 mg/kg), and the 3-MA group was given intraperitoneal injection of 3-MA (15 mg/kg), both once daily for 7 days. The rats in each group were scored on the Simone 10-point behavioral scale at 1, 4, 7, 14, 21 and 28 days after surgery. Nissl staining was performed to observe the morphology and number of facial neuron cells at 7, 14, 21, and 28 days. The expression levels of p-AMPK, p-ULK1, Beclin1 and GDNF in the facial neuron tissues of rats were detected by western blot assay.  RESULTS AND CONCLUSION: Behavioral scoring showed that the improvement of facial paralysis symptoms in the 3-MA group was worse and later than that in the model group (P < 0.05). Nissl staining showed that the morphology and number of Nissl bodies in facial neurons in the 3-MA group recovered poorly and the number was less than that in the model group (P < 0.05). Western blot detection results showed that the expression of p-AMPK and Beclin1 in the model group was higher than that in the 3-MA group and the sham group (P < 0.05). The protein expression of p-ULK1 in the model group was lower than that in the 3-MA group and the sham group (P < 0.05). To conclude, autophagy inhibitor delays nerve repair after facial nerve injury, which may be related to down-regulation of GDNF expression, inactivation of AMPK, and phosphorylation of ULK1, thereby inhibiting neuronal autophagy levels. Figures and Tables | References | Related Articles | Metrics

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Effects of kinesio taping on the biomechanical characteristics of the lower limbs during side-step cutting You Jing, Huang Wenqi, Zheng Wei, Lu Jieming, Guo Yanhua, Gao Yuan, Xiong Zheyu 2024, 28 (27):  4383-4389.  doi: 10.12307/2024.553 Abstract ( 109 )   PDF (1251KB) ( 16 )   Save BACKGROUND: Kinesio taping has been widely used as a means of sports protection, but its role as a means to correct abnormal biomechanical changes of the lower limbs during side-step cutting remains unclear. OBJECTIVE: To analyze and compare the changes in lower limb kinematics and dynamics when the subjects complete the side-step cutting of the knee joint  under the conditions of kinesio taping, placebo taping and blank control. METHODS: Thirty-nine male college students majoring in basketball were recruited as subjects. Each subject was tested with kinesio taping, placebo taping or no taping. The mechanical correction method was used to patch the dominant knee joint of each subject. The run-up speed of 4.5-5.5 m/s was selected to complete the 45° side-step cutting motion, and the kinematics and kinetics data were collected synchronously by the three-dimensional dynamic capture system and the force measuring platform. The kinematics and kinetics parameters at the moment of initial touchdown and peak ground reaction force were selected for data analysis. SPSS 27.0 software was used for statistical analysis of the test data. RESULTS AND CONCLUSION: Kinematic indexes: compared with no taping and placebo taping, the hip abduction and knee valgus angles at the initial touchdown moment were significantly decreased when kinesio taping was used (P < 0.05); at the moment of peak lateral ground reaction force, the angles of hip abduction, knee valgus and ankle plantar flexion decreased significantly (P < 0.05), and the knee flexion angle was significantly increased (P < 0.05). Kinetic indexes: Compared with no taping, both kinesio taping and placebo taping significantly reduced hip abduction and external rotation torque, knee valgus and external rotation torque at the moment of initial touchdown (P < 0.05), and significantly reduced peak vertical ground reaction force and peak horizontal backward ground reaction force (P < 0.05); in addition, kinesio taping significantly reduced peak lateral ground reaction force compared with no taping and placebo taping (P < 0.05). These results indicate that kinesio taping of the knee joint may improve some kinematic and kinetic indexes associated with lower limb injury risk factors during the completion of the side-step cutting in basketball specialized college students to some extent, and may have a positive effect on the prevention of injury during the side-step cutting. In addition, the trends in the effects of placebo taping and kinesio taping on the knee joint are more consistent in terms of changes in some indexes, suggesting that there may be a placebo effect on the mechanism of action of kinesio taping. Figures and Tables | References | Related Articles | Metrics

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Mechanism by which exercise improves inhibitory control and drug craving in methamphetamine abstinent patients Liao Shuaixiong, Deng Kai, Bai Nan, Yang Wenliang, Wang Feng, Hao Zongji, Li Xueying 2024, 28 (27):  4390-4396.  doi: 10.12307/2024.545 Abstract ( 134 )   PDF (1365KB) ( 11 )   Save BACKGROUND: Inhibitory control and drug craving are the core elements of evaluating drug withdrawal in methamphetamine addicts, which has attracted much attention in academic circles. As we all know, in order to achieve complete abstinence from drug addiction, the key is to restore the damaged inhibition and control function of drug addicts and effectively reduce the craving for drugs. OBJECTIVE: To systematically analyze the relationship between exercise and methamphetamine abstinence inhibitory control and drug craving, to find out an effective exercise intervention scheme that can promote methamphetamine abstinence, and to further explore the internal mechanism of exercise, in order to provide theoretical support and applied reference for the future use of exercise in drug withdrawal. METHODS: CNKI, WanFang, VIP, Web of Science, and PubMed databases were searched for relevant literature using the keywords of “exercise, physical activity, methamphetamine, inhibitory function, craving, addiction” in Chinese and “sport*, exercise, methamphetamine, drug craving, executive function, addiction” in English. According to the inclusion and exclusion criteria, 86 documents were finally included for review. RESULTS AND CONCLUSION: In terms of inhibitory control in methamphetamine abstinent individuals, either acute and long-term moderate-intensity aerobic exercise or acute high-intensity interval training can significantly improve the inhibitory control capacity of methamphetamine abstinent individuals. For long-term aerobic exercise, aerobic group exercise or full-body comprehensive exercise is more effective. If the exercise format is power cycling, it is recommended to increase the frequency of exercise intervention. In terms of the drug craving intensity in methamphetamine abstinent individuals, acute moderate-intensity aerobic exercise and resistance training, as well as long-term moderate-intensity, high-intensity, or progressive load aerobic and resistance training, can effectively reduce the drug craving in methamphetamine abstinent individuals. Exercise exerts intrinsic regulatory effects on methamphetamine-mediated addiction. Exercise can influence the expression of tyrosine hydroxylase in the brain’s ventral tegmental area, thereby stimulating the expression of dopamine receptor coupling proteins and promoting dopamine synthesis in the brain’s reward regions, thereby compensating for dopamine depletion caused by methamphetamine addiction. Furthermore, exercise can also regulate protein kinase A inhibitors, affecting the protein kinase A signaling pathway mediated by dopamine D1 receptors, by inhibiting protein kinase A, thus affecting cAMP response element-binding protein and regulating methamphetamine addiction. Additionally, exercise can also, at the genetic level, affect the expression of the c-fos gene in the brain’s nucleus accumbens region, activate a subset of glutamatergic neurons in this area, generate a rewarding effect, and thus improve methamphetamine addiction. Although current research has confirmed the relationship between exercise and methamphetamine addiction and has clarified the brain mechanisms underlying the effects of exercise, whether there are other brain regulatory pathways for the effects of exercise remains to be explored through more scientifically rigorous animal or human experiments, starting from the cellular or molecular level. Figures and Tables | References | Related Articles | Metrics

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The role of mitochondrial autophagy-related receptor proteins and signaling pathways in the prevention and treatment of sarcopenia through exercise Guo Hui, Kong Jianda, Tian Chunlan 2024, 28 (27):  4397-4404.  doi: 10.12307/2024.546 Abstract ( 124 )   PDF (1433KB) ( 20 )   Save BACKGROUND: Sarcopenia is an age-related degenerative syndrome, and the relationship between mitochondrial autophagy and exercise in preventing and treating sarcopenia has been demonstrated. However, there is a lack of comprehensive reviews detailing the specific receptor proteins and signaling pathways involved in the role of exercise in sarcopenia prevention and treatment. OBJECTIVE: To comprehensively introduce the specific receptor proteins and signaling pathways related to mitochondrial autophagy and their role in the prevention and treatment of sarcopenia through exercise. METHODS: A literature search was conducted between February 1, 2023, and April 1, 2023, covering literature from database inception to April 2023. Databases included the Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), WanFang Data, and VIP. Keywords used for the search included sarcopenia, muscle wasting, aging, elderly, mitochondria, mitochondrial function, proteins, pathways, and others. After strict inclusion and exclusion criteria, 76 articles were ultimately included. RESULTS AND CONCLUSION: Sarcopenia is a disease characterized by a decline in muscle mass and function with age, and its pathogenesis involves neuro-muscular functional decline, chronic inflammation, acid-base imbalance, and mitochondrial dysfunction. Mitochondrial autophagy is an important process for clearing damaged mitochondria in cells, in which receptor proteins and signaling pathways are involved in the regulation of mitochondrial autophagy. Exercise can promote the occurrence of mitochondrial autophagy by regulating the activity of these receptor proteins and signaling pathways, thereby playing an important role in the prevention and treatment of sarcopenia. Exercise can induce mitochondrial autophagy in sarcopenia by upregulating AMPK, phosphorylating ULK1, and reducing mitochondrial energy, enhancing the expression of mitochondrial autophagy-related proteins associated with AMBRA1, and regulating the PINK1/Parkin pathway, to improve mitochondrial dysfunction caused by sarcopenia. In addition, exercise can activate the mTOR pathway to promote muscle growth and increase glucose uptake, thereby preventing and treating sarcopenia. Future studies are needed to further investigate the specific mechanisms and regulatory pathways of mitochondrial autophagy-related receptor proteins and signaling pathways in the prevention and treatment of sarcopenia by exercise, and to conduct more clinical trials in humans, thereby to promote further development in this field. Figures and Tables | References | Related Articles | Metrics

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Mechanism and potential of vitamin C supplementation in sarcopenia prevention and treatment Liu Xu, Chen Bo, Ning Ke, Chen Xiaohong 2024, 28 (27):  4405-4412.  doi: 10.12307/2024.517 Abstract ( 153 )   PDF (1482KB) ( 13 )   Save BACKGROUND: Vitamin C, as an essential nutrient, has a wide range of biological effects and a variety of biological functions related to the pathogenesis of sarcopenia. Vitamin C supplementation is expected to be a novel prevention and treatment measure for sarcopenia. OBJECTIVE: To review recent research advances in the application of vitamin C in the pathogenesis and treatment of sarcopenia, and to discuss the potential role of vitamin C in the prevention and treatment of sarcopenia and possible mechanistic pathways based on published evidence. METHODS: The first author performed a computer search of PubMed, Web of Science, CNKI and other databases for relevant studies involving vitamin C in sarcopenia. The search keywords were “vitamin C, ascorbic acid, L-ascorbic acid, ascorbate, antioxidants, oxidative stress, sarcopenia, muscular atrophy, muscle weakness, muscle development, skeletal muscle regenerate, muscles, skeletal muscle” in English and Chinese, respectively. The search period was from each database inception to July 2023. After screening, 85 articles were included for further review. RESULTS AND CONCLUSION: Ensuring adequate dietary vitamin C intake or maintaining normal circulating levels of vitamin C will help to reduce age-related muscle loss and decrease the prevalence of sarcopenia. In addition, vitamin C supplementation is also useful for improving skeletal muscle mass, strength and physical function with potential synergistic effects in exercise strategies for sarcopenia. The effects of vitamin C on sarcopenia may be via the following biological mechanisms: vitamin C limits the activation of the ubiquitin-proteasome pathway mainly by inhibiting oxidative stress and inflammatory responses in skeletal muscle, thus positively regulating protein metabolic homeostasis, and may enhance mitochondrial antioxidant defenses through its antioxidant effects to maintain healthy mitochondrial function. In addition, vitamin C affects myoblast proliferation, differentiation and myotube size, mainly by increasing the expression of myogenic regulatory factors and activating protein synthesis signaling pathways, which contribute to the promotion of muscle development as well as the repair and regeneration of damaged muscle tissue. The positive effects of vitamin C in sarcopenia need to be studied in large samples and with optimized designs for important influencing factors, such as the choice of supplementation dose and duration, the design of exercise prescription when vitamin C is combined with an exercise intervention, and the assessment of the redox status of the individual. It is recommended that future studies should be conducted in older patients with sarcopenia (< 50 μmol/L) with suboptimal vitamin C status to investigate the efficacy of a combined intervention of long-term supplementation with 1 000 mg/d vitamin C (for 6 months or longer) with at least two or more types of multi-type combined exercise, with supplementation timed to take place at 1 hour after the end of the exercise, and with monitoring of markers of oxidative damage produced during the exercise such as malondialdehyde or protein hydroxyl levels were monitored. In conclusion, the optimal dose and timing of vitamin C supplementation for older adults with sarcopenia needs to be explored more, while the appropriate design of exercise prescriptions (especially the type and intensity of exercise) needs to be further determined. Figures and Tables | References | Related Articles | Metrics

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Mitochondrial dysfunction in Parkinson’s disease and the potential ameliorative effects of exercise Kong Jianda, Xie Yingao, Ma Wen, Liu Youhan, Wang Qinglu 2024, 28 (27):  4413-4420.  doi: 10.12307/2024.558 Abstract ( 129 )   PDF (1270KB) ( 18 )   Save BACKGROUND: Parkinson’s disease is a neurodegenerative disease, and its pathogenesis involves mitochondrial dysfunction. Exercise has a potential ameliorative effect on mitochondrial dysfunction related to Parkinson’s disease, but there is no comprehensive review and in-depth analysis in this field. OBJECTIVE: To comprehensively review and analyze mitochondrial dysfunction related to Parkinson’s disease and the potential ameliorative effect of exercise, thereby providing new ideas and methods for the treatment and prevention of Parkinson’s disease. METHODS: We searched the Web of Science, PubMed, CNKI, WanFang, and VIP databases with the keywords of “mitochondria, mitochondrial function, mitochondrial disease, mitochondrial dysfunction, Parkinson’s disease, Parkinson, exercise, physical activity, exercise training, exercise therapy, mitochondrial impairment, mitochondrial damage, mitochondrial defects” in Chinese and “mitochondria, Parkinson’s disease, Parkinson disease, physical exercise, exercise, physical activity, mitochondrial dysfunction, mitochondrial damage, mitochondrial impairment, athletic training, exercise training, rehabilitation” in English. A total of 89 articles were included for review and analysis. RESLUTS AND CONCLUSION: Parkinson’s disease is closely related to mitochondrial dysfunction, including mitochondrial biogenesis inhibition, reduced autophagy, increased apoptosis, abnormal elevation of Ca2+ concentration, and increased oxidative stress in Parkinson’s disease patients. Exercise has a positive effect on mitochondrial dysfunction related to Parkinson’s disease, by promoting mitochondrial biogenesisand autophagy, regulating mitochondrial morphology, altering the plasticity of the mitochondrial respiratory chain, and reducing oxidative stress, thus helping to improve the development and progression of Parkinson’s disease. However, the detailed mechanism between mitochondrial dysfunction and the ameliorative effect of exercise is still not fully understood, and future clinical studies can be conducted to validate the results of animal models and gain insights into the benefits and mechanisms of exercise in patients with Parkinson’s disease. Figures and Tables | References | Related Articles | Metrics

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Proprioceptive training after anterior cruciate ligament reconstruction: improving joint stability and motor balance ability Ye Yuntian, Chen Jixin, Liu Aifeng 2024, 28 (27):  4421-4428.  doi: 10.12307/2024.577 Abstract ( 107 )   PDF (918KB) ( 32 )   Save BACKGROUND: Anterior cruciate ligament rupture is one of the injuries that seriously affect life and sports performance, and the anterior cruciate ligament as a stabilizing structure is irreplaceable in maintaining sports performance. In view of its severe injury manifestations, the current treatment for anterior cruciate ligament rupture is a surgery for anterior cruciate ligament reconstruction. Since an anterior cruciate ligament injury can cause loss of mechanoreceptors, which in turn causes a reduction in proprioception, it is a great problem for patients to recover their motor performance. OBJECTIVE: To summarize the effects of proprioceptive training on clinical outcomes after anterior cruciate ligament reconstruction and to explore the underlying mechanisms, thereby providing more references for clinical prevention and treatment. METHODS: A computerized search of PubMed, CNKI, WanFang Data, and VIP databases was conducted for literature (from January 2013 to March 2023) related to proprioceptive training after anterior cruciate ligament reconstruction that improves joint stability and motor balance ability. A total of 108 articles were finally included for review. RESULTS AND CONCLUSION: Proprioceptive training can effectively improve the proprioceptive functions of patients, such as positional sense and kinesthetic sense after anterior cruciate ligament reconstruction, and improve joint stability, postural control and motor ability. The proprioceptive training improves the proprioceptive function through three mechanisms: stimulation of periprosthetic receptors around the knee joint, activation of spinal reflex stimulation, reinforcement of motor control in the brain, and enhancement of cognitive processing. The proprioceptive training may improve proprioceptive functions by activating the potential mechanisms of growth associated protein-43 activity, Piezo2 mechanotransducer, and NT-3/TrkC signaling pathway. Hydrotherapy is the mainstay in the early stages, while neuromuscular training, individual strength training and visual feedback training are prioritized in the middle and late stages. There exists an as-yet-unsegmented reconstructive surgery graft, sex, and a lack of devices or proprioceptive training methods based on the idea of combining multiple sensory stimuli. Figures and Tables | References | Related Articles | Metrics