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    18 December 2024, Volume 28 Issue 35 Previous Issue    Next Issue
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    Effects of treadmill exercise on metabolism and chronic neuroinflammation in type 1 diabetes mice of different sexes
    Xie Yanli, Wei Siang, Zhang Guodong
    2024, 28 (35):  5577-5583.  doi: 10.12307/2024.804
    Abstract ( 101 )   PDF (2101KB) ( 23 )   Save
    BACKGROUND: Exercise has been widely recognized in the prevention and treatment of diabetes. Aerobic exercise has become an important part of the treatment of type 1 diabetes. However, the effect of treadmill exercise on the metabolism and chronic neuroinflammation of type 1 diabetes in different sexes needs further discussion.
    OBJECTIVE: To study the effects of treadmill exercise on metabolism and chronic neuroinflammation in type 1 diabetes mice of different sexes.
    METHODS: Forty C57BL/6 mice were divided into male group and female group, with 20 mice in each group. Then, a diabetes model was established by continuous injection of streptozotocin at 80 mg/kg for 3 days. Ten rats from each group were randomly selected to perform 6-week treadmill exercise as the diabetes+exercise group and another 10 rats from each group were selected as the diabetes group. Serum sex hormones, liver tissue oxidative stress, brain tissue inflammatory factors, and liver pathology were detected, and Morris water maze was performed for the observation of behavioral changes in mice.
    RESULTS AND CONCLUSION: Compared with the diabetes group, the diabetes+exercise group delayed the rise of blood sugar in type 1 diabetes mice (P < 0.05) and showed a significant reduction in serum follicle-stimulating hormone, luteinizing hormone, liver superoxide dismutase, malondialdehyde, brain tumor necrosis factor α, interleukin-6 and interleukin-1β  levels (P < 0.01), while serum estradiol, progesterone, estrogen, and liver glutathione peroxidase protein levels were significantly increased (P < 0.01, P < 0.05). Compared with male type 1 diabetes mice, female type 1 diabetes mice had significantly higher estradiol levels and lower luteinizing hormone levels (P < 0.05). Compared with the male diabetes+exercise group, the female diabetes+exercise group had lower liver glutathione peroxidase levels (P < 0.05). Compared with type 1 diabetes mice, the escape latency of exercise training mice was shorter (P < 0.01). In male mice, exercises significantly increased the time and platform crossing times of type 1 diabetes mice in the target quadrant (P < 0.01 or P < 0.05), while in female mice, exercises significantly increased the time of type 1 diabetes mice in the target quadrant (P < 0.05). Correlation analysis results showed that the levels of follicle-stimulating hormone, luteinizing hormone, progesterone, superoxide dismutase, malondialdehyde, tumor necrosis factor α, and interleukin-6 were positively correlated with the level of interleukin-1β (P < 0.05 or P < 0.01), whereas the levels of estradiol and progesterone were negatively correlated with the levels of superoxide dismutase, malondialdehyde, tumor necrosis factor α, interleukin-6 and interleukin-1β (P < 0.05 or P < 0.01). Overall, there are sex differences in the effects of treadmill exercise on metabolic indicators and chronic neuroinflammatory regulation in diabetes mice. Sex hormones are an important variable of treadmill exercise in the metabolic, inflammatory and cognitive responses in diabetes mice.
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    Effect of Tiaodu Tongmai acupuncture therapy on rheumatoid arthritis at different ages by generalized estimating equation
    Zhang Xiurong, Cui Xinmei, Zhao Haiyan, Dai Jin, Fu Jiaxin, Wang Bo
    2024, 28 (35):  5584-5590.  doi: 10.12307/2024.807
    Abstract ( 102 )   PDF (1199KB) ( 17 )   Save
    BACKGROUND: Rheumatoid arthritis is a chronic autoimmune disease characterized by joint pain, swelling, and dysfunction. Acupuncture, as a traditional medical treatment, has proved its effectiveness and safety in many diseases. However, the efficacy of acupuncture in the treatment of rheumatoid arthritis remains controversial. Therefore, the purpose of this study is to evaluate and explore the effect of Tiaodu Tongmai acupuncture in the treatment of preclinical rheumatoid arthritis of different ages through the generalized estimating equation, and to provide a basis for the application of acupuncture in rheumatoid arthritis.
    OBJECTIVE: To investigate the effect of Tiaodu Tongmai acupuncture therapy on preclinical rheumatoid arthritis (pre-RA) patients at different ages based on generalized estimating equation. 
    METHODS: A total of 123 patients with preclinical rheumatoid arthritis treated from January to September 2023 were selected as the study objects and divided into study group (n=64) and control group (n=59) according to different treatment methods. The study group was given Tiaodu Tongmai acupuncture treatment, and the control group was given acetaminophen tablets. The baseline balance was adjusted by propensity score matching method. The clinical efficacy and cytokine levels before and after treatment between the two groups were compared. The generalized estimating equation model was established to evaluate the efficacy of Tiaodu Tongmai acupuncture therapy on preclinical rheumatoid arthritis patients at different ages.
    RESULTS AND CONCLUSION: (1) After 0 days of treatment, there were significant differences in joint pain and C-reactive protein expression between study and control groups (P < 0.05). After 4 weeks of treatment, there were significant differences in visual analogue scale scores, joint pain, C-reactive protein and erythrocyte sedimentation rate between the two groups (P < 0.05). After 8 weeks of treatment, there were significant differences in visual analogue scale scores, C-reactive protein and erythrocyte sedimentation rate between the two groups (P < 0.05). After 12 weeks of treatment, there were significant differences in visual analogue scale scores, C-reactive protein and erythrocyte sedimentation rate between the two groups (P < 0.05). (2) The total effective rate of the study group was 93.75%, while that of the control group was 79.17%. The clinical efficacy of the study group was significantly better than that of the control group (P < 0.05). (3) There were significant differences in interleukin-6, interferon-γ, macrophage migration inhibitory factor, rheumatoid factor IgA, rheumatoid factor IgM, metallomatrix proteinase 3, metallomatrix proteinase 9, and anti-cyclic citrulline antibody in the study group before and after treatment (P < 0.05). The levels of interleukin-6, interferon-γ, rheumatoid factor IgA, rheumatoid factor IgM, metallomatrix proteinase 3, metallomatrix proteinase 9, and anti-cyclic citrulline antibody in the control group after treatment were significantly different from those before treatment (P < 0.05). There were significant differences in interleukin-6, interferon-γ, macrophage migration inhibitory factor, rheumatoid factor IgA, rheumatoid factor IgM, metallomatrix proteinase 3, and anti-cyclic citrulline antibody between the two groups after treatment (P < 0.05). (4) After 12 weeks of treatment, the comprehensive efficacy of patients of all ages in the study group was better than that of the control group (P < 0.05). After 8 weeks of treatment, the comprehensive efficacy of patients aged 23-35, 36-50, and 51-60 years old in the study group was better than that of the control group (P < 0.05), and the comprehensive efficacy of patients aged 18-22 years old was comparable between the two groups. After 4 weeks of treatment, the comprehensive efficacy of patients aged 36-50 and 51-60 years old in the study group was better than that of the control group (P < 0.05), and the comprehensive efficacy was comparable between the two groups of patients aged 18-22 and 23-35 years. Overall, Tiaodu Tongmai acupuncture therapy has advantages in treating preclinical rheumatoid arthritis patients aged 36-50 and 51-60 years.
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    Key biomarkers for the diagnosis of intervertebral disc degeneration associated with oxidative stress: identification based on bioinformatics and machine learning
    Lan Yao, Chen Liuyang, Song Wenhui
    2024, 28 (35):  5591-5597.  doi: 10.12307/2024.828
    Abstract ( 90 )   PDF (1902KB) ( 27 )   Save
    BACKGROUND: Oxidative stress is closely associated with the occurrence and progression of intervertebral disc degeneration, but its underlying mechanisms and effective treatment methods remain unclear.
    OBJECTIVE: To identify key genes associated with intervertebral disc degeneration accompanied by oxidative stress based on bioinformatics and three machine learning algorithms, as well as to conduct an immune infiltration analysis, followed by experimental validation.
    METHODS: Gene expression profiles related to intervertebral disc degeneration were obtained from the GEO database and oxidative stress-related genes obtained from the GeneCards database. Differential analysis and weighted gene co-expression networks analysis were performed on the intervertebral disc degeneration dataset. The intersection of the two analyses and the intersection with the oxidative stress-related genes were taken to obtain candidate hub genes. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses on the candidate hub genes were performed. Machine learning algorithms (LASSO regression, SVM-RFE, and random forest) were used to select the optimal feature genes and perform the receiver operator characteristic curve validation. Simultaneously, immune infiltration analysis was conducted. Nucleus pulposus samples from patients with cervical spondylosis who were treated at the Second Hospital of Shanxi Medical University from July to November 2023 were enrolled as the intervertebral disc degeneration group and nucleus pulposus samples from patients with cervical spinal cord injury as the control group. The relative expression of feature genes in the degenerated intervertebral disc was validated using qPCR method.
    RESULTS AND CONCLUSION: After differential gene analysis, 424 differentially expressed genes were obtained. Weighted gene co-expression networks analysis yielded 5 087 genes, and 1 399 oxidative stress genes were identified, leading to the identification of 23 candidate hub genes. Gene ontology analysis revealed that these candidate hub genes are primarily involved in bacterial defense response, molecular response to bacteria, and other biological processes. In terms of cellular component, they are associated with secretion granule lumen and cytoplasmic vesicle lumen, among others. As for molecular function, they are related to endopeptidase activity and compound binding, including sulfur compounds. Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that these candidate hub genes are associated with neutrophil extracellular trap formation and the renin-angiotensin system pathway, among other signaling pathways. By applying three machine learning algorithms and conducting the receiver operator characteristic curve validation, two key genes, HSPA6 and PKD1, were determined. Immune infiltration analysis revealed a strong correlation between HSPA6 and activated dendritic cells (r=0.88, P < 0.001) as well as activated CD4+ T cells (r=-0.72, P < 0.01). Similarly, PKD1 showed close associations with effector memory CD8+ T cells (r=0.55, P < 0.05) and activated dendritic cells (r=-0.56, P < 0.05). qPCR experimental results indicated that the expression level of HSPA6 was lower in the intervertebral disc degeneration group compared with the control group (P < 0.000 1), while the expression level of PKD1 was higher in the intervertebral disc degeneration group (P < 0.000 1). These findings suggest that HSPA6 and PKD1 can serve as biomarkers for intervertebral disc degeneration accompanied by oxidative stress. Interventions targeting HSPA6 and PKD1 may hold promise for improving intervertebral disc degeneration.
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    Luzhongjiangu decoction for the treatment of femoral head necrosis in rats: changes in intestinal flora and serum hormones
    Jing Tianyuan, Wang Ping, Wang Yi, Hu Yanan, Liu Shanxin, Sun Guodong, Du Haitao
    2024, 28 (35):  5598-5605.  doi: 10.12307/2024.550
    Abstract ( 102 )   PDF (3187KB) ( 22 )   Save
    BACKGROUND: Osteonecrosis of the femoral head is a common and disabling disease, which is mainly characterized by microcirculation disorders and bone cell metabolism disorders. Luzhongjiangu decoction was developed by Shandong Academy of Chinese Medicine and used in the form of soup in the clinic, which has good efficacy in the treatment of osteonecrosis of the femoral head. However, its mechanism of action has not been clarified. 
    OBJECTIVE: To study the effect mechanism of Luzhongjiangu decoction on intestinal flora in rats with osteonecrosis of the femoral head based on 16S rDNA sequencing technique.
    METHODS: The model of osteonecrosis of the femoral head was established in Wistar rats by intragastric administration of retinoic acid. The therapeutic effect of Luzhongjiangu decoction was evaluated by serum hormone, bone histopathology and serum hormone levels. 16s rDNA sequencing technique was used to detect the intestinal flora of rats in the blank control group, model group and middle-dose Luzhongjiangu decoction group. The corresponding library was constructed and OTU clustering and microbial community diversity and abundance analysis were carried out to determine the composition of intestinal flora and the changes of species and diversity among groups.
    RESULTS AND CONCLUSION: Luzhongjiangu decoction could significantly increase the expression of osteocalcin, osteopontin and other osteogenic related factors, alleviate the destruction of bone trabeculae, increase bone mineral density, and had a significant therapeutic effect on osteonecrosis of the femoral head, of which the middle dose group showed the most significant effect. The results of intestinal flora sequencing showed that Luzhongjiangu decoction improved the flora disorder of rats with osteonecrosis of the femoral head to some extent, and screened out different colonies such as Bacillus, Desulfurizans, Desulfurization, Isobacteria, Bifidobacterium and so on; it could up-regulate the abundance of beneficial bacteria such as Bifidobacterium, down-regulate the abundance of harmful bacteria such as Desulfovibrio, and improve the structure of intestinal flora. Functional prediction analysis indicated that Luzhongjiangu decoction could mainly affect amino acid metabolism and energy metabolism. Correlation analysis showed that the differential bacteria of Bifidobacterium and Intestinimonas in the middle dose group of Luzhongjiangu decoction were positively correlated with vitamin D3, estradiol and calcitonin, and negatively correlated with prostaglandin E2. In the model group, Escherichia-Shigella, Desulfovibrio, Globicatella and Streptococcus were positively correlated with prostaglandin E2 and negatively correlated with vitamin D3, estradiol and calcitonin. To conclude, Luzhongjiangu decoction may play a role in the treatment of osteonecrosis of the femoral head by regulating the structure of intestinal flora, up-regulating the abundance of beneficial bacteria and affecting the secretion of vitamin D3, estradiol, calcitonin and prostaglandin E2.
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    Osteoclast differentiation induced by total immune complex in serum of patients with rheumatoid arthritis leads to osteoporosis and its factors analysis
    Zhou Erye, Zeng Keqin, Wu Jian, Ren Tian, He Michun
    2024, 28 (35):  5606-5611.  doi: 10.12307/2024.574
    Abstract ( 103 )   PDF (979KB) ( 18 )   Save
    BACKGROUND: The incidence of osteoporosis significantly increases in the patients with rheumatoid arthritis, and it remains unclear whether the presence of a large number of immune complexes in serum promotes the onset and development of osteoporosis. 
    OBJECTIVE: To investigate the correlation between serum immune complexes and osteoporosis in patients with rheumatoid arthritis. 
    METHODS: (1) Clinical trial: Serum and clinical data of 50 healthy controls and 50 patients with untreated rheumatoid arthritis were collected and retrospectively analyzed. Total immune complex level in serum was compared between two groups. Correlation of serum total immune complexes with bone mineral density, bone turnover markers and other clinical indicators in patients with rheumatoid arthritis was analyzed. (2) Cell experiment: Peripheral blood mononuclear cells from healthy volunteers were isolated and cultured, and divided into four groups: rheumatoid arthritis group was added with total immune complex suspension from rheumatoid arthritis patients; normal control group was added with total immune complex suspension from healthy medical checkups; positive control group was added with α-MEM medium containing macrophage colony-stimulating factor and receptor activator of nuclear factor-kappa B ligand, and negative control group was added with α-MEM medium. Tartrate-resistant acid phosphatase staining was performed to observe the formation of osteoclasts after 7 days of treatment, 
    RESULTS AND CONCLUSION: (1) Clinical trial: The total immune complex and serum alkaline phosphatase levels in patients with rheumatoid arthritis were significantly higher than those in health controls (P < 0.01, P < 0.05). Pearson correlation analysis showed that serum total immune complex level was positively correlated with erythrocyte sedimentation rate (r=0.330, P=0.019), serum alkaline phosphatase (r=0.545, P=0.001), anti-cyclic citrullinate peptide (r=0.377, P=0.007) and c-terminal telopeptide of type I collagen (r=0.738, P=0.001), and negatively correlated with lumbar bone mineral density (r=-0.595, P=0.001) in patients with rheumatoid arthritis. Binary Logistic regression analysis showed that age [odds ratio (OR)=1.086, 95% confidence interval (CI) (1.022,1.154), P=0.008], anti-cyclic citrullinate peptide [OR=1.002, 95% CI (0.999,1.005), P=0.035], c-terminal telopeptide of type I collagen [OR=0.141, 95% CI (0.015, 8.900), P=0.008] and serum total immune complexes [OR=2.895, 95% CI (1.228, 6.827), P=0.001] were the influencing factors for abnormal bone mass (reduced bone mass or osteoporosis) in patients with rheumatoid arthritis. (2) Cell experiment: Tartrate-resistant acid phosphatase positive osteoclasts were observed in the positive control group, normal control group and rheumatoid arthritis group, and there were more osteoclasts in the rheumatoid arthritis group than in the normal control group (P < 0.01). To conclude, serum total immune complexes can be used as a potential serologic predictor of rheumatoid arthritis complicated with osteoporosis, and removing immune complexes in serum or interfering with the binding of immune complexes to their receptors may be an effective means for the prevention and treatment of rheumatoid arthritis complicated with osteoporosis.
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    Neuroprotective mechanism of nicotine in a mouse model of rotenone-induced Parkinson’s disease
    Zhang Xinyue, Zhu Liuhui, He Yu, Guan Ying, Zhu Zhouhai, Ren Hui, Yang Xinglong
    2024, 28 (35):  5612-5617.  doi: 10.12307/2024.821
    Abstract ( 129 )   PDF (1982KB) ( 107 )   Save
    BACKGROUND: Studies have found that nicotine can activate the dopamine system, slowing the progression of Parkinson’s disease, but the specific mechanism is still unclear. Research on the neuroprotective mechanism of nicotine in animal models of Parkinson’s disease is lacking.
    OBJECTIVE: To investigate the neuroprotective effect of nicotine on rotenone-induced Parkinson’s disease in mice.
    METHODS: Twenty-eight C57BL/6 mice were randomly divided into vehicle group, rotenone group, autophagy agonist group and nicotine group, with seven mice in each group. Dopaminergic nerve damage was induced by rotenone in C57BL/6 mice, and the autophagy agonist (rapamycin) or nicotine was given before modeling. The spatial exploration function of the mice was observed by open field test. Western blot and Q-PCR were used to detect the expression of α-synuclein, autophagy related factors Beclin-1 and P62, and apoptosis-related factors Bax, Bcl-2 and Cleaved-caspase3 in the nigra of each group. The deposition of mitochondria, autophagosomes and lipofuscin in nigra cells were observed by transmission electron microscopy. The survival of neurons was observed by Nissl staining. The expression of tyrosine hydroxylase was observed by immunofluorescence and immunohistochemical staining.
    RESULTS AND CONCLUSION: The open field test showed that the distance, average speed and time of movement were reduced in the rotenone group compared with the solvent group. Compared with the rotenone group, the exercise distance, average speed and exercise time of mice were increased in the nicotine group and autophagy agonist group (P < 0.05). The results of immunofluorescence and immunohistochemistry showed that the mean fluorescence intensity and mean absorbance value of tyrosine hydroxylase in the rotenone group decreased compared with that in the solvent group. Compared with the rotenone group, the mean fluorescence intensity and mean absorbance value of tyrosine hydroxylase were increased in the nicotine group and autophagy agonist group. Western blot and Q-PCR results showed that compared with the solvent group, the expressions of α-synuclein and P62 in the rotenone group were increased, while Beclin-1 expression was decreased (P < 0.05); compared with the rotenone group, the expression of α-synuclein and P62 decreased in the nicotine group and autophagy agonist group, and the expression of Beclin-1 increased (P < 0.05). Compared with the solvent group, the expressions of Bax and Cleaved caspase3 were increased and Bcl-2 expression was decreased in the rotenone group (P < 0.05); compared with the rothenone group, the expressions of Bax and Cleaved-caspase3 were decreased and the expression of Bcl-2 was increased in the nicotine and autophagy agonist groups (P < 0.05). To conclude, nicotine may have a dopaminergic neuroprotective effect on rotenone-induced Parkinson’s disease mouse models by improving autophagy dysfunction and reducing apoptosis.
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    Effects of moderate-intensity continuous training and high-intensity interval training on obesity-related muscle atrophy in mice
    Hong Weihao, Tian Hang, Luan Yisheng, Ma Yixuan, Xiong Yingzhe, Zhang Bing
    2024, 28 (35):  5618-5623.  doi: 10.12307/2024.576
    Abstract ( 115 )   PDF (1558KB) ( 27 )   Save
    BACKGROUND: Obesity has become a global health issue, often accompanied by complications including obesity-related muscle atrophy. While exercise has been reported to improve various obesity-related diseases, there is limited research focusing on exercise modes. 
    OBJECTIVE: To compare the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on obesity-related muscle atrophy in mice under the premise of the same exercise distance, providing a scientific basis for exercise interventions for obesity-related muscle atrophy. 
    METHODS: Seventy-two male C57BL/6 mice were divided into six groups (n=12 per group): standard chow diet, standard chow diet+MICT, standard chow diet+HIIT, high-fat diet, high-fat diet+MICT, and high-fat diet+HIIT. The study evaluated the effects of 8-week treadmill training with different exercise modes on long-term high-fat diet-induced muscle atrophy by detecting muscle mass, muscle index, muscle fiber cross-sectional area, muscle lipid deposition, and the expression of muscle atrophy marker genes Murf-1 and Atrogin-1 in the gastrocnemius muscle of mice exposed to long-term high-fat diet. 
    RESULTS AND CONCLUSION: Compared to the high-fat diet group, both MICT and HIIT improved the decrease in gastrocnemius muscle index (MICT+18.8% vs. HIIT+17.6%, not significant between the two modes), muscle fiber atrophy (MICT+15.5% vs. HIIT+13.7%, not significant between the two modes), and muscle lipid deposition (MICT-19.8% vs. HIIT-17.1%, not significant between the two modes). At the gene level, compared with the high-fat diet group, both MICT and HIIT could significantly down-regulate the expression of Murf-1 (MICT-62.4% vs. HIIT-52.6%, the down-regulation caused by MICT was significantly greater than that by HIIT; P < 0.01) and Atrogin-1 (MICT-43.3% vs. HIIT-29.8%, the down-regulation caused by MICT was significantly greater than that by HIIT; P < 0.01). Based on exercise mode comfort and genetic evidence, MICT mode might be more suitable for exercise interventions in obesity-related muscle atrophy.
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    Neferine inhibits interleukin-1beta-induced chondrocyte apoptosis
    Zhou Guanjin, Li Yanan, Li Tao
    2024, 28 (35):  5624-5629.  doi: 10.12307/2024.827
    Abstract ( 111 )   PDF (1364KB) ( 18 )   Save
    BACKGROUND: Apoptosis is involved in the formation of degenerative joint diseases. Therefore, anti-chondrocyte apoptosis may be an effective way to treat osteoarthritis. Neferine has a wide range of pharmacological activities including anti-inflammatory, anti-tumor and anti-apoptotic activities, and its effect on chondrocyte apoptosis is not clear.
    OBJECTIVE: To investigate the effect of neferine on chondrocyte apoptosis induced by interleukin-1β and elucidate its possible mechanism. 
    METHODS: (1) The rat chondrocytes at logarithmical stage were taken and intervened in five groups. The control group was cultured routinely. The model group was routinely cultured for 24 hours after treatment with interleukin-1β for 2 hours. The low-, medium-, and high-dose groups were treated with interleukin-1β for 2 hours and then cultured with 5, 10, and 20 μmol/L neferine for 24 hours, respectively. At the end of culture, cell apoptosis, chondroglycoprotein 39 and type II collagen levels in cell supernatants, mRNA and protein expression of apoptosis-related proteins, and mRNA and protein expression of proteins related to the protein kinase R-like endoplasmic reticulum kinase (PERK)/activating transcription factor 4 (ATF4) signaling pathway were detected. (2) Rat chondrocytes at logarithmic growth period were taken and divided into four groups: control group and model group were treated with the same intervention as above, drug group was treated with interleukin-1β for 2 hours and then cultured with 20 μmol/L neferine for 24 hours, and activator group was treated with interleukin-1β for 2 hours and then cultured with 20 μmol/L neferine and CCT020312, an activator of PERK/ATF4 signaling pathway, for 24 hours. At the end of culture, cell proliferation was detected by cell counting kit-8 assay, apoptosis was detected by flow cytometry, and mRNA and protein expressions of apoptosis-related proteins and PERK/ATF4 signaling pathway-related proteins were detected. 
    RESULTS AND CONCLUSION: (1) Compared with the control group, the model group showed increased apoptosis (P < 0.05), decreased proliferative activity (P < 0.05), increased level of chondroglycoprotein 39 (P < 0.05), decreased level of type II collagen (P < 0.05), decreased mRNA and protein expression of Bcl-2 protein (P < 0.05), increased mRNA and protein expression of Bax protein, increased caspase-3 mRNA expression, increased Cleaved-caspase-3 protein expression (P < 0.05), increased mRNA expression of PERK, ATF4, and C/EBP homologous protein (P < 0.05), and increased protein expression of p-PERK, ATF4, and C/EBP homologous protein (P < 0.05). Compared with the model group, neferine reversed the above effects of interleukin-1β on chondrocytes in a concentration-dependent manner. (2) Compared with the drug group, the activator group showed increased apoptosis (P < 0.05), decreased proliferative activity (P < 0.05), elevated mRNA expression of caspase-3, ATF4, and C/EBP homologous protein (P < 0.05), and elevated protein expression of Cleaved-caspase-3, ATF4, and C/EBP homologous protein (P < 0.05). (3) To conclude, neferine inhibits interleukin-1β-induced chondrocyte apoptosis and enhances cell proliferation activity, and the mechanism of action may be related to blocking the PERK/ATF4 signaling pathway in the endoplasmic reticulum.
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    The construction of rat intestinal smooth muscle collagen band and evaluation of periodic stretching culture in vitro
    Yu Pengxin, Han Yuqiu, Guo Lina, Wang Xiuli
    2024, 28 (35):  5630-5635.  doi: 10.12307/2024.806
    Abstract ( 111 )   PDF (1920KB) ( 14 )   Save
    BACKGROUND: The in vitro construction of intestinal smooth muscle layer, as an important component of the intestinal wall, has attracted much attention in the bionic construction of tissue-engineered intestinal canal. 
    OBJECTIVE: To explore the effects of cyclic mechanical stretching on the growth activity of intestinal smooth muscle cells and the expression of functional genes within collagen strips.
    METHODS: The collagen band culture system of intestinal smooth muscle cells was constructed using a self-designed collagen strip stretching culture device with self-made rat tail collagen as a scaffold and primary rat intestinal smooth muscle cells as seed cells. EthD-1/Calcein-AM cell activity staining, magenta staining, cytoskeleton-Ki67 immunofluorescence staining were used to observe the growth activity and proliferation of the cells, and quantitative RT-PCR was used to detect the expression of desmin, α-sma, and vimentin functional genes.
    RESULTS AND CONCLUSION: The collagen band culture system of intestinal smooth muscle cells was successfully constructed, and intestinal smooth muscle cells in the band had good cell activity. The number of Ki67 positive cells increased and desmin, α-sma and vimentin were significantly overexpressed under cyclic stretching and dynamic culture conditions (P < 0.001). To conclude, mechanical stimulation is beneficial to maintain the growth phenotype of smooth muscle cells and promote their functional differentiation during three-dimensional culture in vitro. 
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    Puerarin inhibits the differentiation of Raw264.7 cells into osteoclasts through the Notch signaling pathway
    Liu Chunli, Yan Yujuan, Mo Liwen, Wu Zhijie, Zhang Li
    2024, 28 (35):  5636-5641.  doi: 10.12307/2024.595
    Abstract ( 95 )   PDF (1383KB) ( 15 )   Save
    BACKGROUND: Previous studies have shown that puerarin can inhibit the differentiation of osteoclasts, and the expression of Notch signaling pathway-related proteins such as Notch1, HES1, and Jagged1 is decreased. However, the specific mechanism of the Notch1 signaling pathway for the inhibition of osteoclast differentiation by puerarin is not clear.
    OBJECTIVE: To explore the effect of Notch signaling pathway on puerarin inhibiting the differentiation of mouse macrophage Raw264.7 into osteoclasts.
    METHODS: Raw264.7 cells were divided into seven groups for intervention culture. Blank control group was cultured in high-sugar DMEM medium; the osteoclast induction group was cultured in osteoclast induction medium; the puerarin intervention group was cultured with 50 μmol/L puerarin at the same time of osteoclast induction; Notch1 siRNA control group, Notch1 siRNA group, Notch1 overexpression control group and Notch1 overexpression group were transfected with Notch1 siRNA control sequence, Notch1 siRNA, Notch1 overexpression control plasmid and Notch1 overexpression plasmid, respectively, and then cultured with osteoclast induction medium and puerarin. The number and size of osteoclasts were observed by tartrate-resistant acid phosphatase staining, the skeleton formation of osteoclasts was observed by F-actin staining, and the gene expression level of osteoclast formation markers was detected by RT-PCR.
    RESULTS AND CONCLUSION: Tartrate-resistant acid phosphatase staining results showed that puerarin intervention could inhibit the generation of osteoclasts, Notch1 silencing could further reduce the number of osteoclasts, while the number of osteoclasts in the osteoclast-induced group increased significantly after Notch1 overexpression. The results of F-actin showed that Raw264.7 cells could form a well-defined F-actin ring after osteoclast induction. Puerarin intervention would inhibit the formation of cytoskeleton, and Notch1 silencing could aggravate the inhibitory effect of cytoskeleton formation, while Notch1 overexpression could alleviate this inhibitory effect of puerarin. RT-PCR results showed that puerarin could inhibit the mRNA expression levels of tartrate-resistant acid phosphatase, Cathepsin K and c-Fos, the expression of the above-mentioned three factors decreased significantly after Notch1 gene silencing, and Notch1 overexpression could upregulate the expression of these factors. These finding indicate that puerarin inhibits the differentiation of Raw264.7 cells into osteoclasts through the Notch signaling pathway.
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    Constructing an animal model of temporomandibular joint osteoarthritis in Sprague-Dawley rats by digital technology
    Liu Penghui, Wu Fan, Wang Zejie, Wu Gaoyi, Zhou Libo
    2024, 28 (35):  5642-5648.  doi: 10.12307/2024.573
    Abstract ( 115 )   PDF (1859KB) ( 21 )   Save
    BACKGROUND: Temporomandibular joint osteoarthritis is a common oral disease with a high incidence. However, temporomandibular joint osteoarthritis is not easy to be detected in the early stage, and it is difficult to obtain clinical pathological specimens, so it is difficult to carry out related research. The application of digital 3D printing technology to animal models of Temporomandibular joint osteoarthritis increases the consistency of the animal models, thus promoting the study of temporomandibular joint osteoarthritis.
    OBJECTIVE: To establish a standardized animal model of temporomandibular joint osteoarthritis using novel digital technology. 
    METHODS:  According to the different modeling methods of unilateral anterior crossbite, 30 female Sprague-Dawley rats were randomly divided into traditional model group, digital model group, and control group (n=10 per group). Cartilage specimens of the condyles were collected at 4 and 8 weeks after modeling. The apparent morphology was observed by stereoscopic microscope. The pathological morphology was observed by hematoxylin-eosin staining and Safranin O/fast green staining. Changes in the expression of interleukin-1β and tumor necrosis factor-α were observed by ELISA, and changes in the expression of aggrecan, type II collagen and matrix metalloproteinase-13 were observed by immunohistochemical staining.
    RESULTS AND CONCLUSION: Different degrees of degeneration were observed in the digital and traditional model groups. The body mass of rats in both the model groups decreased during the 1st week after intervention and subsequently demonstrated growth trend and were significantly lower than that in the control group. The results of stereoscopic microscope showed that at 4 and 8 weeks after modeling, the deformation and defect degree of the digital model group was significantly higher than that of the traditional model group. At these two time points, the Osteoarthritis Research Society International scores of the digital model group and the traditional model group were higher than those of the control group, and the Osteoarthritis Research Society International score of the digital model group was higher than that of the traditional model group (P < 0.05). Histopathological observation showed that the modified Mankin score and Osteoarthritis Research Society International score of the two model groups were significantly higher than those of the control group of the same age at 4 and 8 weeks after modeling (P < 0.05). Immunohistochemical staining results showed that at two time points, compared with the control group of the same age, the expression of aggrecan and type II collagen decreased in the traditional model group and the digital model group, while the expression of matrix metalloproteinase 13 increased (P < 0.05). ELISA results showed that the expression levels of inflammatory factors interleukin-1β and tumor necrosis factor-α in the traditional and digital model groups were higher than those in the control group at 8 weeks, and the expression levels of interleukin-1β and tumor necrosis factor-α in the digital model group were higher than those in the traditional model group (P < 0.05). To conclude, the personalized metal tube designed and produced by 3D printing technology can quickly guide the osteoarthritis-like lesions of the temporomandibular joint without repeated trial and adjustment, which is reproducible and suitable for promotion and application. 
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    Protective effect of ulinastatin on acute bone loss in sepsis
    Yang Peng, Tang Yubin, Yang Jing, Liu Jian, Yao Runjie, Chen Lin, Su Nan
    2024, 28 (35):  5649-5655.  doi: 10.12307/2024.824
    Abstract ( 94 )   PDF (1802KB) ( 8 )   Save
    BACKGROUND: Sepsis-induced systemic inflammation leads to rapid bone mass loss; however, there is a lack of effective treatments. Ulinastatin is an anti-inflammatory drug, but its protective effect and mechanism on bone under sepsis-induced systemic inflammation are still unclear. 
    OBJECTIVE: To explore whether ulinastatin can relieve acute bone loss caused by lipopolysaccharide. 
    METHODS: (1) Animal experiment. Thirty male C57BL/6 mice were randomly divided into three groups (n=10 per group): control group, model group and experimental group. The control group was injected intraperitoneally with normal saline, the model group was injected intraperitoneally with lipopolysaccharide, and the experimental group was injected intraperitoneally with lipopolysaccharide and ulinastatin. In the experimental group, ulinastatin was injected continuously for 3 days. After intraperitoneal injection of ulinastatin for 14 days, femoral tissues were taken for CT scanning and pathological observation. (2) Cell experiment. C57BL/6 mouse primary osteoblasts were isolated and divided into three groups: the control group was routinely cultured, lipopolysaccharide was added to the model group, and lipopolysaccharide with ulinastatin was added to the experimental group. Cell proliferation and osteogenic differentiation were detected. C57BL/6 mouse bone marrow mononuclear cells were isolated and divided into three groups: the control group was routinely cultured, lipopolysaccharide was added to the model group, and lipopolysaccharide and ulinastatin were added to the experimental group. Osteoclast differentiation was detected.
    RESULTS AND CONCLUSION: (1) Animal experiment. CT scanning and hematoxylin-eosin staining showed that bone mass in lipopolysaccharide-treated mice was reduced but increased after treatment with ulinastatin.  Tartrate resistant acid phosphatase staining showed that the number of osteoclasts in bone tissue increased in the model group, but significantly decreased in the experimental group compared with the model group. (2) Cell experiment. Cell counting kit-8 assay showed that lipopolysaccharide treatment inhibited the proliferation of osteoblasts, and ulinastatin elevated the proliferation of osteoblasts after lipopolysaccharide treatment. Alkaline phosphatase staining, alizarin red staining and osteogenesis-related gene (alkaline phosphatase, Runx2, osteocalcin, osteoblastin, nuclear factor κB receptor-activating factor ligand, osteoprotegerin) detection showed that lipopolysaccharide treatment inhibited osteogenic differentiation of osteoblasts and elevated the nuclear factor κB receptor-activating factor ligand/osteoprotegerin ratio; ulinastatin did not have any significant effect on the reduction of osteoblast function induced by lipopolysaccharide but decreased the nuclear factor κB receptor-activating factor ligand/osteoprotegerin ratio. Tartrate resistant acid phosphatase staining and osteoclast-related gene (tartrate resistant acid phosphatase and matrix metalloproteinase 9) detection showed that lipopolysaccharide treatment could promote osteoclast differentiation of bone marrow monocytes, while ulinastatin could inhibit lipopolysaccharide-induced osteoclast differentiation of bone marrow monocytes. (3) Overall, ulinastatin can significantly inhibit lipopolysaccharide-induced bone loss, mainly through promoting osteoblast proliferation and directly or indirectly inhibiting osteoclast differentiation to alleviate bone loss and achieve osteoprotective effects.
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    Regulatory mechanism of ferroptosis on pressure ulcers: bioinformatics analysis and experimental validation
    Tang Lulu, Pan Xiaojia, Lai Yingtao, Wang Li
    2024, 28 (35):  5656-5661.  doi: 10.12307/2024.600
    Abstract ( 86 )   PDF (4576KB) ( 22 )   Save
    BACKGROUND: Ferroptosis-mediated ischemia-reperfusion injury plays a crucial role in the occurrence and progression in pressure ulcers, and there may be pressure ulcer-associated ferroptosis biomarkers, but the mechanism has not been elucidated.
    OBJECTIVE: To investigate the molecular mechanisms underlying pressure ulcers using bioinformatic analysis, with a focus on identifying differentially expressed genes associated with ferroptosis during the process of pressure ulcer formation, thereby providing novel insights into the clinical treatment of pressure ulcers.
    METHODS: The single-cell transcriptome sequencing dataset and ferroptosis-related genes were obtained and preprocessed from the Gene Expression Omnibus (GEO) and FerrDb databases. We performed clustering and proportion analyses, metabolic activity and pseudotime analysis, cell communication analysis, ferroptosis gene set cell population identification, and enrichment analysis to determine differentially expressed genes related to ferroptosis. Animal experiments were then conducted for further validation, with 20 Sprague-Dawley rats randomly assigned into a control group and a model group (n=10 per group). The control group received no treatment, while the model group underwent a cycle of ischemia-reperfusion to establish pressure ulcer models. Changes in differentially expressed genes and proteins in the wound tissues of pressure ulcer rats were detected using fluorescent quantitative PCR and western blot, respectively.
    RESULTS AND CONCLUSION: The single-cell transcriptome sequencing data were clustered into six cell types, with a higher proportion of type 2 and type 3 keratinocytes observed in the pressure ulcer group. There was evident metabolic heterogeneity and evolutionary trajectory among cell populations. Type 2 and type 3 keratinocytes exhibited stronger cell communication, while type 2 keratinocytes demonstrating optimal ligand-receptor interactions. Type 2 keratinocytes demonstrated higher scores for ferroptosis, accompanied by significant upregulation or downregulation of specific genes. A total of 27 Gene Ontology enrichments, 20 Kyoto Encyclopedia of Genes and Genomes enrichments, and 24 ferroptosis-related differentially expressed genes, including glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long chain family member 4 (ACSL4), were identified. Animal experiments further confirmed the downregulation of GPX4, the ferroptosis-inhibiting protein, and the upregulation of ACSL4, the ferroptosis-promoting protein, in the model group. Overall, these findings indicate the presence of ferroptosis in pressure ulcer tissue. GPX4 and ACSL4 are important genes regulating ferroptosis in pressure ulcer tissues.
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    Effect of type 2 diabetes mellitus on bone mineral density in different age groups: a two-sample Mendelian randomization study
    Huang Wenzhuo, Xiang Haizhu, Ma Weiwei, Huang Xin, Fu Hongjun, Xiong Yong
    2024, 28 (35):  5662-5668.  doi: 10.12307/2024.575
    Abstract ( 119 )   PDF (4040KB) ( 22 )   Save
    BACKGROUND: Epidemiologic studies have shown a correlation between type 2 diabetes mellitus and bone mineral density, but the causal association between the two and whether it is age-related remains unknown.
    OBJECTIVE: To study the correlation between type 2 diabetes mellitus and whole body bone mineral density at unspecified age and at all ages based on the Mendelian randomization technique. 
    METHODS: The genome-wide association study (GWAS) data of type 2 diabetes mellitus and bone mineral density at all ages were selected from the IEU GWAS database of the University of Bristol. The exposure data were single nucleotide polymorphisms with significant correlation with type 2 diabetes mellitus as instrumental variables, and bone mineral density at all ages was selected as the outcome variable. Two-sample Mendelian randomization analysis of type 2 diabetes mellitus and bone mineral density was performed using inverse variance weighted method, weighted median estimator, and MR-Egger regression. The βvalue was used to evaluate the causal relationship between type 2 diabetes mellitus and bone mineral density at all ages.
    RESULTS AND CONCLUSION: A total of 118 single nucleotide polymorphisms were extracted from the GWAS summary data as instrumental variables. The MR-Egger regression results showed that there was no horizontal pleiotropy, but there was heterogeneity. Therefore, this study was based on the inverse variance weighted results. Inverse variance weighted results showed that type 2 diabetes mellitus may be a potential protective factor for bone mineral density and is associated with age: age-unspecified bone mineral density [β=0.038, 95% confidence interval (CI): 1.01-1.07, P=0.002], bone mineral density over 60 years old (β=0.052, 95% CI: 1.01-1.09, P=0.027), bone mineral density between 45-60 years old (β=0.049, 95% CI: 1.01-1.09, P=0.009 ), bone mineral density between 30-45 years old (β=0.033, 95% CI: 0.99-1.07, P=0.127). bone mineral density of 15-30 years old (β=0.025, 95% CI: 0.95-1.10, P=0.506), bone mineral density of 0-15 years old (β=0.006, 95% CI: 0.96-1.04, P=0.716 ). Similar results were obtained from the MR-Egger regression and weighted median estimator analyses. These findings indicate that type 2 diabetes mellitus may be one of the protective factors of bone mineral density, and there is a correlation with age.
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    Vascular endothelial growth factor 165/bone morphogenetic protein improves osteoblast injury under hypoxic and reoxygenated conditions
    Zhao Yiting, Zhang Yuxiang, Ma Jie, He Xuejiao
    2024, 28 (35):  5669-5674.  doi: 10.12307/2024.809
    Abstract ( 105 )   PDF (1285KB) ( 13 )   Save
    BACKGROUND: It has been found that vascular endothelial growth factor 165 and bone morphogenetic proteins interact with each other during hypoxia-reoxygenation and are involved in the repair process of osteoblast injury by regulating the activation of intracellular signaling pathways.
    OBJECTIVE: To further investigate the relationship between vascular endothelial growth factor 165/bone morphogenetic protein and hypoxic-reoxygenated osteoblast injury. 
    METHODS: Osteoblasts were selected and the hypoxic-reoxygenated injury model was established. Vascular endothelial growth factor 165 and bone morphogenetic protein expressions at mRNA and protein levels were detected by real-time PCR and western blot before and after modeling. After modeling, osteoblasts were given different concentrations of vascular endothelial growth factor 165 and bone morphogenetic protein 2 (10, 20, 40 ng/mL). Cell proliferation was detected by cell counting kit-8 method and apoptosis was detected by DAPI at 12, 24, 36, 48, and 72 hours after treatment.
    RESULTS AND CONCLUSION: Compared with before modeling, the mRNA and protein expressions of vascular endothelial growth factor 165 and bone morphogenetic protein 2 in osteoblasts after modeling were significantly decreased (P < 0.05). The proliferation rate of osteoblasts was significantly increased with the increase of vascular endothelial growth factor 165 concentration (P < 0.05), while the apoptosis rate of osteoblasts decreased significantly with the increase of vascular endothelial growth factor 165 concentration (P < 0.05). The proliferation rate of osteoblast was significantly increased with the increase of bone morphogenetic protein 2 concentration (P < 0.05), while the apoptosis rate of osteoblast decreased significantly with the increase of bone morphogenetic protein 2 concentration (P < 0.05). To conclude, vascular endothelial growth factor 165 and bone morphogenetic protein are lowly expressed in hypoxic-reoxygenated osteoblast injury, and treatment with vascular endothelial growth factor 165 and bone morphogenetic protein can reduce the injury of hypoxic-reoxygenated osteoblast in a concentration-dependent manner, suggesting that vascular endothelial growth factor 165 and bone morphogenetic protein have a significant protective effect against the injury of hypoxic-reoxygenated osteoblasts.
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    Arthroscopic long head of the biceps tendon transposition for augmented repair of massive rotator cuff tear
    Ding Kai, Yao Yujing, Li Zhipeng, Wang Lei, Gu Changyuan, Shu Hao, Sun Luning
    2024, 28 (35):  5675-5680.  doi: 10.12307/2024.596
    Abstract ( 118 )   PDF (1560KB) ( 21 )   Save
    BACKGROUND: Transposition of the long head of biceps tendon is a commonly surgical method for massive rotator cuff tears. Currently, there are a few reports on the clinical efficacy of the transposition of the long head of biceps tendon and there is no consensus on the influencing factors for retearing.
    OBJECTIVE: To observe the outcome of arthroscopic long head of the biceps tendon in the treatment of massive rotator cuff tear.
    METHODS: The clinical data of 28 patients with massive rotator cuff tears, aged (61.79±10.50) years, admitted at Jiangsu Province Hospital of Chinese Medicine from March 2019 to May 2022 were retrospectively analyzed. All patients underwent arthroscopic long head of the biceps tendon. Patients were assessed for visual analog scale scores, University of California at Los Angeles scores, American Shoulder and Elbow Surgeons scores, Constant-Murley scores, and shoulder range of motion before and 1 year after operation. MRI of the shoulder joint was performed for observing the integrity of the repaired structure at 1 year after operation. Twenty-three patients (5 of 28 lost to follow-up) were categorized into the intact tendon group (n=18) and the tendon retear group (n=5) according to the Sugaya typing at 1 year after operation; the patients were divided into the normal group (n=8), the degeneration group (n=9), and the partial tear group (n=6) according to the intraoperative quality of the long head of the biceps tendon. Differences in the above indexes were compared between groups. 
    RESULTS AND CONCLUSION: When followed up at 1 year after surgery, the range of motion, visual analog scale scores, University of California at Los Angeles scores, American Shoulder and Elbow Surgeons scores, Constant-Murley scores of the shoulder were significantly improved compared with preoperative data (P < 0.05). There was a significant difference in Goutellier grading between intact tendon and tendon retear groups (P < 0.05), while no significant difference was observed in the other influencing factors (P > 0.05). There were no significant differences in visual analog scale scores, University of California at Los Angeles scores, American Shoulder and Elbow Surgeons scores, Constant-Murley scores, and shoulder range of motion at 1 year after operation among the normal, degeneration, and partial tear groups (P > 0.05). MRI findings indicated that the sutured tendon healed well in 18 patients, with a healing rate of 78%. Arthroscopic long head of the biceps tendon for augmented repair can provide a reliable repair for massive rotator cuff tear that is refractory, significantly alleviate the pain of the shoulder joint, and restore the function of the shoulder joint.
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    Bibliometric and visual analysis of postmenopausal osteoporosis based on highly cited SCI papers
    Li Yan, Liu Ning, Wang Xiaoyang, Xiao Xiangyu, Liu Ping, Zhang Yili, Jiang Hongjiang, Zhu Liguo, Wei Xu
    2024, 28 (35):  5681-5687.  doi: 10.12307/2024.803
    Abstract ( 109 )   PDF (1956KB) ( 20 )   Save
    BACKGROUND: Bibliometrics and visual analyses based on thematic literature are particularly important for understanding the foundation and frontiers of postmenopausal osteoporosis research.
    OBJECTIVE: To perform bibliometric, citation, and visualization analyses of highly cited SCI papers in postmenopausal osteoporosis research over the last 20 years. 
    METHODS: The top 100 highly cited papers on postmenopausal osteoporosis published between 2003 and 2022 included in SCI-EXPANDED catalog of the Web of Science database were obtained for bibliometric measure and visual analysis using CiteSpace software. 
    RESULTS AND CONCLUSION: The top 100 highly cited papers have a total of 67 377 citations in the Web of Science Core Collection, with an annual average of 49.17 citations per paper. Postmenopausal osteoporosis research primarily involves medical, engineering, biological, and multidisciplinary fields. The subcategories are dominated by endocrinology and metabolism, and medicine: internal medicine. Stable and close cooperative network relationships have been formed globally. United States, University of California System, Cummings, and Steven R are the country, research institution, and author, respectively, with the most highly-cited publications. The frontiers of postmenopausal osteoporosis research mainly include calcium and vitamin D supplementation and fracture risk, clinical studies of bisphosphonates in the treatment of postmenopausal osteoporosis, atypical femur fracture, clinical studies of new drugs and sequential treatment of postmenopausal osteoporosis, predictors of fracture risk, mid- and long-term follow-up of osteoporotic vertebral compression fractures, genetic polymorphisms and hereditary factors, formulation and updating of clinical practice guidelines for postmenopausal osteoporosis. Large cohort studies, high-quality randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines are the great engines that drive the development of clinical research in postmenopausal osteoporosis. We should make efforts in the above areas to improve China’s international influence in the field of osteoporosis.  
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    Causal relationship between trunk and lower limb fat mass and intervertebral disc degeneration based on a Mendelian randomization analysis
    Yang Jingyan, Ma She, Huang Renjun, Wang Chaoyi, Zhao Yuyang, Yu Dong
    2024, 28 (35):  5688-5694.  doi: 10.12307/2024.825
    Abstract ( 103 )   PDF (3082KB) ( 12 )   Save
    BACKGROUND: It has been found in recent observational studies that assessing localized fat mass is crucial in the evaluation of disc degeneration. Although obesity has been recognized as a risk factor for disc degeneration, the causal relationship between fat mass, which is a key factor in obesity, and intervertebral disc degeneration has been unclear in previous studies.
    OBJECTIVE: To investigate the causal risk factors of intervertebral disc degeneration associated with different distributions of fat mass, thereby enhancing the understanding of the pathogenesis of intervertebral disc degeneration and contributing to the development of preventive, therapeutic, and prognostic strategies.
    METHODS: Genetic markers associated with trunk and lower limb fat mass were extracted as instrumental variables from the publicly available IEU Open GWAS under the conditions of strong correlation and fulfillment of linkage disequilibrium. These markers were combined with the Mendelian randomization analysis to investigate the relationship between body fat and intervertebral disc degeneration. We used the latest version 9 database of FinnGen and assessed the results using several regression models, including inverse variance weighting, MR-Egger regression, simple mode, weighted mode, and weighted median estimator. We also assessed the heterogeneity of the genetic markers using Cochran’s Q test, and multiplicity was assessed using the MR-Egger intercept test. Additionally, we used the leave-one-out method to determine the sensitivity of individual genetic markers to the causal effect of the exposure and outcome. The results were presented as odds ratios (OR) and 95% confidence intervals (CI).
    RESULTS AND CONCLUSION: The results from the inverse variance weighting method revealed that there was a positive causal relationship between trunk fat mass and the risk of developing intervertebral disc degeneration (OR=1.25, 95% CI: 1.15-1.35, P < 0.001). Additionally, there was an inverse causal relationship between bilateral lower limb fat mass and the risk of developing intervertebral disc degeneration (OR=0.7, 95% CI: 0.63-0.78, P < 0.001; OR=0.69, 95% CI: 0.62-0.76, P < 0.001). Furthermore, the MR-Egger intercept analysis did not detect any potential horizontal pleiotropy. No bias single nucleotide polymorphisms were detected, while heterogeneity tests were present, and the leave-one-out sensitivity analysis suggested reliable results. The results above demonstrate a positive causal relationship between trunk fat mass and intervertebral disc degeneration. As trunk fat mass increases, the risk of intervertebral disc degeneration rises. With an increase in both lower limb fat mass, the risk of intervertebral disc degeneration decreases. Fat content and distribution affects the risk of developing intervertebral disc degeneration and should be given more attention.
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    Regulatory role of transforming growth factor beta subfamily in osteoarthritis
    Guo Lei, Qi Yansong, Niu Xiaobo
    2024, 28 (35):  5695-5701.  doi: 10.12307/2024.557
    Abstract ( 106 )   PDF (1049KB) ( 27 )   Save
    BACKGROUND: Osteoarthritis is one of the most common senile chronic degenerative diseases in China. Due to its complex pathogenesis and cellular molecular communication pathways, there is currently no effective method to slow down the progression of osteoarthritis. Studies have found that transforming growth factor-β is one of the key factors in the maintenance and regulation of joint stability and plays a significant role in the formation of early joints, as well as the development of bone and cartilage, and the remodeling of joints at various stages.
    OBJECTIVE: To review the regulatory role of the transforming growth factor-β subfamily in the occurrence and development of osteoarthritis, both domestically and internationally in recent years, to analyze the impacts it has at different stages of osteoarthritis, and to explore the potential application prospects of transforming growth factor-β in the clinical treatment of osteoarthritis, with a view to informing clinical treatment protocols..
    METHODS: The relevant articles were searched by computer from CNKI Database and PubMed Database. The search terms were “osteoarthritis, transforming growth factor, signaling pathway, bone remodeling, cartilage degeneration, angiogenesis, treatment” in Chinese and English, respectively. Finally, 57 articles were included for review. 
    RESULTS AND CONCLUSION: The pathogenesis of osteoarthritis remains a subject of ongoing exploration with no unified consensus. Numerous studies highlight the close correlation between osteoarthritis and cytokines, focusing on the transforming growth factor-β superfamily as a pivotal mechanism and therapeutic breakthrough. Transforming growth factor-β plays a crucial role in early joint cartilage formation and maintenance, promoting cartilage repair. However, post-joint formation, its protective effect weakens, leading to potential destructive consequences. This dual regulatory role is a current clinical treatment focus, necessitating further research to delineate its application scope for standardized protocols. Highly active transforming growth factor-β participates in the regulation of bone cells, osteoblasts, and osteoclasts under mechanical stress, and intervenes in the subsequent remodeling of bone microstructure. Specific inhibitors present potential targeted therapeutics, yet their safety and efficacy in clinical settings require refinement. Vascular proliferation may serve as a potential disruptive pathway in transforming growth factor-β-mediated cartilage degeneration and subchondral bone remodeling. Abnormal communication pathways can further disrupt the homeostasis of the microenvironment of osteochondral units, thereby accelerating key pathological progressions of osteoarthritis. Research on transforming growth factor-β in osteoarthritic contexts is comprehensive, holding broad clinical application prospects. Drugs related to transforming growth factor-β are in clinical trial phases, but addressing potential impacts on other tissues and precise control of targeted delivery are critical concerns. As research advances, there is optimism for innovative breakthroughs in slowing the progression of osteoarthritis in the future.
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    The mechanism, safety and application of berberine in promoting bone regeneration
    Li Yulin, Yu Haipeng, Tang Huajing, Zhang Zitong, Lin Xingnan
    2024, 28 (35):  5702-5708.  doi: 10.12307/2024.592
    Abstract ( 118 )   PDF (1419KB) ( 40 )   Save
    BACKGROUND: Berberine has the potential to induce osteogenic differentiation of various mesenchymal stem cells under normal conditions and special conditions such as high glucose, infection and inflammation. It is a natural small molecule drug that can induce bone formation in seed cells instead of growth factors, and has great application prospect in bone tissue engineering.
    OBJECTIVE: To review and summarize the research progress in the osteogenic mechanism and efficacy of berberine, especially its osteogenic potential under high glucose, infection and inflammation conditions, and its biological safety, so as to provide theoretical basis for its development and application in bone tissue engineering.
    METHODS: PubMed, WanFang, and CNKI were searched for relevant literature using the keywords of “berberine, bone defects, bone repair, bone regeneration, osteoinductive, osteoporosis, osteoblast, osteoclast, bone tissue engineering, bone, high glucose, diabetes, inflam*, infect*” in English and Chinese, respectively. A total of 105 literatures were selected for review.
    RESULTS AND CONCLUSION: Berberine can be used to treat multiple diseases including bone diseases, and it has the ability to promote bone regeneration. This article systematically reviews the mechanism of berberine on bone regeneration and in vivo and in vitro studies. Studies have shown that it can play a role in bone repair by promoting osteogenesis, inhibiting osteoclast formation and activity, and preventing osteoporosis. It shows excellent osteogenic differentiation potential mainly via Wnt/β-catenin, PI3K/AKT, EGFR/MEK/p38MAPK, cAMP/PKA/CREB, ERK and other signaling pathways. Berberine can also relieve the inhibition of osteogenic differentiation caused by high glucose, infection and inflammation, which provides more possibilities for the treatment of bone defects in patients with diabetes or infection and inflammation in the bone defect site. Berberine also has the advantages of low toxicity, low price, easy access (currently it can be synthesized), which is a relatively ideal bone induction potential drug. In recent years, the application of berberine in the treatment of bone defect tends to be localized, mainly through the combination with bone tissue engineering technology to improve bioavailability, and has shown good bone repair effect and excellent biological safety in animal experiments. In addition, preclinical experiments have shown splendid bone regeneration potential in the conditions of diabetes, local infection and inflammation. In the future, more studies are needed to fully reveal the osteogenic mechanism and biological safety of berberine, and seek the most suitable controlled release loading system to make artificial bone replacement materials with good mechanical strength, efficacy and biological safety.
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    Propulsion deficits in hemiplegic gait of stroke patients
    Zhi Liang, Wang Yulong, Zhang Qingfang, Hong Yaqing, Ke Meihua, Liu Quanquan, Long Jianjun
    2024, 28 (35):  5709-5715.  doi: 10.12307/2024.580
    Abstract ( 108 )   PDF (971KB) ( 51 )   Save
    BACKGROUND: The abnormal gait of stroke patients seriously affects their propulsive force during walking, which subsequently reduces their walking speed, walking distance, and stability, increases their risk of falls, and seriously affects their quality of life.
    OBJECTIVE: To review the relevant research on propulsive force deficits in stroke patients with hemiplegia, to summarize the understanding of existing researchers on propulsive force deficits, to analyze the relationship between propulsive force and gait, and finally to explain and compare the latest rehabilitation technologies used to improve propulsive force deficits, providing reference for clinical treatment.
    METHODS: Relevant literature was retrieved from WanFang, CNKI, PubMed, and Web of Science Core Collection through computer search. The Chinese and English search terms were “propulsive force OR propulsive, stroke OR cerebral infarction OR hemiplegia, walk* OR gait.” The search time limit was from 2003 to 2023, and 71 articles were finally included for review and analysis.
    RESULTS AND CONCLUSION: Training targeting the hip and ankle joints may be more effective for patients’ walking function, especially training with the application of flexible exoskeleton robots, but more sufficient evidence is still needed to use propulsion as a prognostic indicator of walking function in stroke patients. Biomechanical variables related to propulsive force include: the hip joint extension angle at terminal stance, ankle joint dorsiflexion torque, and knee joint extension. Damage to the corticospinal tract, cerebellar-cortical pathways, and the reticulospinal tract in hemiplegic patients are associated with reduced propulsive force and gait asymmetry. Propulsive force is crucial for the stability of healthy gait, and a decrease in propulsive force is unfavorable for gait stability. Gait symmetry is correlated with propulsive force, stride length symmetry, trunk displacement, and lower limb swing ability, with propulsive force being a key factor. Propulsive force can serve as a quantitative indicator for assessing the gait of hemiplegic patients, and evaluation of gait using propulsive force is beneficial for the long-term development of walking ability. Main rehabilitation techniques for improving propulsive force include: lower limb exoskeleton robot walking training, treadmill training combined with functional electrical stimulation, adaptive speed treadmill training, biofeedback technology, and whole-body vibration training. Among them, whole-body vibration training and biofeedback technology are more effective. The specific contributions and mechanisms of the hip, knee, and ankle joints in improving propulsive force are still controversial, but it is expected that the contributions of the hip and ankle joints are greater. Focusing on the improvement of propulsive force as a rehabilitation goal may yield more sustainable advancements in walking function. However, several current challenges persist in this field: understanding the neurobiological basis of propulsive force deficits in stroke patients, assessing the long-term efficacy of current rehabilitation techniques for enhancing propulsive force, and determining the most suitable patient populations for the application of major rehabilitation techniques aiming at improving propulsive force. These areas require further exploration by subsequent researchers.
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    Circular RNAs are involved in the pathogenesis of osteoarthritis through intracellular mechanisms
    Zhou Lijun, Zhang Keyuan, Wang Xi, Yu Li, Xu Feihu, Ding Hong, Ma Hairong
    2024, 28 (35):  5716-5722.  doi: 10.12307/2024.599
    Abstract ( 97 )   PDF (1104KB) ( 18 )   Save
    BACKGROUND: Currently, there is no drug that can completely cure osteoarthritis and its pathogenesis is still unclear. Circular RNAs (circRNAs) are differentially expressed in patients with osteoarthritis and are closely associated with various pathological processes in osteoarthritis. circRNAs play an important role in various physiological and pathological processes, such as chondrocyte homeostasis, extracellular matrix formation, and inflammatory response.
    OBJECTIVE: To mainly review the effects of circRNAs on pathological factors related to osteoarthritis, as well as the types and expression levels of circRNAs in osteoarthritis.
    METHODS: Related articles published from 1976 to August 2023 were retrieved from CNKI, WanFang, VIP, PubMed, Medline, Web of Science and Elsevier databases. The keywords were “osteoarthritis, circular RNA, non-coding RNA, synovial tissue, chondrocytes” in Chinese and English, respectively. All the relevant articles were screened, summarized, analyzed, and finally 69 papers were included in the review.
    RESULTS AND CONCLUSION: circRNAs are non-coding RNAs widely found in eukaryotic cells, with covalently closed continuous loop structure, but with no 5′ hat structure and 3′poly A tail, which are involved in multi-gene and multi-target regulatory networks and cannot be degraded by nucleic acid exonucleases (RNase R). circRNAs have a high abundance, high conservativeness and stability, and cell and tissue specificity. circRNAs have biological functions such as acting as molecular sponges for miRNAs, regulating linear RNA transcription and RNA shearing, interacting with RNA-bound proteins, and translating proteins. circRNAs regulate chondrocyte apoptosis and proliferation, degradation of cartilage extracellular matrix, and inflammation and other physiopathologic processes. circRNAs are expected to become biomarkers and potential therapeutic targets for clinical diagnosis and prognosis of osteoarthritis, and may become a new strategy for clinical treatment of osteoarthritis in the future.
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    Exercise intervention methods for senile sarcopenia
    Lu Donglei, Feng Zhanpeng, Cao Liquan, Tang Yi, Tan Sijie, Yu Zhongtao
    2024, 28 (35):  5723-5731.  doi: 10.12307/2024.597
    Abstract ( 117 )   PDF (1264KB) ( 42 )   Save
    BACKGROUND: Sarcopenia refers to age-related progressive, systemic muscle mass reduction and/or muscle strength decline or muscle physiological function decline, which is related to the occurrence of a variety of adverse outcomes in older adults. Exercise is considered to be one of the main strategies for combating sarcopenia in older adults, but there is a lack of specific intervention methods of different exercise patterns to intervene in sarcopenia.
    OBJECTIVE: To elaborate the main influencing factors of sarcopenia and the research progress of different exercise methods to improve sarcopenia in older adults, providing reference and basis for combating sarcopenia in older adults.
    METHODS: Web of Science, PubMed, CNKI, VIP, WanFang databases were retrieved for relevant literature published from January 2000 to October 2023 using the keywords of “sarcopenia, sport, exercise intervention, resistant training, aerobic exercise, whole body vibration training, mixed training, physical performance, muscle strength, muscle mass” in Chinese and English, respectively. A total of 126 articles were included for review.
    RESULTS AND CONCLUSION: Resistance exercise is still the most effective way to prevent and treat senile sarcopenia, and the effect of high-intensity resistance exercise is more significant. However, in practical application, we should pay attention to the gradual increase of training load intensity. Aerobic exercise combined with resistance exercise is more effective to improve muscle mass and function in the elderly than a single exercise mode. It is suggested that older adults can carry out the transition of low-intensity aerobic exercise in the early stage and increase resistance exercise individually in the late stage. Whole body vibration training is a new treatment method for the prevention and treatment of senile sarcopenia, but particular attention should be paid to the effects of frequency, amplitude, and duration on patients during practical application. Multicomponent exercise combines different exercise modes, which can give full play to their respective advantages, so as to personalize exercise interventions.
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    Effect of cold water immersion dose on the recovery of skeletal muscle fatigue induced by exercise: a systematic review and Meta-analysis
    Li Qiang, Ji Yuqin, Ye Qiang
    2024, 28 (35):  5732-5740.  doi: 10.12307/2024.591
    Abstract ( 162 )   PDF (1877KB) ( 44 )   Save
    OBJECTIVE: Cold water immersion methods are not standardized in terms of operational indicators such as immersion temperature, duration and depth, leading to controversy over the efficacy of recovery from exercise fatigue in skeletal muscle. In this article, we analyze the effects of cold water immersion on muscle injury, muscle soreness and muscle strength recovery under different factors, in order to find the best immersion implementation plan, and thus provide evidence for the recovery of muscle fatigue. 
    METHODS: A search of CNKI, WanFang Data, Web of Science, and PubMed databases was conducted for relevant literature published from January 1, 2000 to August 15, 2023. A total of 4 759 articles were initially retrieved, with 4 735 articles excluded through screening and 24 articles finally included. The Physical Therapy Evidence Database Scale was used to assess the methodological quality of the included literature, and Stata-MP 16 software was used to perform effect size combinations, subgroup analyses, Meta-regression, sensitivity tests, and publication bias analyses.
    RESULTS: (1) The article included a total of 24 randomized controlled trial studies, including 617 subjects, with overall high legal quality. (2) Meta-analysis showed that cold water immersion can significantly reduce creatine kinase blood value [standardized mean difference (SMD)=-0.17, 95% confidence interval (CI): -0.29 to -0.05, P < 0.01], alleviate muscle pain (SMD=-0.60, 95% CI: -0.81 to -0.38, P < 0.01), and promote maximum muscle strength recovery (SMD=0.17, 95% CI: 0.05 to 0.30, P < 0.01). (3) Subgroup analysis showed that: The immersing regimen with water temperature > 14 °C (SMD=-0.48, 95% CI: -0.76 to -0.20, P < 0.01) and duration of 12-14 minutes (SMD=-0.38, 95% CI: -0.61 to -0.15, P < 0.01) had the best effect in reducing creatine kinase blood values, and had a more significant intervention effect on endurance exercise (SMD=-0.45, 95% CI: -0.71 to -0.20, P < 0.01), while the immersion regimen with water temperature < 10 °C (SMD=-0.61, 95% CI: -0.79 to -0.43, P < 0.01), duration < 12 minutes (SMD=-0.76, 95% CI: -0.98 to -0.53, P < 0.01), and immersion depth above the iliac spine (SMD=-0.74, 95% CI: -0.97 to -0.52, P < 0.01) had the best effect on relieving muscle soreness, and had a more significant analgesic effect after endurance exercise (SMD=-0.42, 95% CI: -0.61 to -0.22, P < 0.01). (4) Meta regression showed that immersion water temperature, immersion duration, and exercise type were important regulatory factors affecting the effect size of creatine kinase; immersing water temperature and immersing depth were important regulatory factors affecting the effect size of visual analogue scale score, while exercise type was an important regulatory factor affecting the maximum isometric muscle strength effect size.
    CONCLUSION: (1) Evidence of extremely low to moderate strength suggests that cold water immersion can effectively reduce muscle damage, alleviate muscle soreness, and promote muscle strength recovery. (2) In terms of reducing muscle injury, immersion water temperature, immersion duration, and exercise type are significant regulatory factors that affect the efficacy of immersing. Among them, immersion water temperature > 14 °C and duration of 12-14 minutes are the best solutions to reduce muscle injury after exercise, and the immersing effect is better for endurance exercise. (3) In terms of reducing muscle soreness, immersion water temperature and immersion depth are important regulatory factors that affect the intervention effect. Among them, immersion water temperature < 10 °C, duration < 12 minutes, and immersing depth above the iliac spine are the best solutions to reduce muscle soreness, and have a better analgesic effect after endurance exercise. (4) In terms of promoting muscle strength recovery, exercise type is a key regulatory factor that affects the maximum isometric muscle strength effect.
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