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18 September 2024, Volume 28 Issue 26 Previous Issue    Next Issue

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Punicalagin treats postmenopausal osteoporosis by promoting osteogenesis Zhang Shudong, Huang Yilin, Yao Qi 2024, 28 (26):  4101-4105.  doi: 10.12307/2024.438 Abstract ( 328 )   PDF (977KB) ( 107 )   Save BACKGROUND: Punicalagin has a wide range of effects and high safety, but its effect on osteoblasts and postmenopausal osteoporosis is unknown. OBJECTIVE: To investigate the effect of punicalagin on osteoblasts and postmenopausal osteoporosis. METHODS: The effect of punicalagin on the proliferation of MC3T3-E1 cells was detected. Punicalagin was added to the osteogenic induction medium to detect its effect on osteogenic differentiation. Punicalagin was used to treat ovariectomized rats and Micro CT scan and serum procollagen type 1 N-terminal propeptide test were performed after 3 months to detect the therapeutic effect. RESULTS AND CONCLUSION: Cell counting kit-8 assay showed that punicalagin could promote the proliferation of osteoblasts (P < 0.05). The results of qRT-PCR and western blot showed that punicalagin could promote the mRNA and protein expressions of alkaline phosphatase and Runx2 in osteoblasts (P < 0.05). The results of Micro CT scan and serological test showed that punicalagin could improve bone mineral density, bone volume fraction, trabecular thickness, trabecular number and procollagen type 1 N-terminal propeptide level of ovariectomized rats. To conclude, punicalagin can promote osteoblast proliferation and differentiation, and have therapeutic effects in postmenopausal osteoporosis rats. Figures and Tables | References | Related Articles | Metrics

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Two-sample Mendelian randomization analysis of the relationship between statins and the risk of osteoarthritis Wu Ruiqi, Zhang Xuan, Zhou Yi, Meng Lin, Li Hongyu 2024, 28 (26):  4106-4112.  doi: 10.12307/2024.440 Abstract ( 461 )   PDF (3951KB) ( 195 )   Save BACKGROUND: Observational studies have suggested that statins may have a protective effect against osteoarthritis, including knee osteoarthritis and hip osteoarthritis. However, the association between statins and the risk of osteoarthritis remains unclear. OBJECTIVE: To investigate the association between statins and the risk of osteoarthritis through Mendelian randomization analysis using summary data from large-scale population-based genome-wide association studies (GWAS).  METHODS: Firstly, single nucleotide polymorphism data related to statins were obtained from the latest 9th edition of the FinnGen database, while data of osteoarthritis, knee osteoarthritis and hip osteoarthritis were obtained from the IEU Open GWAS, UK Biobank, and ArcOGEN (Genetics of Osteoarthritis) databases, respectively. The inverse variance weighted method was used as the primary analysis approach to evaluate the causal effects. The weighted median method, simple median method, weighted mode-based method, and MR-Egger regression were used as supplementary analyses. The causal relationship between statins and the risk of osteoarthritis, knee osteoarthritis and hip osteoarthritis was assessed using odds ratios (OR) with 95% confidence intervals (CI). Sensitivity analyses were conducted to validate the reliability of the results, including the Cochran’s Q test for heterogeneity and the MR-Egger-intercept test for horizontal pleiotropy, as well as leave-one-out analysis to identify potentially influential single nucleotide polymorphisms. RESULTS AND CONCLUSION: The inverse variance weighted analysis demonstrated a negative causal relationship between genetically predicted statins and the risk of osteoarthritis (OR=0.998, 95% CI: 0.996-0.999, P=0.01), knee osteoarthritis (OR=0.964, 95% CI: 0.940-0.989, P=0.005), and hip osteoarthritis (OR=0.928, 95% CI: 0.901-0.955, P=4.28×10-7). MR-Egger intercept analysis did not detect potential horizontal pleiotropy (osteoarthritis: P=0.658; knee osteoarthritis: P=0.600; hip osteoarthritis: P=0.141). The results of this study provide evidence that statins reduce the risks of osteoarthritis, knee osteoarthritis and hip osteoarthritis as described in observational studies. Further research is needed to explore the specific mechanisms of statin treatment for osteoarthritis. Figures and Tables | References | Related Articles | Metrics

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Effects of aerobic exercise on the expression of Notch1 and Caspase-3 in the hippocampus of Alzheimer’s disease mice Yang Liyuan, Zhang Yeting, Li Chuikun, Wei Cuilan 2024, 28 (26):  4113-4120.  doi: 10.12307/2024.393 Abstract ( 205 )   PDF (2834KB) ( 49 )   Save BACKGROUND: β-amyloid protein and Tau protein have adverse effects on the cognitive function of Alzheimer’s disease patients, and Notch1 and Caspase-3 can regulate the expression of β-amyloid protein and Tau protein. It is not clear whether Notch1 and Caspase-3 mediate the process of aerobic exercise to improve the cognitive ability of Alzheimer’s disease patients. At present, there is a lack of studies on the effect of long-term aerobic exercise on the expression of Notch1 and Caspase-3 in the hippocampus of Alzheimer’s disease mice. OBJECTIVE: To observe the expression of Notch1 and Caspase-3 in the hippocampus of Alzheimer’s disease mice undergoing long-term aerobic exercise and to investigate the effects of Notch1 and Caspase-3 in Alzheimer’s disease mice. METHODS: Wild type and APP/PS1 double-transgenic Alzheimer’s disease mice aged 3 months were randomly divided into four groups: wild control group, wild exercise group, Alzheimer’s disease control group and Alzheimer’s disease exercise group, with 20 mice in each group. Mice in the control groups were not subjected to exercise, while those in the exercise groups received aerobic exercise intervention for 5 months. After the exercise intervention, Morris water maze was used to detect the spatial learning and memory ability of mice. Real-time PCR, immunofluorescence and western blot were used to detect the expressions of Aβ1-42, Tau, Notch1 and Caspase-3 in the hippocampal tissues of mice in each group. RESULTS AND CONCLUSION: The spatial learning and memory ability of Alzheimer’s mice was significantly worse than that of wild-type mice (P < 0.05). The spatial learning and memory ability of mice in the exercise groups were significantly better than that in the corresponding control groups (P < 0.05). The expressions of Aβ1-42, Tau, Notch1 and Caspase-3 in the hippocampus were significantly higher in the Alzheimer’s disease control group than the wild control group (P < 0.05) and were significantly lower in the Alzheimer’s disease exercise group than the Alzheimer’s disease control group (P < 0.05). To conclude, long-term aerobic exercise can improve the spatial learning and memory ability of Alzheimer’s disease mice, which may be related to the decreased expression of Notch1, Caspase-3, Aβ1-42 and Tau protein in the hippocampus of Alzheimer’s disease mice. Figures and Tables | References | Related Articles | Metrics

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Screening and analysis of differentially expressed long non-coding RNAs in adriamycin-induced myocardial injury antagonized with daisy leaf gentianone Liu Ying, Liu Yalei, Liu Yu 2024, 28 (26):  4121-4128.  doi: 10.12307/2024.346 Abstract ( 155 )   PDF (2218KB) ( 24 )   Save BACKGROUND: It has been shown that long non-coding RNA (lncRNA) plays an important role in the development and progression of cardiac diseases, and whether it is involved in daisy leaf gentianone antagonizing adriamycin-induced cardiac injury in mice has not been reported. OBJECTIVE: To screen differentially expressed lncRNAs in myocardial tissue of mice with adriamycin-induced myocardial injury antagonized with daisy leaf gentianone and conduct a bioinformatics analysis. METHODS: Forty-eight C57 mice were randomly divided into normal group, model group, daisy leaf gentianone group and positive drug group, with 12 mice in each group. The mice in the model group, daisy leaf gentianone group and positive drug group were injected with adriamycin intraperitoneally once every other day for 8 times in total. The daisy leaf gentianone group and positive drug group were given daisy leaf gentianone suspension and captopril solution by gavage based on adriamycin injection once a day for 21 continuous days. After medication, mice in each group underwent electrocardiogram examination and the myocardial tissue was taken for pathomorphological observation. At the same time, high-throughput sequencing analysis of mouse myocardial tissue was carried out, differentially expressed lncRNAs were screened, and target genes were predicted for differentially expressed lncRNAs. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes signaling pathway analyses of target genes were performed. RESULTS AND CONCLUSION: The ST segment of the electrocardiogram of mice in the model group was significantly elevated. Compared with the model group, the degree of ST-segment elevation on the electrocardiogram was reduced in the daisy leaf gentianone group. Results from hematoxylin-eosin, Masson, and Sirius red staining indicated that in the model group, the myocardial cytoplasm was unevenly colored with varying shades of color, the integrity and continuity of myocardial fibers were poor, and a large number of collagen fibers were deposited. After treatment with gentianone daisy leaves, the abnormalities in myocardial tissue of mice were improved. The results of high-throughput sequencing analysis showed that compared with the model group, a total of 270 lncRNAs were identified in the myocardial tissue of mice in the daisy leaf gentianone group, including 165 up-regulated and 105 down-regulated lncRNAs. Combining the experimental results with related literature, three lncRNAs (NONMMUT149833.1, NONMMUT003237.2, and ENSMUST00000219015) and four related mRNAs (Alas2, Igf2, Acta1, and Cilp) were finally identified. The results of target gene prediction, gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes signaling pathway analyses showed that differentially expressed lncRNAs in myocardial tissue of mice with myocardial injury could regulate the expression of their target protein-coding genes through cis- and/or trans-regulation, and participate in regulating molecular functions and biological processes. To conclude, daisy leaf gentianone significantly improves cardiac function and partial lncRNA expression in mice with adriamycin-induced myocardial injury. Figures and Tables | References | Related Articles | Metrics

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Mechanisms of acupuncture in the treatment of irritable bowel syndrome with diarrhea based on proteomics Liu Jing, Liang Fangyuan, Li Jia, Wang Hua 2024, 28 (26):  4129-4136.  doi: 10.12307/2024.421 Abstract ( 178 )   PDF (1324KB) ( 76 )   Save BACKGROUND: As a common clinical digestive disorder, irritable bowel syndrome becomes an advantageous disease of acupuncture treatment. However, the therapeutic mechanisms remain unclear. The methodological characteristics of omics coincide with the multi-target and multi-level characteristics of acupuncture, providing the possibility of revealing the principle of acupuncture in the treatment of the disease. OBJECTIVE: To investigate the pathogenesis of irritable bowel syndrome with diarrhea (IBS-D) and the effect of acupuncture at the combined points (selected based on etiologies and symptoms) on IBS-D based on proteomics.  METHODS: Twelve 3-month-old male Sprague-Dawley rats were randomly divided into three groups: a control group, an IBS-D model group and an acupuncture group. The IBS-D rat models were prepared using the CAS method. After successful modeling, bilateral Zusanli points, bilateral Neiguan points and Guanyuan points were selected for acupuncture treatment in the acupuncture group, with a frequency of 120 times/minute, 1 minute of acupuncture every 4 minutes, and 15 minutes of needle retention, at an interval of 1 day every 6 days, for 28 days in total. Rats in the normal control group and the model group were not given any intervention. The pressure threshold of rat abdominal retraction reflex was measured to evaluate the visceral hypersensitivity of rats. Proteomics analysis was performed using the liquid chromatography-tandem mass spectrometry -based platform. MaxQuant software, Perseus software and DAVID, KOBAS, VENNY, STRING online tools were used for the bioinformatics analysis of proteomic data. Visualization analysis was done using Cytoscape 3.7.1 software.  RESULTS AND CONCLUSION: There were 47 differentially expressed proteins between the IBS-D model and control groups. Function analysis of differentially expressed proteins revealed that the pathogenic mechanism of IBS-D was associated with abnormal energy metabolism, the imbalance of colon motor function and increased visceral sensitivity. Important proteins related to IBS-D pathogenesis included Atp5a1, Atp5c1, Idh3b, Atp2a3, Pdhb, Ppp1ca and Mapk3. Sixty-one differentially expressed proteins were identified between the acupuncture group and IBS-D model group. Acupuncture at the combined points reversed the up-regulation of nine differentially expressed proteins and the down-regulation of nine differentially expressed proteins. Bioinformatics analysis revealed that acupuncture at the combined points for IBS-D could function via multi-targets and multi-pathways, reverse the damage of energy metabolism caused by IBS-D, and play a role against oxidative stress and inflammation, thereby relieving pain and regulating the imbalance of intestinal function. Important proteins related to acupuncture effects included Atp5a1, Atp5c1, Pdhb, Sars, Uqcrc2, Prdx2, Prdx4, Ppp1ca, Manf and Tmsb4x3. All these findings preliminarily illustrate the potential molecular mechanisms of IBS-D and the effect of acupuncture at the combined points in the treatment of IBS-D at the protein level, which provide a basis for the clinical application of acupuncture at the combined points.   Figures and Tables | References | Related Articles | Metrics

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Effect and mechanism of angiotensin (1-7) supplementation combined with exercise therapy on cardiac remodeling in rats with renal hypertension Xu Wenjie, Xie Xudong, He Ruibo, Ma Gang, Peng peng 2024, 28 (26):  4137-4144.  doi: 10.12307/2024.360 Abstract ( 159 )   PDF (1583KB) ( 45 )   Save BACKGROUND: The renin-angiotensin system plays a key role in the occurrence and development of hypertension, in which angiotensin (1-7) has antihypertensive effect and reversely regulates the adverse effects of angiotensin II. Exercise rehabilitation therapy is an important non-pharmaceutical means to prevent and treat hypertension; however, whether angiotensin (1-7) and exercise have a synergistic effect is not yet clear.  OBJECTIVE: To explore the effect of angiotensin (1-7) supplementation combined with exercise therapy on cardiac remodeling in rats with renal hypertension and to investigate the possible mechanism of angiotensin (1-7) and its receptor signal axis.  METHODS: Sixty male Sprague-Dawley rats were selected, of which 12 rats were randomly selected as normotensive group and the remaining 48 rats were used to make animal models of renal hypertension using two-kidney one-clip method and were then randomly divided into hypertension control group, hypertension exercise group, angiotensin (1-7) group and combined treatment group. One week after successful modeling, different interventions were given (for a period of 6 weeks) as follows: the hypertension exercise group was subjected to a running training on an electric treadmill, the angiotensin (1-7) group was perfused with angiotensin (1-7) by implanting Alzet microosmotic pump subcutaneously on the back of the rats, and the combined treatment group was perfused with angiotensin (1-7) after running training, while the normotensive group and hypertension control group were caged quietly. At 48 hours after the last training session, the tail artery blood pressure was measured with a non-invasive sphygmomanometer; the heart structure and function were detected by echocardiography; the left ventricular myocardium was taken for histopathological observation by hematoxylin-eosin and Masson staining, and the cardiomyocyte cross-sectional area and collagen volume fraction were obtained by image analysis software as markers of myocardial hypertrophy and fibrosis, respectively; the content of angiotensin (1-7) in the heart was detected by high performance liquid chromatography; the mRNA expression of cardiac embryonic genes, atrial natriuretic peptide and β-myosin heavy chain, was detected by real-time fluorescence quantitative PCR; and the protein expression of cardiac Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was measured by western blot assay.  RESULTS AND CONCLUSION: Compared with the normotensive group, blood pressure increased (P < 0.05), cardiac function had no significant changes (P > 0.05), cardiomyocyte cross-sectional area and collagen volume fraction increased (P < 0.05), mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was upregulated (P < 0.05), angiotensin (1-7) content and protein expression of Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was downregulated (P < 0.05) in the hypertension control group. Compared with the hypertension control group, blood pressure decreased (P < 0.05), cardiac function improved (P < 0.05), collagen volume fraction decreased (P < 0.05), cardiomyocyte cross-sectional area and angiotensin (1-7) content showed no significant changes (P > 0.05), mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was downregulated (P < 0.05), and the protein expression of Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was upregulated (P < 0.05) in the hypertension exercise group; except for an increase in myocardial angiotensin (1-7) content (P < 0.05), other parameters had no statistical significance (P > 0.05) in the hypertension angiotensin (1-7) group. Compared with the hypertension exercise group, blood pressure decreased (P < 0.05), cardiomyocyte cross-sectional area and cardiac function had no significant changes (P > 0.05), collagen volume fraction decreased (P < 0.05), angiotensin (1-7) content increased (P < 0.05), mRNA expression of atrial natriuretic peptide and β-myosin heavy chain was downregulated (P < 0.05), and the protein expression of Mas receptor, angiotensin II type 2 receptor and endothelial nitric oxide synthase was upregulated (P < 0.05) in the combined treatment group. To conclude, supplementation of angiotensin (1-7) alone cannot improve cardiac remodeling in rats with renal hypertension, but it can enhance the efficacy of exercise. The mechanism is related to the improvement of angiotensin (1-7) receptor deficiency and restoration of its signaling pathway function. Figures and Tables | References | Related Articles | Metrics

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Visual analysis of the effect of apoptosis on ischemic stroke Duan Yanzhe, Hua Jianlin, Ding Zhibin, Jiang Nan, Song Lijuan, Yan Yuqing, Ma Cungen 2024, 28 (26):  4145-4150.  doi: 10.12307/2024.430 Abstract ( 195 )   PDF (3633KB) ( 23 )   Save BACKGROUND: Ischemic stroke is a highly prevalent disease associated with apoptosis. Neuronal death occurs after cerebral ischemia, including necrosis and apoptosis. The ischemic core region is dominated by necrosis, while delayed neuronal death in the penumbra is dominated by apoptosis. The penumbra has become a target for the treatment of ischemic stroke. This bibliometric analysis was used to identify the characteristics, hotspots, and frontiers of global scientific output related to apoptosis in ischemic stroke over the past 5 years.  OBJECTIVE: To analyze the role of apoptosis and its mechanisms in the pathological process of ischemic stroke through a bibliometric approach. METHODS: A total of 927 relevant literature records from 2018 to 2022 were retrieved from Science Citation Index Expanded (SCI-Expanded) and Social Science Citation Index Expanded (SSCI-Expanded) of the Web of Science Core Collection. Research trends and hotspots of apoptosis in ischemic stroke were visualized using Citespace, VOSviewer and Bibliometrix.  RESULTS AND CONCLUSION: From 2018 to 2020, the number of papers on the role of apoptosis in ischemic stroke showed an upward trend, but in 2020, the number of papers began to reduce. China had the largest number of publications, and the United States ranked the second. Capital Medical University and BRAIN RESEARCH BULLETIN were the institutions and journals with the most articles, respectively. In recent years, the two keywords “expression” and “oxidative stress” have appeared more frequently. The bibliometric study showed that in the past 5 years, most of the studies focused on basic research, in which research on the role of apoptosis in ischemic stroke has gradually decreased in the last 3 years, showing a downward trend. On the contrary, nerve regeneration has gradually become a research hotspot, especially the regulation of neurotrophic factors under the influence of different mechanisms, and the research on angiogenesis and glial cell repair is on the rise. At the same time, apoptosis in nerve regeneration is a potential point of discovery. Figures and Tables | References | Related Articles | Metrics

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The molecular mechanism of Liuwei Dihuang Pill in the treatment of premature ovarian insufficiency in a mouse model Li Xiaorong, Zhong Jiawen, Luo Yuxue, Gao Ting, Qin Ling, Wang Xueyi 2024, 28 (26):  4151-4157.  doi: 10.12307/2024.429 Abstract ( 178 )   PDF (2183KB) ( 58 )   Save BACKGROUND: Most of the formulas for the clinical treatment of premature ovarian insufficiency have evolved from the basic formula of Liuwei Dihuang Pills, and have achieved good therapeutic efficacy. Currently, most of the experimental studies on Liuwei Dihuang Pills focus on morphological observations and physiological and biochemical detection of in vivo animal models, while fewer studies on molecular mechanisms have been reported. OBJECTIVE: To explore the molecular mechanism of Liuwei Dihuang Pills in the treatment of premature ovarian insufficiency based on the receptor gamma coactivator-1 alpha/mitochondrial transcription factor A/reactive oxygen species pathway.  METHODS: Premature ovarian insufficiency model was established in mice by intraperitoneal injection of cyclophosphamide 120 mg/kg combined with busulfan 12 mg/kg, and then Liuwei Dihuang Pill suspension was used to intervene in premature ovarian insufficiency mice. After 12 weeks of intervention, the levels of follicle-stimulating hormone, luteinizing hormone, estradiol, anti-Mullerian hormone, 8-hydroxydeoxyguanosine, total antioxidant capacity and reactive oxygen species in serum of mice were detected by ELISA method. The morphological changes in mouse ovaries were observed by hematoxylin-eosin staining. The ultrastructure of mouse follicular granulosa cells and the apoptosis of granulosa cell mitochondria were observed by transmission electron microscopy. The expression levels of receptor gamma coactivator-1 alpha and mitochondrial transcription factor A in mouse ovarian granulosa cells were detected by immunohistochemistry. RESULTS AND CONCLUSION: Compared with the model group, serum levels of follicle-stimulating hormone, luteinizing hormone, reactive oxygen species, and 8-hydroxydeoxyguanosine were decreased in the experimental group (P < 0.05), and the levels of estradiol, anti-Mullerian hormone, and total antioxidant capacity were increased (P < 0.05). Hematoxylin-eosin staining showed that in the model group, there were more atretic follicles and corpus luteum forms, some secondary follicles, and interstitial fibrosis and hyperplasia; in the experimental group, a large number of atretic follicles, few corpus luteum forms, primordial follicles were observed at the edges but there were few secondary follicles and no mature follicles. Transmission electron microscopy showed that the organelles in ovarian granulosa cells of mice in the experimental groups were relatively intact. Immunohistochemical results showed that compared with the model group, the expression level of receptor gamma coactivator-1 alpha in the ovarian tissue of mice increased slightly in the experimental group at the 4th week, and there was no significant change at the 8th and 12th weeks. The expression level of mitochondrial transcription factor A in the ovarian tissues of mice in the experimental group was transiently increased at the 4th week, and then slightly decreased, which were all significantly different from those of the model group. To conclude, Liuwei Dihuang Pills inhibit ovarian granulosa cell apoptosis in mice with premature ovarian insufficiency to a certain extent through the receptor gamma coactivator-1 alpha/mitochondrial transcription factor A/reactive oxygen species signaling pathway, thereby improving the endocrine function of the ovary, enhancing the antioxidant capacity, and attenuating the degree of oxidative stress damage. Figures and Tables | References | Related Articles | Metrics

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Effect and mechanism of tetramethylpyrazine regulating ferroptosis in rats with spinal cord injury Tao Jingwei, Zhou Jingya, Zhao Yi, Ren Jingpei, Hu Chuanyu, Xu Lin, Mu Xiaohong, Fan Xiao 2024, 28 (26):  4158-4163.  doi: 10.12307/2024.432 Abstract ( 178 )   PDF (1410KB) ( 60 )   Save BACKGROUND: Studies have shown that there is a close association between spinal cord injury and ferroptosis, and that tetramethylpyrazine has the function of regulating redox reactions.  OBJECTIVE: To investigate the regulatory effect of tetramethylpyrazine on ferroptosis in rats with spinal cord injury and its mechanism. METHODS: Thirty-six female specific pathogen-free Sprague-Dawley rats were randomly divided into sham-operated group, model group and tetramethylpyrazine group, with 12 rats in each group. Animal models of spinal cord injury were established using the modified Allen’s method in the latter two groups. No treatment was given in the sham-operated group, while rats in the model and tetramethylpyrazine groups were given intraperitoneal injection of normal saline and tetramethylpyrazine solution, once a day, for 28 days. RESULTS AND CONCLUSION: The Basso, Beattie & Bresnahan Locomotor Rating Scale score in the tetramethylpyrazine group was lower than that in the sham-operated group but higher than that in the model group after 14, 21, and 28 days of treatment (P < 0.05). After 28 days of treatment, hematoxylin-eosin staining showed that in the model group, the spinal cord tissue of rats showed cavity formation, necrotic tissue and inflammatory infiltration with fibrous tissue formation; in the tetramethylpyrazine group, the area of spinal cord tissue defects was smaller, and inflammatory infiltration and fibrous tissue formation were less than those in the model group. After 28 days of treatment, Prussian blue staining showed that a large amount of iron deposition was seen in the spinal cord tissue of rats in the model group, and less iron deposition was seen in the spinal cord tissue of rats in the tetramethylpyrazine group than in the model group. After 28 days of treatment, the levels of glutathione and superoxide dismutase in the rat spinal cord tissue were decreased (P < 0.05) and the level of malondialdehyde was increased in the model group compared with the sham-operated group (P < 0.05); the levels of glutathione and superoxide dismutase in the rat spinal cord tissue were increased (P < 0.05) and the level of malondialdehyde was decreased in the tetramethylpyrazine group compared with the model group (P < 0.05). After 28 days of treatment, qRT-PCR and western blot assay showed that the mRNA and protein levels of glutathione peroxidase 4, ferritin heavy chain, and ferroportin in the rat spinal cord tissue in the model group were decreased compared with those in the sham-operated group (P < 0.05), while the mRNA and protein levels of glutathione peroxidase 4, ferritin heavy chain, and ferroportin in the rat spinal cord tissue in the tetramethylpyrazine group were increased compared with those in the model group (P < 0.05). Immunofluorescence staining showed that after 28 days of treatment, the neuronal nuclei positive staining in the spinal cord of rats was the most in the sham-operated group and the least in the model group. To conclude, tetramethylpyrazine can improve motor function and play a neuroprotective role in rats with spinal cord injury by regulating ferroptosis. Figures and Tables | References | Related Articles | Metrics

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Establishment of a rat model of traumatic brain injury using the modified Feeney’s free-fall method Gao Simiao, Wu Xiaoguang, Han Xue, Xu Shiqi, Li Kuihua, Peng Yong 2024, 28 (26):  4164-4169.  doi: 10.12307/2024.451 Abstract ( 159 )   PDF (1377KB) ( 15 )   Save BACKGROUND: There is less report about mitigating sustained bone grinding injuries during craniotomy based on a model of traumatic brain injury established using the modified Feeney’s free-fall method. OBJECTIVE: To modify a modified traumatic brain injury model by altering the opening of the skull window. METHODS: Thirty-six Sprague-Dawley rats were equally randomized into sham group, model group and modified model group. The modified procedure of opening the bone window was used in the modified model group. Six to eight small holes of 0.3-0.5 mm in diameter were punched at the edge of the impact area and the drill was immediately withdrawn without touching the cortex. In the modified model group, the skull window was opened by using the modified method, while the skull window in the model group was opened using the conventional method. The modified model group and model group were established using the Feeney’s free-fall method. In the sham group, only the skull window was opened without impact. The modified neurological severity scoring was performed at 1 day after modeling. T2 weighted imaging was performed and T2 values were measured at 1 and 7 days after modeling. Hematoxylin-eosin staining of the brain section was made for histopathological observation at 7 days after modeling. The level of blood viscosity, interleukin-6, interleukin-1β, and tumor necrosis factor-α were determined at 7 days after modeling. RESULTS AND CONCLUSION: Compared with the sham group, the modified neurological severity scores in the model group and modified model group were significantly increased at 1 day after modeling (P < 0.000 1). Meanwhile, the modified neurological severity scores in the modified model group were lower than those in the model group (P < 0.000 1). Compared with the sham group, the T2 values were significantly increased in the model group and modified model group at 1 and 7 days after modeling (P < 0.05), while the T2 values in the modified model group were lower than those in the model group (P < 0.05). Compared with the sham group, the level of blood viscosity, interleukin-6, interleukin-1β and tumor necrosis factor-α were increased in the model group and modified model group at 7 days after modeling (P < 0.05), while the level of interleukin-6 in the modified model group was lower than that in the model group (P < 0.05). To conclude, establishing a modified traumatic brain injury model based on the Feeney’s free-fall method provides better controls of injury factors during cranial opening. Figures and Tables | References | Related Articles | Metrics

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Characteristic changes in morphology and function of skeletal muscles in a rat model of “tendon off-position” Yang Zongrui, Ge Haiya, Shi Jinyu, Wang Zhengming, Wang Yuanyuan, Li Zhengyan, Du Guoqing, Zhan Hongsheng 2024, 28 (26):  4170-4177.  doi: 10.12307/2024.422 Abstract ( 151 )   PDF (1917KB) ( 51 )   Save BACKGROUND: “Tendon off-position” is a disease name included in the International Classification of Diseases 11th Revision, and also a clinical indication of manipulation, acupuncture and other treatments. However, its specific mechanism is still unclear. It is urgent to establish an animal model that can reflect the clinical and pathological characteristics of “tendon off-position,” so as to further study the mechanism of effective clinical treatments. OBJECTIVE: To establish an animal model of “tendon off-position” in rats based on isometric contraction of skeletal muscles, and to explore the changes of skeletal muscle function and morphological phenotype after “tendon off-position.” METHODS: Sixty rats were randomly divided into control group, static-loading group and extra loading group, with twenty rats in each group. Rats in the control group were kept normally without treatment. In the latter two groups, the rats were fixed by the self-made static-loading modeling device and a static-loading (the body mass of each rats was applied as the static-loading) was applied to cause sustained isometric contraction of the upper limb muscles. Then, animal models of “tendon off-position” were successfully established. In the extra loading group, 50% of the body mass was added to the ankle joint after modeling. The skeletal muscle samples were harvested at 2 and 4 weeks after modeling. The changes of limb grip strength, wet mass of skeletal muscle, and serum levels of creatine kinase-muscle and lactate dehydrogenase A were measured, and the changes of skeletal muscle histomorphology and ultrastructure were observed. RESULTS AND CONCLUSION: At 2 weeks after modeling, the rats in the static-loading group and extra loading group showed significantly decreased grip strength and wet muscle mass, significantly increased serum levels of creatine kinase-muscle and lactate dehydrogenase A, and abnormal muscle fiber morphology and structure accompanied by a large number of deposited collagen fibers. Electron microscopy results showed that the structure of myofibrils was disordered, the Z-line was distorted, and the light and dark boundaries were blurred. At 4 weeks after modeling, the grip strength of the model rats was increased compared with that at 2 weeks, the serum creatine kinase-muscle and lactate dehydrogenase A levels were decreased, and the changes of muscle fiber morphology and ultrastructure were recovered to varying degrees. It is suggested that the rat skeletal muscle injury model based on continuous isometric contraction of skeletal muscle can well reflect the pathological characteristics of “tendon off-position” at 2 weeks, and can be used to study the mechanism of acupuncture and manipulation in the treatment of “tendon off-position.” Figures and Tables | References | Related Articles | Metrics

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Deficiency of interleukin-9 inhibits osteogenic potential in mice Wang Yi, Chen Chichi, Zhou Xichao, Shi Qin 2024, 28 (26):  4178-4183.  doi: 10.12307/2024.434 Abstract ( 164 )   PDF (1518KB) ( 14 )   Save BACKGROUND: Mouse osteogenic potential is regulated by the JAK-STAT signaling pathway, and interleukin-9 can regulate multiple cellular functions through the JAK-STAT pathway, which has the potential to be a novel cytokine that regulates osteogenic potential. OBJECTIVE: To investigate the effect of interleukin-9 deficiency on osteogenic potential in mice METHODS: The femurs collected from 2-month-old wild-type and interleukin-9 knockout mice were subjected to Micro-CT scanning to analyze the changes in bone mass. Then, hematoxylin-eosin staining, Masson staining, and immunohistochemical staining of type I collagen were performed on the slices of the femurs of mice. Bone marrow cells from 2-month-old wild-type and interleukin-9 knockout mice were extracted for colony-forming assay and detection of osteogenic gene expression in bone marrow mesenchymal stem cells. To further verify whether interleukin-9 worked through the JAK-STAT pathway, the expression of STAT3 protein was detected by western blot. RESULTS AND CONCLUSION: Micro-CT results showed the bone mass of interleukin-9 knockout mice decreased significantly compared with that of wild-type mice. In addition, the bone mineral density, bone volume fraction, trabecular number significantly decreased and trabecular separation markedly escalated in interleukin-9 knockout mice. The findings of hematoxylin-eosin staining were consistent with Micro-CT results. Interleukin-9 knockout mice had lower bone trabecular density. Type I collagen immunohistochemistry staining and Masson staining indicated the number of type I collagen positive osteoblasts was significantly reduced and the capacity of collagen formation was damaged in interleukin-9 knockout mice. The results of colony-forming assay indicated that the mineralization capacity of osteoblast in interleukin-9 knockout mice were significantly lower than that in wild-type mice. Western blot results showed that osteogenesis induction activated STAT3 signaling, and the pSTAT3 level in wild-type mice with osteogenic induction was significantly higher than that in interleukin-9 knockout mice with osteogenic induction. These findings suggest that interleukin-9 regulates osteogenesis through the JAK-STAT3 pathway and interleukin-9 deficiency inhibits osteoblast differentiation and function, which may lead to reduced bone mass in interleukin-9 knockout mice. Figures and Tables | References | Related Articles | Metrics

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Effect of hesperetin on inflammatory degeneration of chondrocytes by inhibiting oxidative stress Luo Shanchao, Tang Jiren 2024, 28 (26):  4184-4188.  doi: 10.12307/2024.460 Abstract ( 161 )   PDF (1235KB) ( 47 )   Save BACKGROUND: Studies have shown that hesperetin exerts protective effects on chondrocytes through a variety of mechanisms or signaling pathways, but the protective mechanisms have not been fully elucidated. OBJECTIVE: To investigate the effect of hesperetin on lipopolysaccharide-induced inflammatory degeneration of chondrocytes.  METHODS: Knee joint chondrocytes from suckling Sprague-Dawley rats were isolated and cultured in vitro, and identified by Safranine O staining. The cytotoxicity of hesperetin on chondrocytes was determined by the MTT assay to ensure the optimal concentration of hesperetin. Chondrocytes were randomly divided into three groups, including the control group, model group, and experimental group. The cellular model of osteoarthritis was established in the latter two groups by simulating chondrocytes with lipopolysaccharide. Chondrocytes in the experimental group was then intervened with hesperetin for 24 hours. Calcein-AM/EthD-I staining was used to detect cell viability. Immunohistochemical staining was performed to determine the expression of type II collagen in chondrocytes. Intracellular reactive oxygen species level was detected by a reactive oxygen species detection kit. Total glutathione level was detected by ELISA. Real-time fluorescent PCR was employed to detect the expression of interleukin 1β, interleukin 6, tumor necrosis factor α and type II collagen. RESULTS AND CONCLUSION: Safranine O staining results showed that the cells extracted were chondrocytes. Cytotoxicity test results showed 0.5 μmol/L hesperetin had the most significant effect on chondrocyte vitality. Compared with the control group, the model group showed a decrease in chondrocyte proliferation ability, an increase in reactive oxygen species levels, a decrease in total glutathione levels, an increase in type II collagen degradation, an increase in the levels of interleukin 1β, interleukin 6, and tumor necrosis factor α, and a decrease in the expression of type II collagen (P < 0.05). Compared with the model group, in the experimental group, the proliferation ability of chondrocytes increased, reactive oxygen species levels decreased, total glutathione levels increased, and type II collagen degradation decreased, levels of interleukin 1β, interleukin 6, and tumor necrosis factor α downregulated, and the expression of type II collagen upregulated (P < 0.05). To conclude, hesperetin has a protective effect on lipopolysaccharide-induced inflammatory degeneration of osteoarthritic chondrocytes, and the mechanism may be associated with inhibition of reactive oxygen species-mediated oxidative stress. Figures and Tables | References | Related Articles | Metrics

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Establishment of a rat femoral nonunion model by intramedullary fixation Lyu Lijun, Peng Wei, Li Chuangbing, Ye Shuo, Gao Qiuming 2024, 28 (26):  4189-4153.  doi: 10.12307/2024.435 Abstract ( 167 )   PDF (1077KB) ( 28 )   Save BACKGROUND: Establishing an objective and standard animal model of bone nonunion is essential for experimental studies and treatment of nonunion.  OBJECTIVE: To establish an objective animal model for experimental studies of nonunion.  METHODS: Specific pathogen-free male Wistar rats were selected and prepared by cutting off a 5 mm bone defect in the middle femur, peeling off a large periosteum and removing bone marrow. Animal models were fixed with a 1.2 mm Kirschner wire. At 1, 4 and 8 weeks, bone nonunion was observed by gross specimen observation, X-ray examination and histopathological examination.  RESULTS AND CONCLUSION: The gross specimen, X-ray film and histopathological examination showed that there was no callus formation in the bone defect area, the broken end was filled with fiber tissue, and the bone callus was rare or even invisible. To conclude, the rat model of nonunion can be successfully established by osteotomy of the middle femur, large periosteum peeling and bone marrow removal. This modeling method is simple, reliable and effective.  Figures and Tables | References | Related Articles | Metrics

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Human osteoarthritic chondrocytes up-regulate the expression of osteoprotegerin in osteoblasts via the Indian hedgehog signaling pathway Li Jiale, Luo Dasheng, Zheng Liujie, Liu Wei, Yao Yunfeng 2024, 28 (26):  4194-4201.  doi: 10.12307/2024.419 Abstract ( 158 )   PDF (1426KB) ( 19 )   Save BACKGROUND: Upregulation of hedgehog protein signaling can increase the expression of osteoarthritis markers, Runx2, a disintegrin and metalloproteinase with thrombospondin motifs, collagen type X alpha 1, and matrix metalloproteinase 13, while inhibition of hedgehog proteins attenuates the severity of osteoarthritis. It is speculated that osteoarthritic chondrocytes can influence bone formation by affecting osteoblasts through the Indian hedgehog protein (IHH) signaling pathway. OBJECTIVE: To investigate the effect of human osteoarthritic chondrocytes on subchondral osteoblasts. METHODS: Tibial plateau specimens from patients with osteoarthritis were collected. Chondrocytes were extracted using enzymatic digestion, and osteoblasts were extracted using enzymatic pre-digestion + bone block method. Chondrocytes were identified by toluidine blue staining and immunofluorescence and osteoblasts were identified by alkaline phosphatase staining and immunofluorescence. Chondrocytes were cultured in sodium alginate beads to maintain chondrocyte phenotype and co-cultured with osteoblasts. The co-culture system was added with IHH signaling pathway inhibitor (cyclopamine, 10 nmol/L) and activator (purmorphamine, 10 nmol/L) separately. After 48 hours of co-culture, osteoblasts from each group were collected, mRNA expressions of Gli1, osteoprotegerin, Runx2, parathyroid hormone-related peptide, alkaline phosphatase, receptor activator of nuclear factor-kB ligand (RANKL) and osteocalcin were detected by qRT-PCR, and protein expressions of GLi1, oseoprotegerin and RANKL in osteoblasts were detected by western blot. RESULTS AND CONCLUSION: The mRNA expression levels of GLi1, osteoprotegerin and RUNX2 in osteoblasts were significantly increased, while the mRNA expression levels of parathyroid hormone-related peptide were decreased (P < 0.05) when co-cultured with human osteoarthritic chondrocytes. The mRNA and protein levels of Gli1 were significantly decreased after the addition of IHH signaling pathway inhibitor (cyclopamine) (P < 0.05), and the mRNA and protein levels of Gli1 were significantly increased after the addition of IHH signaling pathway activator (purmorphamine) (P < 0.05). Osteoprotegerin showed the same trend as Gli1 in the experiment. The osteoprotegerin/RANKL ratio followed the same trend as osteoprotegerin.  To conclude, human osteoarthritic chondrocytes can promote the expression of Gli1, osteoprotegerin, Runx2 and other proteins in osteoblasts. The upregulation of osteoprotegerin is related to the IHH signaling pathway. Osteoarthritic chondrocytes can up-regulate the expression of osteoprotegerin in osteoblasts through the IHH signaling pathway and thus up-regulate the osteoprotegerin/RANKL ratio, which will contribute to bone formation in subchondral bone. Figures and Tables | References | Related Articles | Metrics

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Macrophage-specific promoter SP146-C1 enhances vascular endothelial growth factor C expression in atherosclerotic mice Li Sijin, Feng Xiaoteng, Wang Yiru, Liu Ping 2024, 28 (26):  4202-4208.  doi: 10.12307/2024.392 Abstract ( 186 )   PDF (1650KB) ( 37 )   Save BACKGROUND: The expression efficiency of recombinant adeno-associated virus serotype 9 (rAAV9) carrying the macrophage-specific promoter synthetic promoter 146-C1 (SP146-C1) and the exogenous gene vascular endothelial growth factor C (VEGFC) in atherosclerosis is uncertain. OBJECTIVE: To investigate the expression efficiency of rAAV9-SP146-C1-VEGFC in atherosclerotic mice and its effect on lymphangiogenesis. METHODS: Thirty ApoE-/- mice were fed high-fat diet for 12 weeks to establish atherosclerosis models and were randomly divided into six groups, five in each group: 7-, 14-, 21-, 28-, and 35-day transfection groups and control group. The mice in the transfection groups were transfected with 5.0×1011 vg rAAV9-SP146-C1-VEGFC by caudal vein injection. In the control group, the mice were injected with the same amount of control virus rAAV9-SP146-C1-Scramble. Animals in the first five groups were killed under anesthesia at 7, 14, 21, 28 and 35 days after transfection, respectively, and those in the control group were killed under anesthesia at 7 days. Serum, femur, tibia, heart and aorta tissue samples were collected and retained in each group. The femur and tibia of mice in each group were used to extract bone marrow-derived macrophages. The gene expression of vascular endothelial growth factor C (VEGFC), vascular endothelial growth factor receptor 3 (VEGFR3), Podoplanin and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in bone marrow-derived macrophages and the aorta were detected by RT-qPCR. VEGFC protein expression levels in bone marrow-derived macrophages and the aorta were detected by western blot, serum level of VEGFC was detected by ELISA, and VEGFC expression in the aortic sinus and LYVE-1 expression around the aorta and in the myocardium was detected by immunofluorescence. RESULTS AND CONCLUSION: The serum level of VEGFC, the mRNA expression of VEGFC, VEGFR3, Podoplanin, and LYVE-1 in bone marrow-derived macrophages and the aorta, the protein expression of VEGFC in bone marrow-derived macrophages, and the fluorescence intensity of VEGFC in aortic sinus plaques were significantly increased in the 7-day transfection group compared with the control group (P < 0.05, P < 0.01). Serum VEGFC level of mice transfected with rAAV9-SP146-C1-VEGFC gradually increased with time and began to decrease at 28 days. mRNA levels of VEGFC, VEGFR3, Podoplanin and LYVE-1 in mouse aorta and bone marrow-derived macrophages, VEGFC protein level in bone marrow-derived macrophages, VEGFC fluorescence intensity in aortic sinus plaques, LYVE-1 fluorescence intensity around the aortic sinus and in the myocardium gradually increased with time (P < 0.05). In addition, the mRNA level of LYVE-1 in the aorta and the fluorescence intensity of LYVE-1 around the aortic sinus and in the myocardium were the highest at 28 days (P < 0.05), and gradually decreased (P < 0.05). The expression of the other indicators reached the peak at 21 days. To conclude, rAAV9-SP146-C1-VEGFC could effectively transfect bone marrow-derived macrophages and promote lymphatic hyperplasia in atherosclerotic mice. Figures and Tables | References | Related Articles | Metrics

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Effect of transcranial direct current stimulation on human single-leg landing stability Lin Qinzhao, Wei Mengli, Zhong Yaping, Wu Qian, Zhou Botao, Wang Haifeng 2024, 28 (26):  4209-4215.  doi: 10.12307/2024.439 Abstract ( 168 )   PDF (1427KB) ( 37 )   Save BACKGROUND: Transcranial direct current stimulation (tDCS), as a non-invasive brain stimulation technique, can enhance human muscle strength or improve single-leg landing stability instantly, but no relevant research has demonstrated this yet. OBJECTIVE: To investigate the effect of tDCS on the stability of single-leg landings in human subjects. METHODS: Male undergraduate students from Wuhan Sports University were recruited as study participants. They were divided into two groups, A (n=6) and B (n=5), using a random number table. Group A underwent a sham stimulation session followed by a 3-day washout period, after which they received tDCS. Conversely, Group B received tDCS initially, followed by a 3-day washout period, and subsequently underwent the sham stimulation session. Following the respective stimulation sessions, an immediate single-leg landing test was administered to assess and collect biomechanical parameters. Data resulting from the tDCS intervention were aggregated and analyzed as the experimental group dataset, whereas data stemming from the sham stimulation were consolidated as the control group dataset. RESULTS AND CONCLUSION: Regarding core stability, the tDCS intervention showed a significant interaction with landing height on the maximal trunk flexion angle (P < 0.05). A paired comparison of the data showed a significant decrease in the maximum trunk flexion angle following true stimulation compared to sham stimulation at a 30-cm landing height. Additionally, the tDCS intervention had a significant main effect on the maximum trunk lateral bending angle and the mean trunk lateral bending angular velocity (P < 0.05). Following true stimulation, there was a significant decrease in the maximum trunk lateral bending angle and the mean trunk lateral bending angular velocity compared to sham stimulation. In terms of lower limb joint stability, the tDCS intervention had a significant main effect on the maximum dynamic ankle valgus angle (P < 0.05). This resulted in a significant decrease in the angle following true stimulation compared to sham stimulation. In addition, the tDCS intervention had a significant main effect on the peak muscle activation of the lateral head of the gastrocnemius lateralis (P < 0.05). This showed a significant increase after true stimulation compared to sham stimulation. An interaction between the tDCS intervention and landing height was observed for the peak muscle activation of the tibialis anterior (P < 0.05). Paired comparison analyses revealed a significant increase in muscle activation after true stimulation specifically at a 60-cm landing height. Regarding center of pressure stability, there were no significant interactions or main effects of the tDCS intervention on the mean lateral displacement, mean lateral displacement velocity, mean anterior-posterior displacement, or mean anterior-posterior displacement velocity at the center of pressure (P > 0.05). Furthermore, the tDCS intervention had no significant main effects on any of the center of pressure indicators (P > 0.05). In conclusion, tDCS can immediately improve core stability and lower limb joint stability during single-leg landing, making it an effective warm-up technique for improving single-leg landing stability and reducing the risk of lower limb injuries. Figures and Tables | References | Related Articles | Metrics

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Universal stepwise rehabilitation training promotes the functional recovery of quadriceps femoris after intertrochanteric femoral fracture surgery Wang Chunhong, Lu Ming 2024, 28 (26):  4216-4220.  doi: 10.12307/2024.433 Abstract ( 124 )   PDF (902KB) ( 15 )   Save BACKGROUND: If quadriceps femoris muscle is not effectively rehabilitated, the strength of quadriceps femoris muscle in patients with intertrochanteric fractures will gradually decline, even causing lower limb muscle atrophy. As a result, postoperative complications such as pain in the affected thigh and inflexibility of the hip and knee joints will occur. OBJECTIVE: To evaluate the effect of universal stepwise rehabilitation training of quadriceps femoris muscle on the postoperative rehabilitation of intertrochanteric fracture of the femur, and to investigate the efficacy of quadriceps femoris rehabilitation in the postoperative rehabilitation of intertrochanteric fractures of the femur. METHODS: A retrospective analysis was performed to analyze the data of 48 patients operated for intertrochanteric fracture of the femur who were rehabbed by applying a quadriceps femoris rehabilitation program between October 2016 and February 2022. Rehabilitation training included isotonic and isometric contraction training of quadriceps femoris muscle, and the time of exercise was from the 1st to the 12th week of the postoperative period. Patient’s Hip function was evaluated using hip joint mobility score in Merle D'Aubigne and Postel evaluation system, WOMAC lower extremity function score, and Harris hip joint function score. The Visual Analog Scale was used to assess patients’ pain. The Hospital Anxiety and Depression Scale was used to assess the patient’s psychological status. Changes in quadriceps muscle strength were also measured.  RESULTS AND CONCLUSION: The average healing time of the fracture was (9.78±1.65) weeks. At 4 weeks postoperatively, the patient’s hip function significantly improved compared with that at the preoperative period (P < 0.01), the Visual Analog Scale scores for pain evaluation decreased (P < 0.01), quadriceps femoris muscle strength increased (P < 0.01), and the Hospital Anxiety and Depression Scale scores decreased (P < 0.05). At 12 weeks postoperatively, as the rehabilitation training continued, the patient's hip function and pain symptoms further improved compared with those at 4 weeks postoperatively (P < 0.05), quadriceps femoris muscle strength further recovered (P < 0.05), and the Hospital Anxiety and Depression Scale scores further decreased (P < 0.01). At 24 weeks postoperatively, the rehabilitation training had been stopped, the patient’s hip joint function and muscle strength were well maintained, and no obvious amyotrophy occurred in the quadriceps femoris muscle, and there were no significant differences between 12 and 24 weeks postoerpatively (P > 0.05). No complications and adverse events occurred during postoperative rehabilitation. To conclude, the application of universal stepwise functional rehabilitation model of quadriceps femoris muscle in the early postoperative period of intertrochanteric formal fracture is helpful for the recovery of hip joint function, increasing muscle strength, and promoting fracture healing to a certain extent. Figures and Tables | References | Related Articles | Metrics

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Role of METTL3 in homocysteine-induced autophagy in mouse islet beta cells Ma Lingju, Wang Lexin, Chi Hongyang, Zhang Jingwen, Peng Hongjian, Gao Chunlan, Jiang Yideng, Huang Hui, Yang Li, Ma Shengchao 2024, 28 (26):  4221-4225.  doi: 10.12307/2024.423 Abstract ( 143 )   PDF (1344KB) ( 13 )   Save BACKGROUND: Hyperhomocysteinemia is closely related to the function of islet β cells, but its specific molecular mechanism is not fully understood. OBJECTIVE: To investigate the role of N6 methyltransferase-like 3 (METTL3) in homocysteine (Hcy)-induced autophagy of mouse islet β cells.  METHODS: The 3rd and 4th generation mouse islet β cells were taken for the experiment. (1) Cell modeling and grouping: cells in control group were not treated with Hcy, while those in homocysteine group were treated with 100 µmol/L Hcy for 48 hours. (2) The mouse islet β-cells were transfected with the plasmids overexpressing Ad-METTL3 and si-METTL3 according to the instructions of LipofectamineTM 2000. Three different interfering fragments were designed, and the one with the best interfering efficiency was verified and screened by PCR. (3) After transfection, the cells were divided into control group, Hcy group, Ad-NC (negative control)+Hcy group, Ad-METTL3+Hcy group, si-NC (negative control)+Hcy group and si-METTL3+Hcy group. (4) qRT-PCR and western blot were used to detect the expression levels of METTL3 and autophagy-related proteins LC3II/I and p62 in cells. Insulin level was determined by ELISA to evaluate insulin secretion capacity of islet cells. Autophagy-related proteins and insulin level were detected after overexpression and interference with METTL3.  RESULTS AND CONCLUSION: Compared with the control group, the expression level of LC3II/I was increased (P < 0.05), the expression of p62 was significantly reduced (P < 0.05), and the insulin secretion capacity was significantly decreased (P < 0.05) in the Hcy group. Compared with the control group, the protein and mRNA levels of METTL3 were reduced in the Hcy group (P < 0.05). After METTL3 silencing in islet β cells, Hcy further upregulated the expression of LC3II/I (P < 0.05), significantly dowregulated the expression of p62 (P < 0.05), and increased the insulin level (P < 0.05). After overexpression of METTL3, Hcy significantly decreased the LC3II/I expression and increased the p62 expression in islet β cells (P < 0.05).  To conclude, METTL3 is involved in the Hcy-induced autophagy regulation of islet β cells and plays a role in the regulation of insulin secretion. Figures and Tables | References | Related Articles | Metrics

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Therapeutic efficacy of massage versus instrument-assisted soft tissue mobilization in patients with lateral epicondylitis of the humerus Liu Yang, Wu Lianqing 2024, 28 (26):  4226-4233.  doi: 10.12307/2024.437 Abstract ( 211 )   PDF (988KB) ( 115 )   Save BACKGROUND: Instrument-assisted soft tissue mobilization is often used as a noninvasive treatment for soft tissue (skeletal muscle, ligament, and fascia) injuries and postoperative recovery to improve pain and enhance strength in the range of joint motion. OBJECTIVE: To compare the clinical efficacy of instrument-assisted soft tissue mobilization and massage therapy in patients with lateral epicondylitis of the humerus. METHODS: A total of 25 athletes with lateral epicondylitis of the humerus were enrolled in this study and randomized into two groups: 13 subjects receiving instrument-assisted soft tissue mobilization as the experimental group and 12 subjects receiving massage therapy as the control group. The treatment period was 4 weeks, with two sessions per week. Elbow joint visual analog scale, Mayo elbow performance index, elbow range of motion measurement, and forearm strength were measured and recorded in both groups before and after treatment.  RESULTS AND CONCLUSION: Both treatments significantly reduced visual analog scale score of the elbow joint after the first and last treatments (P < 0.05), but the visual analog scale score showed no significant difference between the two groups (P > 0.05). The Mayo elbow performance index showed a significant increase in both groups after the first and last treatments (P < 0.05), but there was no significant difference between the two groups (P > 0.05). In the maximum grip strength test, the maximum grip strength of the experimental group in the vertical direction and during internal and external rotations after treatment was better than that before treatment (P < 0.05), while the control group only showed improved maximum grip strength during internal rotation (P < 0.05), with no significant improvement in maximum grip strength in other states. There was also no significant difference in the maximum grip strength in all the three states between the two groups (P > 0.05). After the last treatment, the range of motion of the elbow joint and the angle of forearm pronation and supination were significantly improved in both intervention groups (P < 0.05). The maximum angle of the elbow joint for flexion was smaller than that before treatment (P < 0.05), and there was no significant difference in each angle of motion between the two groups (P > 0.05). The range of motion of the forearm and elbow joint in both groups were significant improved after the first and last treatment (P < 0.05) and there was no significant difference in difference in the range of motion of the forearm and elbow joint between the two groups (P > 0.05). To conclude, both instrument-assisted soft tissue mobilization and massage therapy significantly reduce pain, improve elbow flexibility and increase joint range of motion in patients with lateral epicondylitis of the humerus. However, instrument-assisted soft tissue mobilization is better than massage therapy to improve the maximum grip strength. Figures and Tables | References | Related Articles | Metrics

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Application of MRI-based image navigation and target selection in transcranial magnetic stimulation treatment Wang Li, Chen Peng, Wei Xiuying, Lu Yangjia, Lai Sijia, Wang Kaihua 2024, 28 (26):  4234-4241.  doi: 10.12307/2024.380 Abstract ( 208 )   PDF (1295KB) ( 132 )   Save BACKGROUND: In clinical application, the therapeutic effect of transcranial magnetic stimulation depends on the ability to accurately target the areas of the brain that need to be stimulated. In recent years, with the development of neuronavigation systems, mobile augmented reality technology, and the new methods of processing magnetic resonance imaging (MRI) data, the accuracy of stimulus target localization and the optimization of target selection are expected to improve further. OBJECTIVE: To review the principle of MRI-based image navigation and its application in transcranial magnetic stimulation and summarize the roles of different modal MRI data analyses in guiding the selection of target areas for transcranial magnetic stimulation. METHODS: An online computer search for relevant literature was performed in PubMed, CNKI database and WanFang database, with the keywords “transcranial magnetic stimulation, coil positioning, neuronavigation, augmented reality, magnetic resonance, theory.” Finally, 63 documents were included for review. RESULTS AND CONCLUSION: Among the traditional methods of positioning transcranial magnetic stimulation coils, the “5 cm rule” and the international electroencephalogram 10-20 positioning method are the most commonly used. These methods have the advantages of simplicity and economy, but they rely too much on the operator’s experience and there were technical differences between operators. The neuronavigation system, which is based on stereotactic technology, is the guiding method for positioning transcranial magnetic stimulation coils with the highest visual degree and accuracy. It achieves visual positioning through MRI data acquisition, 3D brain reconstruction, head model registration and stereogeometric positioning. It has high application value in clinical treatment and scientific research, but it cannot be promoted in medical institutions due to its high cost. For various medical institutions, mobile augmented reality is a cost-effective and efficient alternative to the neuronavigation system, which achieves visual positioning of brain tissue under the scalp through MRI data acquisition, 2D/3D image construction, virtual image and real brain image superposition. It has the advantages of directly visualization and low cost, and is expected to be popularized and applied in primary medical units. Although the superiority of clinical efficacy of visual coil positioning over the electroencephalogram 10-20 localization strategy has not yet been fully demonstrated, with the progress of brain MRI data analysis, visual positioning is expected to further optimize the target selection strategy of transcranial magnetic stimulation therapy and to improve the response rate and individuation degree of transcranial magnetic stimulation treatment. This is a promising and challenging research direction in the future. Figures and Tables | References | Related Articles | Metrics

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Signaling pathways related to kaempferol active monomers in the treatment of osteoporosis Yang Qipei, Chen Feng, Cui Wei, Zhang Chi, Wu Ruiqi, Song Zhenheng, Meng Xin 2024, 28 (26):  4242-4249.  doi: 10.12307/2024.338 Abstract ( 210 )   PDF (1201KB) ( 49 )   Save BACKGROUND: Recent studies have shown that the occurrence and prevention of osteoporosis often focus on the cellular molecular level, and the mechanism of related signaling pathways is an important way to further understand osteoporosis. At present, traditional Chinese medicine has been proved to play a significant role in alleviating osteoporosis. Kaempferol as an emerging Chinese herbal extract has become the focus of clinical and basic research due to its anti-osteoporosis effectiveness and mechanism of action. OBJECTIVE: To further understand the mechanism underlying the anti-osteoporosis effect of kaempferol active monomer through regulation of related signaling pathways by analyzing and collating domestic and foreign literature. METHODS: “Kaempferol, osteoporosis, osteoblasts, osteoclasts, bone marrow mesenchymal stem cells, signaling pathways” were used as Chinese and English search terms to search CNKI, WanFang, VIP, PubMed, Web of Science and Embase databases for relevant literature published from database inception to February 2023. RESULTS AND CONCLUSION: Kaempferol affects the occurrence and progression of osteoporosis to varying degrees by participating in the regulation of differentiation, proliferation and apoptosis of bone marrow mesenchymal stem cells, osteoblasts and osteoclasts. Kaempferol can prevent and treat osteoporosis by regulating various signaling pathways. Kaempferol can promote the proliferation and differentiation of osteoblasts and inhibit the formation of osteoclasts by interfering with the Wnt/β-catenin signaling pathway to regulate β-catenin protein counting and the formation of β-catenin-TCf/LEF complex. Kaempferol interferes with the RANK/RANKL pathway to maintain the dynamic balance of osteoclasts and bone homeostasis. Kaempferol can promote bone formation by intervening with the PI3K/Akt signaling pathway to upregulate the levels of related osteogenic factors Runx2 and Osterix and promote bone cell calcification. Kaempferol interferes with osteoclast differentiation and inhibits reactive oxygen species activity by regulating the ER/ERK pathway. Kaempferol inhibits the expression of ERK, JNK, p38/MAPK and decreases reactive oxygen species production by interfering with the MAPK pathway, thus protecting osteogenesis. Kaempferol enhances the expression of osteogenic factors, bone morphogenetic protein-2, p-Smad1/5/8, β-catenin and Runx2, inhibits the expression of Peroxisome proliferation-activated receptor, and promotes the differentiation and proliferation of osteoblasts through the BMP/Smad pathway. Figures and Tables | References | Related Articles | Metrics

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Intestinal flora and osteoporosis and exercise intervention Yang Qihang, Pu Rui, Chen Ziyang, Leng Siyi, Song Yongjing, Liu Hui, Du Guangyou 2024, 28 (26):  4250-4256.  doi: 10.12307/2024.436 Abstract ( 183 )   PDF (872KB) ( 33 )   Save BACKGROUND: Intestinal flora and its metabolites can participate in the pathological process of osteoporosis and play an important role in the diagnosis and treatment of osteoporosis. In addition, exercise can regulate the intestinal flora and thus affect the occurrence and development of osteoporosis. OBJECTIVE: To summarize the effects and mechanism of intestinal flora on osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells, and the potential role of exercise-mediated intestinal flora in regulating osteoporosis. METHODS: “Intestinal flora, intestinal bacteria, metabolites of intestinal flora, bone metabolism, osteoporosis, exercise” were selected as keywords. Literatures from 1990 to 2023 were retrieved from PubMed and CNKI databases. RESULTS AND CONCLUSION: Changes in the abundance and diversity of intestinal flora and changes in the levels of intestinal flora metabolites such as trimethylamine oxide and bile acid can be used as biomarkers for the diagnosis of osteoporosis. The imbalance of intestinal flora can lead to intestinal barrier dysfunction and excessive production of lipopolysaccharides and trimethylamine oxide, induce the secretion of tumor necrosis factor-α and other inflammatory cytokines, activate the nuclear factor κB signaling pathway and aggravate oxidative stress, thus promoting osteoclast differentiation, inducing osteoblast apoptosis and affecting bone marrow mesenchymal cell migration. Remodeling intestinal flora homeostasis can inhibit inflammatory response, downregulate oxidative stress, inhibit osteoclast differentiation, promote osteoblast differentiation, and regulate the osteogenic migration of bone marrow mesenchymal cells to prevent and treat osteoporosis. Exercise can regulate intestinal flora homeostasis, improve intestinal barrier function, promote the secretion of short-chain fatty acids and bile acids, down-regulate serum lipopolysaccharide level, reduce oxidative stress, and then inhibit osteocyte apoptosis, inhibit osteoclast differentiation, promote osteoblast differentiation, and regulate osteocyte nutrient metabolism to exert the potential of preventing and treating osteoporosis. Figures and Tables | References | Related Articles | Metrics

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The mechanism and application of heart rate variability biofeedback regulation of the autonomic nervous system Wang Hao, Wang Wendi, Wu Dongzhe, Gao Xiaolin, Shi Yongjin 2024, 28 (26):  4257-4264.  doi: 10.12307/2024.452 Abstract ( 277 )   PDF (1738KB) ( 81 )   Save BACKGROUND: Heart rate variability biofeedback is a respiratory training method that uses slow and deep breathing at the resonant frequency to induce rhythmic, high-amplitude oscillations in the cardiovascular system, thereby stimulating and exercising the autonomic and baroreflex. However, current studies have not systematically reviewed how heart rate variability biofeedback modulates the autonomic function and produces effects. There is a lack of public understanding of the mechanism of heart rate variability biofeedback, and its application progress and scheme are not fully understood. OBJECTIVE: To review the existing experimental studies on the effects of heart rate variability biofeedback on symptoms in different populations at home and abroad and to introduce the mechanisms and advances in the application of heart rate variability biofeedback to modulate the autonomic nervous system. METHODS: “Heart rate variability biofeedback, resonance breathing, heart rate variability, autonomic nerve, breathing training, chronic diseases, mental illness, biofeedback” were used as Chinese or English keywords to search in CNKI, WanFang Database, PubMed, and Web of Science. A total of 72 core related papers were included according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION: The body’s oscillation system and resonance system are essential for the effectiveness of heart rate variability biofeedback. Oscillations reflect the response to external stimuli and self-regulating reflex systems, while resonances involve synchronous oscillations that result in higher amplitude operations. The balance between sympathetic and parasympathetic nerves is crucial for maintaining a stable internal environment. Autonomic nervous system disorders are associated with reduced heart rate variability and are closely linked to the progression of related diseases. Heart rate variability biofeedback utilizes the resonance characteristics of the cardiovascular system, inducing rhythmic high-amplitude oscillations by employing deep slow breathing at the resonance frequency. This method improves the regulatory function of the sympathetic and parasympathetic system reflexes and enhances the balance regulation between the two systems. Two major mechanisms of cardiovascular system resonance are the baroreflex closed-loop pathway and respiratory sinus arrhythmia. These mechanisms, along with the unique delay of baroreflex, result in a 0° phase angle oscillation between heart rate and respiration and a 180° phase angle oscillation between blood pressure and respiration during breathing at the resonant frequency rhythm. Periodically stimulating the human cardiovascular oscillation system through this method is an easy-to-operate and effective training approach. Currently, heart rate variability biofeedback is mainly applied in the fields of mental illness, chronic disease, and sports. However, the intervention mechanism and efficacy are unclear, the intervention content, frequency and duration are varied, and there are limited review studies on the intervention methods tailored to different types of individuals. As a non-drug and non-invasive intervention, heart rate variability biofeedback can significantly increase heart rate variability, regulate the balance between sympathetic and parasympathetic nerves, and improve the stability and adaptability of the autonomic nervous system. In the future, it is suggested to investigate the mechanisms and potential applications of the pathways of the heart rate variability biofeedback that induce cardiovascular resonance. It is also recommended to incorporate long-term follow-ups to assess the sustained value of heart rate variability biofeedback in various fields. This would provide new directions and strategies for the comprehensive treatment of complex diseases. Figures and Tables | References | Related Articles | Metrics