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18 June 2026, Volume 30 Issue 17 Previous Issue    Next Issue

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Total flavonoids from Semen Cuscutae inhibits osteoblast apoptosis in hormone-induced femoral head avascular necrosis Zhao Yu, Xue Yun, Huang Jiajun, Wu Diyou, Yang Bin, Huang Junqing 2026, 30 (17):  4289-4298.  doi: 10.12307/2026.195 Abstract ( 80 )   PDF (3830KB) ( 23 )   Save BACKGROUND: The PI3K/Akt pathway, as an intracellular signal transduction pathway, plays a crucial role in regulating cell proliferation, growth, and metabolism. Semen Cuscutae, a traditional Chinese medicine used for kidney tonification, possesses potential bone-protective effects due to its total flavonoids; however, the specific molecular mechanisms remain unclear. OBJECTIVE: To investigate the protective effect of total flavonoids from Semen Cuscutae against dexamethasone-induced osteoblast apoptosis and its potential molecular mechanisms through a combination of network pharmacology and in vitro experiments. METHODS: Network pharmacology was used to predict potential targets and signaling pathways for Semen Cuscutae in the treatment of dexamethasone-induced femoral head avascular necrosis. hFOB1.19 cells were cultured in vitro and treated with different concentrations of total flavonoids from Semen Cuscutae (0, 25, 50, 100, 200, 400, and 600 μg/mL) for 24 hours. Cell viability was assessed using the cell counting kit-8 assay to select the optimal treatment dose for subsequent experiments. hFOB1.19 cells were divided into six groups: control, dexamethasone, total flavonoids from Semen Cuscutae at 100, 200,  400 μg/mL plus 2 μmol/L dexamethasone, and total flavonoids from Semen Cuscutae plus LY294002 groups (400 μg/mL total flavonoids from Semen Cuscutae and 10 μmol/L LY294002, a PI3K inhibitor). Cell viability was determined using the cell counting kit-8 assay, apoptosis rate was measured by flow cytometry, apoptosis-related protein expression was assessed by immunofluorescence, reactive oxygen species levels were quantified using the DCFH-DA probe, and expression of proteins related to the PI3K/Akt pathway was analyzed by western blot assay after treatment,. RESULTS AND CONCLUSION: (1) Network pharmacology results indicated that the potential targets of Semen Cuscutae may be related to the regulation of tumor necrosis factor, p53, interleukin-6, serine/threonine protein kinase 1, vascular endothelial growth factor A, caspase-3, interleukin-1β, hypoxia-inducible factor 1α expression, and the PI3K/Akt pathway. (2) CCK-8 results showed that total flavonoids from Semen Cuscutae promoted the proliferation of hFOB1.19 cells within a certain range and alleviated the inhibitory effect of dexamethasone on the proliferation of hFOB1.19 cells. (3) Total flavonoids from Semen Cuscutae inhibited dexamethasone-induced apoptosis and increased reactive oxygen species levels, reduced the expression of cleaved caspase-3 and Bax, and decreased reactive oxygen species levels, while increased the protein expression of Bcl-2. (4) Compared with the dexamethasone group, total flavonoids from Semen Cuscutae enhanced the expression of p-PI3K and p-Akt proteins. (5) The PI3K inhibitor LY294002 reversed the effects of total flavonoids from Semen Cuscutae on apoptosis and reactive oxygen species levels in dexamethasone-treated cells. The results indicate that total flavonoids from Semen Cuscutae can attenuate dexamethasone-mediated apoptosis in hFOB1.19 cells, and the mechanism may be related to the activation of the PI3K/Akt pathway.  Figures and Tables | References | Related Articles | Metrics

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Preparation and evaluation of an animal model of osteoporosis and osteoarthritis comorbidity in rats Fu Jingyue, Zhou Qinfeng, Li Muzhe, Ma Yong, Pan Yalan, Sun Jie, Huang Xiangyang, Guo Yang 2026, 30 (17):  4299-4308.  doi: 10.12307/2026.130 Abstract ( 95 )   PDF (40841KB) ( 19 )   Save BACKGROUND: The current prevalence of osteoporosis and osteoarthritis comorbidity is extremely high in the elderly population, which is a major cause of pain, disability, fracture risk and socio-economic costs globally, but its pathogenesis remains unclear. OBJECTIVE: To explore a suitable animal model of osteoporosis and osteoarthritis comorbidity, thereby providing a research basis for animal experiments of osteoporosis and osteoarthritis comorbidity. METHODS: Sixty female Sprague-Dawley rats were randomly divided into sham-operated group 1, sham-operated group 2, osteoporosis-osteoarthritis model group and osteoarthritis-osteoporosis model group. In the osteoporosis-osteoarthritis model group, the osteoporosis model was first established by bilateral ovariectomy in rats, and 4 weeks later, the osteoarthritis model was constructed by the modified Hulth method. In the osteoarthritis-osteoporosis model group, the osteoarthritis model was first established by the modified Hulth method, and 4 weeks later, the osteoporosis model was constructed by bilateral ovariectomy. In the sham-operated group 1, the ovaries were not removed, and only the joint cavity was opened without damaging the intra-articular tissues, with the rest procedures being the same as those in the osteoporosis-osteoarthritis model group. In the sham-operated group 2, only the joint cavity was opened without damaging the intra-articular tissues, and the ovaries were not removed, with the rest procedures being the same as those in the osteoarthritis-osteoporosis model group. At 4, 8, and 12 weeks after modeling, Micro CT was used to detect the imaging changes of the knee joint and analyze the changes in bone microstructure. The expressions of osteoprotegerin, receptor activator of nuclear factor kappa B ligand, tumor necrosis factor α, and interleukin 1β in serum were detected by ELISA. Hematoxylin-eosin staining and safranin O-fast green staining were used to observe the pathological changes in the cartilage and subchondral bone of the knee joint, and tartrate-resistant acid phosphatase staining was used to observe the activity and distribution of osteoclasts in the subchondral bone of the knee joint. RESULTS AND CONCLUSION: (1) Compared with the sham-operated groups, the bone mineral density of the distal femur in the model group decreased significantly at 4 weeks after operation (P < 0.000 1), and remained stable at 8 weeks after operation. Compared with the sham-operated group, the bone mineral density of the subchondral bone in the two model groups decreased significantly at 4 weeks after operation (P < 0.000 1), and showed an increasing trend at 8 weeks after operation. Compared with the sham-operated groups, the bone volume fraction and the number of bone trabeculae in the two model groups were significantly decreased (P < 0.01), and the separation of bone trabeculae was significantly increased (P < 0.01). Compared with the osteoarthritis-osteoporosis group, the osteoporosis-osteoarthritis group had a significantly lower bone volume fraction (P < 0.000 1) and a significantly higher trabecular separation (P < 0.001) at 4 weeks after operation, but there was no significant difference between the two model groups at 8 and 12 weeks after operation. (2) Compared with the sham-operated groups, the serum levels of inflammatory factors tumor necrosis factor-α and interleukin-1β in the two model groups were significantly increased (P < 0.01), and there were sighificant differences between the two model groups. The osteoprotegerin/receptor activator of nuclear factor kappa B ligand ratio was significantly down-regulated (P < 0.01), and there was no significant difference between the two model groups. (3) The structure of bone trabeculae was complete and continuous, the cartilage surface was smooth and the tide line was clear in the sham-operated groups, while the number of bone trabeculae was reduced, the cartilage surface was uneven, and the chondrocytes were unevenly distributed in the model groups at 4 weeks after operation. At 8 weeks after operation, the trabecular structure was broken, the joint space was reduced, and the tide line was interrupted. At 12 weeks after operation, proteoglycan was severely lost, and the red signal was weakened or completely faded. (4) The results of tartrate-resistant acid phosphatase staining showed that the positive rate in the sham-operated groups was evenly distributed, mainly distributed on the surface of bone trabeculae, without abnormal aggregation. The positive rate in the subchondral bone of the model groups increased, and abnormal aggregation of osteoclasts or invasion of cartilage calcification layer could be seen in some areas. To conclude, bilateral ovariectomy followed by modified Hulth method for 4 weeks can stably establish the animal model of osteoporosis and osteoarthritis comorbidities, with the early stage of comorbidities at 4 weeks postoperatively, and the middle to late stage of comorbidities at 8-12 weeks postoperatively. Figures and Tables | References | Related Articles | Metrics

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Immune microenvironment and inflammatory repair of cystic degeneration in steroid-induced osteonecrosis of the femoral head: a single-cell sequencing analysis Lin Yong, Yang Xiaoqiang, Lin Kun, Yang Fan, He Mincong, Wei Qiushi 2026, 30 (17):  4309-4317.  doi: 10.12307/2026.142 Abstract ( 105 )   PDF (2033KB) ( 14 )   Save BACKGROUND: Cystic degeneration is a critical pathological feature of steroid-induced osteonecrosis of the femoral head and exhibits unusual reparative responses. Studies have shown that immune cell infiltration and upregulation of inflammatory cytokines in cystic areas may be closely related to bone regeneration during repair. Therefore, investigating the role of the immune microenvironment in cystic lesion repair has important clinical significance. OBJECTIVE: To explore the immune microenvironment in cystic degeneration of steroid-induced osteonecrosis of the femoral head based on single-cell sequencing and to elucidate the role of inflammation in the repair process as well as to validate the effects of glucocorticoids on macrophage polarization and inflammatory responses via in vitro cellular experiments. METHODS: (1) Single-cell RNA sequencing was used to analyze the immune microenvironment of cystic regions in steroid-induced osteonecrosis of the femoral head. Pathologic observation of cystic degeneration specimens was also performed. (2) In addition, an in vitro cell model was established. In vitro cultured RAW 264.7 macrophages were divided into control group (normal culture of RAW cells), lipopolysaccharide group (lipopolysaccharide intervention for 24 hours), and dexamethasone+lipopolysaccharide group (dexamethasone pretreatment for 72 hours and lipopolysaccharide intervention for 24 hours). RT-qPCR was used to detect the expression of cellular M1 polarization markers (inducible nitric oxide synthase, tumor necrosis factor α, and interleukin 6) and M2 polarization markers (arginase 1 and interleukin 10). ELISA was used to detect the levels of inflammatory factors in the cell culture supernatants. Flow cytometric assay was performed to detect the levels of cellular reactive oxygen species. RESULTS AND CONCLUSION: (1) Single-cell sequencing results revealed a diverse infiltration of immune cells in the cystic region, with significant upregulation of inflammatory cytokines such as tumor necrosis factor α and interleukin 6. (2) Observation of the pathologic specimen showed the presence of multiple inflammatory cell infiltrates in the cystic degeneration. (3) In vitro experiments demonstrated that combined treatment with dexamethasone and lipopolysaccharide significantly induced M1 polarization of RAW 264.7 macrophages, inhibited the expression of anti-inflammatory M2 phenotype and promoted the generation of reactive oxygen species, thereby enhancing the local inflammatory response (significant upregulation of tumor necrosis factor α, interleukin 6 and interleukin 1β). Overall, the immune microenvironment in the cystic regions of steroid-induced osteonecrosis of the femoral head plays a critical role in bone repair. Immune cell infiltration and inflammatory cytokine expression may exert dual effects during the reparative process. Excessive immune activation may lead to repair failure. Thus, modulating immune responses—especially balancing M1/M2 macrophage polarization—may serve as a potential therapeutic strategy for enhancing cystic repair in steroid-induced osteonecrosis of the femoral head. Figures and Tables | References | Related Articles | Metrics

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Surface electromyographic evaluation of scapular dyskinesia in patients with rotator cuff tears Wang Xuepeng, He Yong 2026, 30 (17):  4318-4324.  doi: 10.12307/2026.096 Abstract ( 106 )   PDF (1463KB) ( 18 )   Save BACKGROUND: Rotator cuff tears are a prevalent condition affecting the shoulder joint, which can substantially diminish a patient’s quality of life. Surface electromyography is a diagnostic technique that captures the electrophysiological signals of muscles during movement. Most of its studies have focused on special populations such as athletes and hemiplegic patients, but its use in patients with rotator cuff tears is still rare. OBJECTIVE: To compare the differences in the movement patterns of the muscles around the scapula between normal subjects and patients with rotator cuff tears using surface electromyography and to investigate the pathogenetic mechanisms of scapular dyskinesia in patients with rotator cuff tears, thereby providing a basis for the establishment of clinical rehabilitation protocol.  METHODS: From September 2021 to February 2023, 40 patients with rotator cuff tears who met the enrolled criteria at Guanghua Hospital affiliated to Shanghai University of Chinese Medicine were included in the trial group, and a control group without shoulder disease (n=40) was set. Demographic and clinical data were obtained using surface electromyography. Using the maximal voluntary isometric contraction (MVIC) method, the %MVIC of the upper trapezius, middle trapezius, lower trapezius, and serratus anterior muscles was measured during shoulder flexion, abduction, and external rotation at the side. Each movement was tested thrice, and the average %MVIC ratios of upper trapezius/lower trapezius, upper trapezius/middle trapezius, and upper trapezius/serratus anterior were calculated for intergroup comparison. RESULTS AND CONCLUSION: Compared with the control group, the trial group showed significantly higher %MVIC ratios of upper trapezius/lower trapezius, upper trapezius/middle trapezius, and upper trapezius/serratus anterior during shoulder flexion, abduction, and external rotation at the side (all P < 0.05). To conclude, the mechanism of scapular dyskinesis in patients with rotator cuff tears may involve overactivation of the trapezius and serratus anterior muscles, resulting in movement imbalance. Figures and Tables | References | Related Articles | Metrics

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A metabolomics study on the mechanism by which Shixiang plaster promotes the healing of chronic refractory wounds in rats Wang Yan, Zhang Kaiwei, Liu Man, Fei Ji, Zhu Xu, Ni Yuntao 2026, 30 (17):  4325-4336.  doi: 10.12307/2026.068 Abstract ( 84 )   PDF (4189KB) ( 23 )   Save BACKGROUND: Previous research has shown that Shixiang plaster is effective in promoting chronic refractory wound healing, but its precise mechanism in metabolomics is not fully understood.  OBJECTIVE: To investigate the effects of Shixiang plaster on chronic refractory wounds using untargeted metabolomics and immunological methods.  METHODS: Animal models of chronic refractory wounds (2 cm × 2 cm full-thickness skin defect + Staphylococcus aureus covered wound) were established in 36 male Sprague-Dawley rats. The day after modeling, model rats were divided into model (n=12), Beifuji (n=12), and Shixiang plaster (n=12) groups. The model group received only saline-moistened sterile dressings. Shixiang plaster or Beifuji (recombinant basic fibroblast growth factor as the main ingredient) was applied to the wounds in the latter two groups, respectively, each covered with sterile dressing and changed every 24 hours. Treatments continued for 14 days. Wound secretions were collected for detection of fibronectin levels using ELISA. Metabolic profiling of wound exudates was performed using liquid chromatography-mass spectrometry, and differential metabolites were screened and identified using principal component analysis and partial least squares-discriminant analysis. KEGG enrichment analysis of differential metabolites and Veen association analysis were performed. RESULTS AND CONCLUSION: (1) With the prolongation of the administration time, the wound area was decreased in all the three groups, with the slowest wound recovery in the model group and the fastest in the Shixiang plaster group. The level of fibronectin in the Shixiang plaster group was higher than that in the model group at 7 and 14 days after administration (P < 0.05). (2) There were 118 unique differential metabolites screened between 7 days and 3 days after administration, 129 unique differential metabolites screened between 14 days and 3 days after administration, and 30 unique differential metabolites screened between 14 days and 7 days after administration. KEGG enrichment analysis showed that Shixiang plaster enhanced wound healing by modulating several metabolic pathways, especially the ABC transporter protein pathway, the cAMP signaling pathway, and the mTOR signaling pathway, which played crucial roles in cell proliferation, migration, immune response, and antioxidant processes. Veen correlation analysis identified common different metabolites, methoxsalen and 5'-methylthioadenosine, at 3, 7, and 14 days after administration. To conclude, Shixiang plaster may optimize ABC transporter proteins, cAMP signaling pathway and mTOR signaling pathway by modulating the expression of methoxsalen and 5'-methylthioadenosine, thus exerting anti-inflammatory, antioxidant and cell proliferation-promoting effects and accelerating wound healing. Figures and Tables | References | Related Articles | Metrics

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Impact of Zi-Zhu ointment on the miRNA expression profile in mouse models of diabetic ulcers: a high-throughput sequencing analysis Li Wenhui, Fan Weijing, Liu Guobin 2026, 30 (17):  4337-4346.  doi: 10.12307/2026.103 Abstract ( 73 )   PDF (2609KB) ( 33 )   Save BACKGROUND: Diabetic ulcers are prone to recurrent outbreaks and are difficult to heal. The occurrence and progression of these ulcers are associated with differential expression of miRNAs. Research on the impact of Zi-Zhu ointment on microRNA (miRNA) expression during the healing process may provide new insights into the treatment of chronic ulcers with traditional Chinese medicine.  OBJECTIVE: To investigate the potential mechanism underlying the intervention of Zi-Zhu ointment in diabetic ulcers using high-throughput sequencing and bioinformatics analysis methods.  METHODS: A total of six mice were used in each of the following groups: normal group, model group, and Zi-Zhu ointment group. In the latter two groups, high-fat feed combined with streptozotocin injection was performed to construct a diabetic model, and the skin was clipped on the back to form a chronic diabetic ulcer. The Zi-Zhu ointment group was given Zi-Zhu ointment at the dose of 0.032 g/cm², once a day, for 14 days. The modeling and wound healing indicators were assessed, and three mice from each group were randomly selected for sequencing. Differentially expressed miRNAs between the groups were analyzed using bioinformatics methods, and a preliminary regulatory network of the differentially expressed miRNAs, their target genes, and gene functions in diabetic ulcer was established.  RESULTS AND CONCLUSION: (1) A total of 1 072 known miRNAs were screened in the model group tissues compared with the normal group, with 94 showing significant differences. Among these, the top three up-regulated miRNAs were miR-1298-5p, miR-29b-3p, and miR-151-5p, while the top three down-regulated miRNAs were miR-223-3p and miR-135a-5p. These miRNAs were primarily associated with cell proliferation, apoptosis, wound healing, angiogenesis, and anti-inflammation processes. (2) In diabetic mice before and after ulcer administration, a total of 1 056 known miRNAs were screened in ulcerated tissue, with 57 showing significant differences. The top three up-regulated miRNAs were miR-451a, miR-363-3p, and miR-122-5p, while the top three down-regulated miRNAs were miR-1964-3p, miR-5099, and miR-182-3p. These miRNAs were mainly associated with cell proliferation, migration, regulation of macrophages, and improvement of insulin resistance. (3) Gene ontology analysis revealed that the target genes were primarily implicated in cell development, neural development, protein binding, phosphatidylinositol 3-kinase activity, and serine/threonine protein kinase activity. (4) Furthermore, Kyoto Encyclopedia of Genes and Genomes functional analysis indicated that the differentially expressed target genes in the model group, compared with the normal group, were enriched in pathways such as mTOR signaling, PI3K-Akt signaling, AMPK signaling, the Wnt signaling pathway, and cancer-related pathways. Conversely, in the diabetic ulcer treated with Zi-Zhu ointment, enriched pathways included breast cancer and liver cancer-related pathways, as well as cAMP signaling, p53 signaling, Wnt signaling, and PI3K-Akt signaling pathways compared with the model group. The study preliminarily established a regulatory network involving differentially expressed miRNAs, their target genes, and gene functional pathways in diabetic ulcers. Zi-Zhu ointment can significantly promote the healing of diabetic ulcers. Diabetes induces differential expression of miRNAs, and treatment with Zi-Zhu Ointment also alters the miRNA profile. This lays a foundation for future research on the mechanisms of disease occurrence and development, as well as treatment strategies from the perspective of miRNAs. Figures and Tables | References | Related Articles | Metrics

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Promoting effect of acupuncture combined with rehabilitation training on the reconstruction of damaged neurological function in rats with cerebral infarction Yang Chong, Wu Yuci, Yang Han, Wang Meiting, Liu Lei 2026, 30 (17):  4347-4356.  doi: 10.12307/2026.121 Abstract ( 75 )   PDF (8382KB) ( 14 )   Save BACKGROUND: Acupuncture combined with rehabilitation training has significant clinical efficacy in the treatment of cerebral infarction and can promote the reconstruction of damaged neurological function in patients with cerebral infarction, but its specific mechanism is still unclear. OBJECTIVE: To investigate the mechanism of acupuncture combined with rehabilitation training in promoting the reconstruction of damaged neurological function in rats with cerebral infarction. METHODS: Sixty male Sprague-Dawley rats were divided into a sham operation group (15 rats) and an operation group (45 rats) by using the randomized numerical table method. In the sham operation group, only the right common carotid artery, internal carotid artery, external carotid artery and vagus nerve were isolated without intervention. In the operation group, the middle cerebral artery occlusion model was established. At 3 days after modeling, model rats were randomized into three groups with 15 rats in each group: a model group, a rehabilitation training group and an acupuncture combined with rehabilitation training group. The model group received no intervention. The rehabilitation training group performed rehabilitation training, including running training and balance training, once a day for 7 consecutive days. The acupuncture combined with rehabilitation training group performed acupuncture at Baihui, Shenting and Shuigou, once a day for 7 consecutive days, on the basis of the rehabilitation training group. The modified neurological severity scores were used to assess the degree of neurological deficits after intervention. Morris water maze was used to observe the spatial learning and memory ability. Hematoxylin-eosin staining was used to observe the pathological changes in the hippocampus. ELISA was used to detect the expression levels of Caspase-3 and Caspase-8 proteins in the cerebral cortex. Western blot was used to detect the expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in the cerebral cortex. RESULTS AND CONCLUSION: (1) Compared with the sham operation group, the modified neurological severity scores were increased (P < 0.01); spatial learning and memory ability were decreased; hippocampal damage was obvious, hippocampal neurons were arranged sparsely and disorderly with visible degeneration, and the number of glial cells was increased; the protein expression levels of Caspase-3 and Caspase-8 were increased (P < 0.01); the protein expression levels of PI3K, Akt and mTOR were decreased (P < 0.01) in the model group. (2) Compared with the model group, the modified neurological severity scores were decreased (P < 0.01); spatial learning and memory ability were increased; hippocampal damage was improved, hippocampal neurons were arranged orderly with degeneration decreased, and the number of glial cells was decreased; the protein expression levels of Caspase-3 and Caspase-8 were decreased (P < 0.01); the protein expression levels of PI3K, Akt and mTOR were increased (P < 0.01) in the rehabilitation training group and the acupuncture combined with rehabilitation training group. Moreover, the improvement of each index was more obvious in the acupuncture combined with rehabilitation training group compared with the rehabilitation training group. To conclude, acupuncture combined with rehabilitation training can promote the reconstruction of damaged neurological function in rats with cerebral infarction and exert neuroprotective effects via the activation of PI3K/Akt/mTOR signaling pathway. Figures and Tables | References | Related Articles | Metrics

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Hind limb muscle atrophy in rats with spinal cord injury: effects of different rehabilitation therapy strategies Fu Yingxue, Wang Xianbin, Chen Xingyu, Wu Shuang 2026, 30 (17):  4357-4365.  doi: 10.12307/2026.114 Abstract ( 71 )   PDF (2459KB) ( 12 )   Save BACKGROUND: Spinal cord injury leads to varying degrees of muscle atrophy. While there are multiple treatment options available for muscle atrophy after spinal cord injury, few studies have compared the efficacy of different rehabilitative strategies in addressing muscle atrophy resulting from spinal cord injury. OBJECTIVE: To investigate the effects of neuromuscular electrical stimulation, repetitive peripheral magnetic stimulation and treadmill training on gastrocnemius muscle function in rats after spinal cord injury. METHODS: Thirty female Sprague-Dawley rats were randomly divided into five groups, including the sham-operated group, the model group, the electrical stimulation group, the magnetic stimulation group, and the treadmill training group. The rats in the sham-operated group only underwent spinous process and laminar dissection without spinal cord injury, while rats in the other groups were subjected to a modified Allen’s method to establish a T10 incomplete moderate spinal cord injury model. After modeling, the sham-operated group and the model group received no intervention, whereas the remaining groups underwent corresponding bilateral gastrocnemius neuromuscular electrical stimulation, repetitive peripheral magnetic stimulation, or treadmill exercise training. The Basso, Beattie and Bresnahan locomotor scale and inclined plate test were used to assess the hind limb motor function of the rats before and 0, 3, 7, and 14 days after modeling. The gastrocnemius muscle tissues were collected on the 14th day after surgery, and the muscle atrophy was assessed by relative wet weight ratio of the gastrocnemius muscle. The cross-sectional area of muscle fibers of the gastrocnemius muscle was detected by hematoxylin-eosin staining. The distribution and activity of acetylcholinesterase at the neuromuscular junction of the gastrocnemius muscle were detected by acetylcholinesterase staining. The expression of Atrogin-1 and MuRF1 protein in gastrocnemius muscle was detected by western blot assay.  RESULTS AND CONCLUSION: (1) Compared with the sham-operated group, the Basso, Beattie and Bresnahan score, inclined angle of the inclined plate test, relative wet weight ratio of the gastrocnemius muscle, muscle fiber cross-sectional area, and average absorbance value of acetylcholinesterase in the gastrocnemius muscle were significantly decreased in the model group (P < 0.05), and the expression of Atrogin-1 and MuRF1 protein was significantly increased (P < 0.05). (2) Compared with the model group, the Basso, Beattie and Bresnahan score, inclined angle of the inclined plate test, relative wet weight ratio of the gastrocnemius muscle, muscle fiber cross-sectional area, and average absorbance value of acetylcholinesterase in the gastrocnemius muscle were significantly increased in the electrical stimulation, magnetic stimulation, and treadmill training groups (P < 0.05). Moreover, the above indicators in the treadmill training group were significantly higher than those in the magnetic stimulation group, while the Basso, Beattie and Bresnahan score, inclined angle of the inclined plate test, relative wet weight ratio of the gastrocnemius muscle, and average absorbance value of acetylcholinesterase in the gastrocnemius muscle in the treadmill training group were significantly higher those in the electrical stimulation group (P < 0.05). (3) In addition, the expression level of Atrogin-1 protein was significantly lower in the electrical stimulation, magnetic stimulation, and treadmill training groups than in the model group, while the expression level of Atrogin-1 protein in the treadmill training group was significantly lower than that in the magnetic stimulation group (P < 0.05). The expression level of MuRF1 protein was significantly lower in the electrical stimulation group and the treadmill training group than in the model group (P < 0.05), while there was no significant difference in the protein expression of MuRF1 between the magnetic stimulation group and the model group (P > 0.05). To conclude, neuromuscular electrical stimulation, repetitive peripheral magnetic stimulation and treadmill training can all improve gastrocnemius muscle function and reduce muscle atrophy in rats with spinal cord injury, with treadmill training showing the best effects. Figures and Tables | References | Related Articles | Metrics

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Anterior cingulate cortex-targeted inhibition by deep brain stimulation improves depression-like behavior in mice Yang Haonan, Yuan Zhengwei, Xu Junpeng, Mao Zhiqi, Zhang Jianning 2026, 30 (17):  4366-4376.  doi: 10.12307/2026.365 Abstract ( 88 )   PDF (2780KB) ( 119 )   Save BACKGROUND: Deep brain stimulation of the anterior cingulate cortex has emerged as a new surgical treatment for psychiatric disorders such as depression; however, the specific mechanisms underlying its therapeutic effects are still not well understood. It has been shown that damage to the anterior cingulate cortex improves depressive behavior in mice, leading to the hypothesis that deep brain stimulation may hold promise as a treatment for depression. OBJECTIVE: To elucidate the neuroregulatory mechanisms of DBS of the anterior cingulate cortex and compares the effects of DBS and electroablation on depression-like behavior in mice using calcium imaging and fiber optic recording combined with C-fos immunohistochemistry. METHODS: (1) Grouping and modeling: C57BL/6J mice were randomly divided into four groups: a control group, a model+sham stimulation group, a model+deep brain electrical stimulation group, and a model + electroablation group. Chronic restraint stress (3.5 weeks) was conducted to establish mouse models of depression in the latter three groups, and deep brain electrical stimulation electrodes were implanted in the anterior cingulate cortex in all four groups. (2) Intervention protocol: Mice in the deep brain stimulation group received daily 2-hour high-frequency electrical stimulation (130 Hz, 200 μA, 50 μs) for 1 week; mice in the model + sham stimulation group received electrode implantation without electrical stimulation; mice in the model + ablation group received a single 0.5-hour alternating current stimulation (130 Hz, 200 μA). (3) Behavioral assessment: Depression-like behavior was quantified using the forced swim test and tail suspension test. (4) Circuit mechanism analysis: Real-time neural activity was monitored by fiber photometry to assess the activation effect of deep brain stimulation on the anterior cingulate cortex-basolateral amygdala circuit. (5) Anxiety behavior analysis: Open field test was performed to assess anxiety-like behavior in mice after intervention. (6) Whole-brain activation map: C-fos immunohistochemical staining was used to quantify neuronal activity in the downstream brain regions of the anterior cingulate cortex. (7) The improvement in depression-like behavior in mice was verified using electroablation.  RESULTS AND CONCLUSION: (1) Behavioral analysis: The forced swim test showed that the immobility time was significantly longer in the model + deep brain stimulation and model + sham stimulation groups than the control group (P < 0.05), but there was no significant difference between the model + deep brain stimulation and model + sham stimulation groups; the immobility time was significantly shorter in the model + electroablation group than that of the model + sham stimulation group (P < 0.01). In the tail suspension test, there was no significant difference in immobility time between the model + deep brain stimulation and model + sham stimulation groups. In the open field test, the central zone residence time and locomotor distance were significantly shorter in the deep brain stimulation group than the control group (P < 0.05), suggesting that deep brain stimulation may exacerbate anxiety-like behavior. (2) Neural mechanisms: Fiber optic recording confirmed that anterior cingulate cortex-deep brain stimulation specifically activated the anterior cingulate cortex-basolateral amygdala circuit. (3) C-fos staining showed that deep brain stimulation significantly enhanced neuronal activity in the downstream brain regions of the anterior cingulate cortex. These results suggest that although traditional high-frequency anterior cingulate cortex-deep brain stimulation effectively activates the target neural circuit, it fails to improve depression-like behavior and may exacerbate anxiety states by enhancing limbic system activity; conversely, functional inhibition of the anterior cingulate cortex by electroablation exhibits marked antidepressant effects, providing new directions for optimizing neuromodulation strategies.  Figures and Tables | References | Related Articles | Metrics

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Intervention effect and mechanism of Compound Herba Gueldenstaedtiae in a mouse model of breast hyperplasia Wu Yilin, Tian Hongying, Sun Jiale, Jiao Jiajia, Zhao Zihan, Shao Jinhuan, Zhao Kaiyue, Zhou Min, Li Qian, Li Zexin, Yue Changwu 2026, 30 (17):  4377-4389.  doi: 10.12307/2026.148 Abstract ( 76 )   PDF (7226KB) ( 9 )   Save BACKGROUND: Breast hyperplasia is a common benign breast disease mainly caused by endocrine disorders, manifested as abnormal hyperplasia of breast tissue. In recent years, traditional Chinese medicine compounds and probiotics have shown good potential in regulating the endocrine system and improving the intestinal microecology, providing new ideas for the treatment of breast hyperplasia. OBJECTIVE: To explore the effects and mechanisms of traditional Chinese medicine compounds and fermented probiotic compounds on breast hyperplasia in mice, providing new theoretical and experimental bases for the clinical treatment and prevention of breast hyperplasia. METHODS: (1) Network pharmacology tools were used to predict the anti-breast-hyperplasia activity of Herba Gueldenstaedtiae (Euphorbia humifusa), as well as its potential targets and signaling pathways. The databases included: TCMSP, OMIM, GeneCards database, UniProt website, Venny2.1.0 website, Metascape, HERB website, and STRING database, all of which are open-access databases. Network pharmacology can predict and screen key information such as the targets corresponding to the active ingredients of traditional Chinese medicine, disease targets, and action pathways through network analysis and computer-system analysis. Therefore, it has been increasingly widely used in the research of traditional Chinese medicine. (2) A breast hyperplasia model was induced in mice by injecting estrogen and progesterone. Mice in the normal blank group were injected intraperitoneally with normal saline every day. Mice in the model group and drug-administration groups were injected intraperitoneally with estradiol benzoate injection at a concentration of 0.5 mg/kg every day for 25 days. From the 26th day, the injection of estradiol benzoate injection was stopped. Mice in the normal blank group were injected intramuscularly with normal saline every day, and mice in the model group and drug-administration groups were injected intramuscularly with progesterone injection at a concentration of 5 mg/kg for 5 days. After the model was established, each group was given drugs respectively. The normal blank group and the model group were gavaged with 0.2 mL/d of normal saline; the positive blank group (Xiaozheng Pill group) was gavaged with an aqueous solution of Xiaozheng Pill at 0.9 mg/g; the low-, medium- and high-dose groups of Compound Herba Gueldenstaedtiae were gavaged with an aqueous solution of the compound medicine at 0.75, 1.5, and 3.0 mg/(g·d) respectively; the low-, medium- and high-dose groups of traditional Chinese medicine-bacteria fermentation were gavaged with an aqueous solution of the compound medicine at 0.75, 1.5, and 3.0 mg/(g·d) respectively. The administration was continuous for 30 days. RESULTS AND CONCLUSION: (1) The results of network pharmacology research showed that the Compound Herba Gueldenstaedtiae (Euphorbia humifusa) contained 46 active ingredients, which were related to 1 213 potential targets. After comparison with 588 known breast-hyperplasia targets, it was speculated that 50 of these targets might be related to the direct effect of the compound on breast hyperplasia. (2) After drug intervention, there was no significant change in the high-dose group of Compound Herba Gueldenstaedtiae compared with the normal blank group. The liver indicators of the other intervention groups all significantly decreased (P < 0.05). (3) In terms of kidney and uterine indicators, the medium-dose group of Compound Herba Gueldenstaedtiae decreased significantly compared with the normal blank group (P < 0.05). In terms of the uterine index, the model group increased significantly compared with the normal blank group (P < 0.01). (4) After 1-month drug treatment, the number of lobules and acini in the breast tissue of the Xiaozheng Pill group, the low, medium, and high-dose group of Compound Herba Gueldenstaedtiae, the low, medium, and high-dose groups of traditional Chinese medicine-bacteria fermentation decreased, and the duct openings narrowed. With the increase of drug dose, diffuse hyperplasia of breast tissue was significantly improved. (5) The ELISA results showed that compared with the model group, the estrogen level was lower in the medium-dose group of traditional Chinese medicine-bacteria fermentation after the intervention (P < 0.05). In addition, the follicle-stimulating hormone level in the low-dose group of Compound Herba Gueldenstaedtiae was lower than that of the model group (P < 0.05). (6) The intervention in the mouse model led to changes in the abundance of short chain fatty acids and intestinal flora in all groups. To conclude, the Compound Herba Gueldenstaedtiae and its probiotic fermentation products significantly improved mammary gland hyperplasia in mice by regulating hormone levels, improving the structure of the gut microbiota, and increasing the content of short-chain fatty acids, providing new ideas and potential sources of drugs for the treatment of breast hyperplasia. Figures and Tables | References | Related Articles | Metrics

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Control strategies during gait termination in older adults under cognitive-motor dual-task conditions  Liang Tianqi, Zhang Xiaoquan 2026, 30 (17):  4390-4399.  doi: 10.12307/2026.214 Abstract ( 59 )   PDF (6136KB) ( 12 )   Save BACKGROUND: With advancing age older adults often experience a decline in gait termination ability. This may lead to reduced postural and balance control under dual-task conditions, further increasing the risk of falls. OBJECTIVE: To explore the control strategies during gait termination in older adults under cognitive-motor dural-task conditions. METHODS: A total of 10 older adults were enrolled in this study, comprising 5 males and 5 females, with a mean age of (60.70±0.64) years. A dual-task paradigm integrating a cognitive task with a gait termination task during walking was adopted. The n-back classic paradigm was used to implement cognitive interventions during gait termination. The lower extremity kinematics and electromyography indicators of 10 subjects were collected using the Vicon infrared motion capture system and Noraxon surface electromyography. Differences in kinematic and electromyography indicators during gait termination (including planned and sudden stopping) under different cognitive loads (0 cognitive load, 1 cognitive load and 2 cognitive load) were compared. RESULTS AND CONCLUSION: (1) A two-way repeated measures analysis of variance revealed that cognitive load had a significant main effect on ankle angle (P < 0.05), while the two-way interaction was not significant. Stop condition showed a significant main effect on knee angle (P < 0.001), with no significant two-way interaction. For hip angle, both stop condition (P < 0.05) and cognitive load (P < 0.001) exhibited significant main effects, and their two-way interaction was also significant (P < 0.05). During both planned and sudden stops, the ankle plantar flexion angle increased significantly under 2 cognitive load compared with 0 cognitive load (P < 0.05). while, the knee flexion angles showed no significant differences under different cognitive loads (P > 0.05). Compared with 0 cognitive load, the hip flexion angles under 1 and 2 cognitive loads during sudden stop were significantly increased (P < 0.05). (2) A two-way repeated measures analysis of variance revealed that the stopping condition had a significant main effect on the integrated electromyography of  the gastrocnemius, biceps femoris, gluteus maximus, rectus femoris and tibialis anterior (P < 0.05). Cognitive load exhibited a significant main effect on the integrated electromyography of the vastus lateralis and tibialis anterior (P < 0.05). A significant interaction effect was observed between cognitive load and stopping condition for the integrated electromyography of the tibialis anterior (P < 0.001). During sudden stop, the integrated electromyography value of the lateral femoris muscle under 2 cognitive load was significantly increased compared with 0 cognitive load (P < 0.05), and the integrated electromyography value of the anterior tibial muscle was significantly decreased compared with 0 cognitive load (P < 0.05). These results indicate that under dual-task condition, the strategy for gait termination exhibited by older adults in sudden stops is similar to that in planned stops: with cognitive load increasing, gait termination is achieved by greater ankle plantar flexion, knee flexion, and hip flexion angles to absorb impact forces. Moreover, during sudden stop, the angles of ankle plantar flexion, knee flexion, and hip flexion are all larger than those during planned stop. Figures and Tables | References | Related Articles | Metrics

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The mechanism by which Zhuanggu Jianxi Decoction inhibits inflammatory response of human synovial macrophages Peng Siwei, Yang Ruifang, Chen Xiaohua, Zheng Zhuoming, Chen Peng, Xiao Yan, Su Youxin, Guo Jiemei 2026, 30 (17):  4400-4406.  doi: 10.12307/2026.111 Abstract ( 95 )   PDF (1068KB) ( 48 )   Save BACKGROUND: Synovial macrophages are one of the main cell types in the synovial tissue and are the primary cell type causing synovial inflammation. As a current research hotspot in knee osteoarthritis inflammation-related studies, our research group has previously conducted a series of targeted studies, preliminarily verifying through rabbit synovial tissue and cell levels that the prescription of Zhuanggu Jianxi Decoction can alleviate synovial inflammation by regulating the liver X receptors (LXRs)/nuclear factor- kappaB (NF-κB) pathway. This study takes human synovial macrophages as the research object, which is closer to the real state of patients with knee osteoarthritis, with the aim of further clarifying the mechanism by which Zhuanggu Jianxi Decoction reduces synovial inflammation. OBJECTIVE: To explore the effects and potential molecular mechanism of Zhuanggu Jianxi Decoction-containing serum on lipopolysaccharide-induced synovial inflammation in human synovial macrophages. METHODS: (1) Twelve 3-month-old New Zealand white rabbits were used to prepare the drug-containing serum of Zhuanggu Jianxi Decoction and blank serum. (2) Human synovial macrophages were induced to establish an inflammatory injury model by lipopolysaccharide (1.0 μg/mL). The cells were randomly divided into the model group (10% blank serum), the drug-containing serum group (10% drug-containing serum), the LXRα blocker group (10% drug-containing serum + 5 μg LXRα blocker), the nuclear receptor co-repressor (N-CoR) blocker group (10% drug-containing serum + 5 μg N-CoR blocker), and the normal group (10% blank serum). All the groups were intervened for 24 hours. (3) Western blot and RT-qPCR were used to detect the expression of LXRα, N-CoR, P50, and P65 proteins and mRNAs in each group of cells, and ELISA was used to detect the levels of interleukin-1β and tumor necrosis factor-α in the cell supernatant. RESULTS AND CONCLUSION: (1) Compared with the normal group, the model group showed significantly decreased LXRα and N-CoR protein/mRNA expressions (P < 0.01), while P50/P65 protein/mRNA expressions and the levels of interleukin-1β/tumor necrosis factor-α were significantly elevated (P < 0.01). (2) Compared with the model group, drug-containing serum significantly upregulated LXRα/N-CoR expressions at protein and mRNA levels and downregulated P50/P65 expressions at protein and mRNA levels as well as the levels of interleukin-1β/tumor necrosis factor-α (P < 0.01). Compared with the model group, both blocker groups showed a reduction in P50/P65 expressions at protein and mRNA levels and the levels of interleukin-1β/tumor necrosis factor-α (P < 0.01, P < 0.05). (3) Compared with the drug-containing serum group, both blocker groups exhibited significantly lower the protein and mRNA expressions of LXRα/N-CoR and higher protein and mRNA expressions of P50/P65 and higher levels of interleukin-1β/tumor necrosis factor-α (P < 0.01, P < 0.05). To conclude, Zhuanggu Jianxi Decoction-containing serum alleviates synovial macrophage inflammation and then prevent/treat knee osteoarthritis by upregulating the expression of LXRα/N-CoR protein and mRNA, downregulating the expression of P50/P65 proteins and mRNA, inhibiting the transmission of the LXRs/NF-κB signaling pathway, and reducing the secretion of downstream inflammatory markers (interleukin-1β and tumor necrosis factor-α). Figures and Tables | References | Related Articles | Metrics

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The basic theory, methods, and applications of proprioceptive neuromuscular facilitation Zhao Qiang, Zhou Yuehui, Dong Hong, Mao Anheng, Wang Longteng, Jiang Mingfei 2026, 30 (17):  4407-4416.  doi: 10.12307/2026.333 Abstract ( 133 )   PDF (2266KB) ( 45 )   Save BACKGROUND: Proprioceptive neuromuscular facilitation optimizes the neuromodulation mechanism by activating the neuromuscular system, which significantly enhances neuromuscular coordination, increases lower extremity explosive power and flexibility, and improves both athletic performance and rehabilitation efficiency. OBJECTIVE: To review the theoretical foundation, technical methods, and applications of proprioceptive neuromuscular facilitation in enhancing athletic performance, neurorehabilitation, and elderly health management and to explore the application and development prospects of this technology in clinical practice. METHODS: The search terms were “proprioceptive neuromuscular facilitation, proprioceptive neuromuscular training, PNF, neuroplasticity, biomechanics, neurorehabilitation, rehabilitation, stroke, Parkinson’s disease” in English and “proprioceptive neuromuscular facilitation, neuroplasticity, neurorehabilitation, stroke, Parkinson’s disease” in Chinese. Relevant literature was searched in PubMed, Web of Science, CNKI, WanFang, and VIP. Finally, 74 articles were included for review. RESULTS AND CONCLUSION: Proprioceptive neuromuscular facilitation is a rehabilitation technique that promotes neuroplasticity and biomechanical and sensory integration through the activation of the neuromuscular system. This technology is categorized into three types: basic, special, and spiral diagonal. The proprioceptive neuromuscular facilitation training relies on the mechanism of neuroplasticity and promotes reconstruction of neural networks in the brain and spinal cord, while improving motor control and coordination through biomechanical and sensory integration. Combined therapies, such as combination of this training with joint release and cord training, can improve knee and upper extremity function, enhance neuromuscular regulation, and promote motor function recovery. Individual therapies help improve muscle strength, joint mobility and motor coordination through maximum resistance training and muscle distraction. In neurological disorders and post-operative rehabilitation, proprioceptive neuromuscular facilitation improves gait and balance, restores motor control, reduces muscle spasms, and promotes neurological adaptations. Figures and Tables | References | Related Articles | Metrics

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Application and molecular mechanism of extracorporeal shock wave for anti-fibrosis Huang Sijing, Cui Rui, Geng Longyu, Gao Beiyao, Ge Ruidong, Jiang Shan 2026, 30 (17):  4417-4429.  doi: 10.12307/2026.104 Abstract ( 89 )   PDF (2093KB) ( 14 )   Save BACKGROUND: Existing studies have shown that extracorporeal shock wave intervention can effectively inhibit the formation of tissue fibrosis. However, there are limited experimental studies and summaries regarding the anti-fibrotic effects of extracorporeal shock wave, and no comprehensive review of the associated signaling pathways has been conducted. OBJECTIVE: To review current clinical or preclinical primary studies and summarize the applications of extracorporeal shock wave in fibrotic tissues and the relevant molecular mechanisms, thereby providing novel insights for the clinical treatment of fibrotic diseases. METHODS: The relevant literatures in PubMed, Web of Science, CNKI, WanFang and VIP databases were searched. The search time was from January 2014 to September 2024, and the search terms were “extracorporeal shockwave therapy, shock wave therapy, shock wave, fibrosis, fibroses” in English and “shock wave, extracorporeal shockwave therapy, fibrosis, anti-fibrosis” in Chinese. A combination of subject headings and free terms was used for the search. After screening and excluding studies based on predefined inclusion and exclusion criteria, a total of 67 articles were ultimately included for review and analysis. RESULTS AND CONCLUSION: (1) Extracorporeal shock wave intervention is beneficial for various fibrosis-related diseases, including scars, musculoskeletal disorders, and organ diseases. It can effectively reduce the degree of tissue fibrosis and improve clinical symptoms in patients. (2) Extracorporeal shock wave mainly influences the expression of fibrosis-related cytokines and extracellular matrix composition by modulating signaling pathways such as transforming growth factor-β1, mitogen-activated protein kinases, vascular endothelial growth factor, and inflammatory signaling pathways, thereby inhibiting excessive fibrosis formation. (3) The current review identifies a limited number of clinical studies with insufficient data to support robust conclusions. Additionally, due to the singularity of experimental results and significant differences in intervention subjects and extracorporeal shock wave intervention protocols across studies, there may be an impact on the clarification of the specific dose-response mechanisms and the overall molecular action system of extracorporeal shock wave in anti-fibrosis. To conclude, extracorporeal shock wave may serve as an effective therapeutic approach for the clinical treatment of fibrosis-related diseases in the future. Figures and Tables | References | Related Articles | Metrics

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Effects and mechanisms of palmitoyl acyltransferase ZDHHC5 in tissue homeostasis and diseases Ji Kaizhong, Kong Yihao, Zhi Yiqing, Jin Yingying, Chen Jianquan 2026, 30 (17):  4430-4445.  doi: 10.12307/2026.131 Abstract ( 142 )   PDF (2917KB) ( 294 )   Save BACKGROUND: Protein S-palmitoylation is a reversible post-translational lipid modification that directly influences protein stability, subcellular localization and interactions with other molecules. It is catalyzed in mammalian cells by 23-24 palmitoyl acyltransferases (PATs) that share the common Asp-His-His-Cys (DHHC) motif. Recent studies have highlighted the important role of S-palmitoylation in disease, and increasing studies have attempted to explore new therapeutic potentials in diverse diseases, driving efforts to target palmitoylation and its catalytic enzymes. Among these, palmitoyl transferase 5 (ZDHHC5) is a more specific member of the palmitoyl group transferase family, which is a plasma membrane-localized PAT that palmitoylates a wide variety of substrates, thereby influencing multiple biological processes. OBJECTIVE: To provide an overview of the biochemical process of palmitoylation and its detection methods, to elucidate the role of ZDHHC5 in physiological processes such as cytoplasmic division, synapse formation and plasticity, and programmed cell death, and to summarize recent research progress on ZDHHC5 in cancer, respiratory diseases and other pathologies. METHODS: The first author conducted a systematic literature search in PubMed and CNKI databases for relevant literature on ZDHHC5 research in recent years, using “ZDHHC5, DHHC5 or palmitoyl transferase 5” as the search terms in English and “palmitoyl transferase 5” as the search term in Chinese. The search period was set from January 2011 to March 2025. After screening the retrieved literature for relevance and quality, the remaining literature was used to analyze the role and mechanism of ZDHHC5 in tissue homeostasis and diseases.  RESULTS AND CONCLUSION: ZDHHC5, a key palmitoyl transferase that dynamically modifies protein palmitoylation, regulates cell division and differentiation, ion flux regulation, synapse formation and plasticity, autophagy and programmed cell death, intracellular membrane transport, cell adhesion, oligodendrocyte and myelin sheath formation, and immune signaling regulation, either by direct modification of key substrates, such as PCDH7, TrpM7, δ-catenin, NCX1, NOD2, and MLKL, or by formation of a complex with proteins, such as GOLGA7. Under pathological conditions, the aberrant expression of ZDHHC5 may promote the development of glioma, pancreatic cancer, lung cancer and other cancers by affecting the palmitoylation levels of EZH2, SSTR5, and INCENP and other proteins. In addition, ZDHHC5 promotes the occurrence and development of various diseases such as respiratory disease, schizophrenia, heart disease, inflammation, fatty liver, diabetic retinopathy, suggesting that its aberrant function may play an important role in the pathogenesis of multiple diseases. Future studies should focus on the substrate-specific recognition mechanism of ZDHHC5 and the regulation of its function under different physiological and pathological conditions. Meanwhile, the development of small molecule inhibitors targeting ZDHHC5 and the integrated application of interdisciplinary technologies will provide a new direction for precision therapeutic strategies based on palmitoylated modifications, which will ultimately promote the diagnosis and treatment of related diseases. Figures and Tables | References | Related Articles | Metrics

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Mechanisms underlying mitophagy, ferroptosis, cuproptosis, and disulfidptosis in Parkinson’s disease Yu Le, Nan Songhua, Shi Zijian, He Qiqi, Li Zhenjia, Cui Yinglin 2026, 30 (17):  4446-4456.  doi: 10.12307/2026.177 Abstract ( 121 )   PDF (1598KB) ( 788 )   Save BACKGROUND: As a typical representative of neurodegenerative diseases, Parkinson’s disease manifests with an intricate web of pathogenic attributes. In the field of programmed cell death, several novel molecular mechanisms have been unveiled in recent years, including but not limited to mitochondrial selective autophagy, iron-dependent cell death, copper ion-mediated apoptosis, and cell damage patterns caused by aberrant disulfide bonds. Studies have indicated that these pathological changes not only contribute to the development of typical clinical symptoms in Parkinson’s disease but also exhibit significant correlations with disease progression. From this, it becomes apparent through scholarly works that these mechanisms exert pivotal roles in neuronal dysfunction manifestation. However, uncharted scientific inquiries regarding detailed interactions at the molecular level among these interconnected pathways need to be solved urgently. OBJECTIVE: To review the molecular mechanisms of novel forms of programmed cell death (mitophagy, ferroptosis, cuproptosis, and disulfidptosis) and the roles of their interactions and synergistic effects in Parkinson’s disease, and to explore the potential impact and therapeutic prospects of these novel forms of programmed cell death in the pathogenesis of Parkinson’s disease. METHODS: The first author conducted a computer-based search of literature indexed in the CNKI and PubMed databases from 2015 to 2025 using the keywords of “Parkinson’s disease, mitophagy, ferroptosis, disulfidptosis, cuproptosis, apoptosis, necroptosis, pyroptosis” in Chinese and English, respectively. Literature that is inconsistent with the research content, outdated, or duplicative was excluded. A total of 1 368 relevant articles were retrieved, and 87 articles were ultimately included in the review analysis. RESULTS AND CONCLUSION: (1) The new types of programmed cell death, including mitophagy, ferroptosis, cuproptosis, and disulfidptosis, are essential regulatory pathways for maintaining normal cellular renewal and homeostasis, making them a currently hot research area in life sciences. (2) Mitophagy is a selective autophagic process that can clear damaged mitochondria, thereby maintaining mitochondrial homeostasis in neuronal cells during Parkinson’s disease, and playing a crucial role in regulating neuronal health and function. (3) Ferroptosis is a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, which can regulate Parkinson’s disease through various pathways, including cystine/glutamate, iron metabolism, and polyunsaturated fatty acids. (4) Cuproptosis, as a newly discovered mode of cell death, involves the role of copper chelators and heat shock proteins in regulating α-synuclein aggregation and cell survival, potentially providing new targets for the treatment of Parkinson’s disease. (5) Disulfidptosis is associated with the aggregation of α-synuclein, which is considered an important feature of Parkinson’s disease. Its specific role in Parkinson’s disease requires further research. (6) The interactive and synergistic effects of various cell death mechanisms in Parkinson’s disease (such as Fe/Cu synergistic regulation of Parkinson’s disease) hold great potential for the future. Figures and Tables | References | Related Articles | Metrics

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Effects of central and peripheral rehabilitation therapies on upper extremity function and activities of daily living in stroke patients: a network meta-analysis Chen Jinhui, Yu Zifu, Gao Shiai, Cao Xinyan, Leng Xiaoxuan, Liu Xihua 2026, 30 (17):  4457-4471.  doi: 10.12307/2026.084 Abstract ( 161 )   PDF (4589KB) ( 47 )   Save OBJECTIVE: Upper extremity dyskinesia is the most common complication in stroke patients, mainly manifested in the peripheral limbs, while the lesions are located in the central brain. However, there is still a lack of meta-analysis of the effects of different central and peripheral interventions applied alone or in combination on the upper extremity motor function and activities of daily living in stroke patients, which imposes a certain limitation on the clinical selection of the best rehabilitation approach. Here, a network meta-analysis was conducted to assess the clinical efficacy of four commonly used central rehabilitation methods (transcranial magnetic stimulation, transcranial direct current stimulation, mirror therapy and motor imagery) and four commonly used peripheral rehabilitation methods (rehabilitation robotics, constraint-induced movement therapy, electromyography biofeedback, and functional electrical stimulation) applied alone or in combination on the motor function of the upper limbs and activities of daily living in stroke patients, thereby determining the optimal rehabilitation program.  METHODS: A computer search of PubMed, Web of Science, Embase, The Cochrane Library, CNKI, WanFang, VIP, and the Chinese Biomedical Literature Database. The time period was from database inception to October 15, 2024. Randomized controlled trials of different central or peripheral rehabilitation methods alone or in combination on upper limb function and activities of daily living in stroke patients were collected. The risk of bias and methodological quality of the included literature were evaluated using the Cochrane Risk of Bias Assessment Tool and the revised Jadad scale. Network meta-analyses of Fugl-Meyer Assessment-Upper Extremity, Wolf motor function test and Modified Barthel index were performed using RevMan 5.4 and Stata 18. The strength of recommendation for the outcome metrics was assessed using the GRADE Level of Evidence system.  RESULTS: (1) A total of 88 studies were included, including 82 high-quality and 6 low-quality studies, involving 5 561 stroke patients, resulting in a total of 19 rehabilitation programs. (2) The Fugl-Meyer scale results indicated that the top eight rehabilitation programs, ranked by the area under the cumulative ranking probability chart, were transcranial direct current stimulation+robot (99.4%) > motor imagery therapy+robot (84.4%) > motor imagery therapy+constraint-induced movement therapy (82.8%) > mirror therapy+electromyography biofeedback (81.2%) > motor imagery therapy+electromyography biofeedback (77.0%) > repetitive transcranial magnetic stimulation+constraint-induced movement therapy (69.9%) > transcranial direct current stimulation+electromyography biofeedback (67.1%) > repetitive transcranial magnetic stimulation+electromyography biofeedback (60.2%). (3) Wolf motor function test results indicated that the top three rehabilitation programs, ranked by the area under the cumulative ranking probability chart, were constraint-induced movement therapy+transcranial direct current stimulation (70.7%) > constraint-induced movement therapy (65.3%) > transcranial direct current stimulation (63.4%). (4) Modified Barthel index results indicated that the top eight rehabilitation programs, ranked by the area under the cumulative ranking probability chart, were transcranial direct current stimulation+robot (95.4%) > transcranial direct current stimulation+electromyography biofeedback (82.3%) > motor imagery therapy+constraint-induced movement therapy (79.7%) > repetitive transcranial magnetic stimulation+constraint-induced movement therapy (79.5%) > functional electrical stimulation (74.2%) > motor imagery therapy+electromyography biofeedback (68.6%) > mirror therapy+robot (65.1%) > mirror therapy+electromyography biofeedback (51.0%). CONCLUSION: The moderate strength of evidence recommends transcranial direct current stimulation+robot as the optimal rehabilitation protocol to promote upper limb motor function and activities of daily living in stroke patients. The central combined with peripheral rehabilitation approach is superior to a single means of rehabilitation to improve upper limb motor function and activities of daily living in stroke patients. Higher-quality and multicentral clinical trials should be carried out in the future to validate the results of this study. Figures and Tables | References | Related Articles | Metrics

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Effects of ischemic preconditioning on sport performance: a systematic review and multilevel meta-analysis Zhang Yilin, Xu Kai, Yin Mingyue, Kong Hao, Liu Chenghao, Xie Yun 2026, 30 (17):  4472-4486.  doi: 10.12307/2026.183 Abstract ( 114 )   PDF (4851KB) ( 44 )   Save OBJECTIVE: Enhancing sports performance remains a central focus in sports science. Ischemic preconditioning, as a non-pharmacological intervention, has been reported to improve performance. However, the results vary across different studies, and the influencing factors remain unclear. This study aimed to conduct a systematic meta-analysis of original research on ischemic preconditioning combined with exercise, to evaluate its true effects and identify potential moderators. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search was conducted on September 4, 2024, across the Web of Science Core Collection, PubMed, Embase, and CNKI databases using the Mesh keywords “ischemic preconditioning,” “performance,” and “sport.” The inclusion criteria were: (1) studies involving non-clinical populations; (2) sham ischemic preconditioning or non-ischemia treatment as the control for ischemic preconditioning; (3) outcomes including balance, jump performance, strength, accumulated oxygen deficit, power output, maximal repetitions, time trial, time to exhaustion, and oxygen consumption; (4) study designs limited to randomized crossover or randomized controlled trials. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool, and the quality of evidence was evaluated with the GRADE approach. Multilevel meta-analyses were conducted using the “meta,” “metafor” and “clubSandwich” packages in R version 4.3.3, along with publication bias tests, subgroup analyses, and meta-regressions. RESULTS: A total of 90 studies involving 1 439 participants aged 18–70 years were included. Compared with sham ischemic preconditioning or non-ischemia treatment, ischemic preconditioning significantly improved sports performance [effect size (ES)=0.13, 95% confidence interval (CI) (0.06, 0.21), P < 0.01; Q=427; I²-Level 2=0%, I²-Level 3=9.13%, I²-Level 4=5.74%; PI=–0.18 to 0.44; low certainty]. Subgroup analysis revealed that ischemic preconditioning had a greater effect versus blank control than versus sham ischemic preconditioning (P=0.02) [ESCON=0.22, 95% CI (0.12, 0.33], P < 0.01; ESSHAM 0.10, 95% CI (0.02, 0.18), P < 0.01]. (3) No significant between-group differences were found in terms of metabolic characteristics (aerobic/anaerobic), training level, or sex. (4) Among ischemic preconditioning protocols, the 1×5 minutes design showed a significantly greater effect (P=0.01), though it was reported in only one study. Within-subgroup analyses indicated that 3×5 minutes [ES=0.14, 95% CI (0.03, 0.26), P < 0.01] and 4×5 minutes [ES=0.10, 95% CI (0.00, 0.21), P=0.02] were statistically significant. (5) Ischemic preconditioning significantly benefited sedentary participants [ES=0.14, 95% CI (–0.10, 0.39), P=0.03], recreationally active participants [ES=0.15, 95% CI (0.03, 0.27), P=0.02], and participants undergoing general training [ES=0.19, 95% CI (0.04, 0.33), P=0.01], but not highly trained, elite, or world-class athletes. Significant effects were found only in male participants [ES=0.20, 95% CI (0.10, 0.30), P < 0.01].  CONCLUSION: Ischemic preconditioning shows a small effect on sports performance, with a significant placebo effect (psychological effect). Ischemic preconditioning protocols (the duration of ischemic preconditioning), particularly protocols of 3×5 minutes or 4×5 minutes, emerge as a key moderating factor. More benefits appear in male participants with low exercise experience, though current evidence does not conclusively support sex, training experience level or age as moderators. Future studies should adopt standardized ischemic preconditioning protocols and rigorously control for placebo effects to better delineate the boundaries and mechanisms underlying the effects of ischemic preconditioning. Figures and Tables | References | Related Articles | Metrics

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Compatibility strategy of Fangxiang Wentong method drug pairs for the prevention and treatment of myocardial inflammaging He Jia, Zhu Weidong, Chen Lidian, Ren Danni 2026, 30 (17):  4487-4497.  doi: 10.12307/2026.196 Abstract ( 95 )   PDF (6339KB) ( 267 )   Save BACKGROUND: Inflammaging, characterized by a chronic low-grade pro-inflammatory state during natural aging, is closely associated with the development of age-related diseases such as cardiovascular disorders. However, a systematic theoretical framework centered on cardiac inflammaging as a core pathological mechanism is still lacking.  OBJECTIVE: To analyze the prescription patterns and medication principles for treating cardiac aging in traditional Chinese medicine (TCM) classics using data mining and network pharmacology methods, and to explore the potential mechanisms of core drugs.  METHODS: (1) Formulations for treating cardiac aging were collected and compiled from the 2020 edition of the Pharmacopoeia of the People's Republic of China, the 10th edition of Chinese Materia Medica, and the Comprehensive Dictionary of TCM Prescriptions. The frequency of medicinal herbs, their properties, and meridian affinity were statistically analyzed, along with association rule analysis and clustering, to identify core herb pairs for treating cardiac aging. A core herb pair-active ingredient-disease-common target network model was established, followed by gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. In addition, molecular docking and dynamic simulation were employed to assess the binding ability and stability between potential key targets and active ingredients. (2) Validation experiment: Sixty C57BL/6 mice were randomly divided into three intervention groups: the blank group (n=20) was administered distilled water via gavage, the low-dose musk-aconite group (n=20) was administered 2.64 g/kg musk-aconite via gavage, and the high-dose musk-aconite group (n=20) was administered 5.28 g/kg musk-aconite group via gavage, once daily for 7 consecutive days. After the final administration, blood was collected from the orbital sinus, and serum was separated to obtain drug-free serum and low- and high-dose drug-containing serum of musk-aconite. Passage 3 human ventricular cardiomyocyte line AC16 was divided into three groups and treated with drug-free serum and low- and high-dose drug-containing serum of musk and aconite, respectively. Cell viability was detected using the cell counting kit-8 method. Passage 3 human ventricular cardiomyocyte line AC16 was divided into four groups and treated with PBS, drug-free serum, and low- and high-dose drug-containing serum of musk-aconite, respectively, for 48 hours. Then, tumor necrosis factor α was added to the latter three groups for 4 hours to induce an inflammatory model. Western blot was used to detect the expression of nuclear factor κB inhibitor protein, phosphorylated nuclear factor κB inhibitor protein, nuclear factor κB p65, and nuclear factor κB p50 protein. RESULTS AND CONCLUSION: (1) A total of 268 prescriptions were identified from the 2020 edition of the Pharmacopoeia of the People's Republic of China. After removing duplicates and irrelevant prescriptions, 88 prescriptions containing 36 Chinese medicinal herbs were selected. The most frequently used herbs were cinnamon, dried ginger, aconite, shallot, and musk. These herbs were predominantly pungent and warm in nature, targeting the heart, kidney, and liver meridians, with a treatment principle of Fangxiang Wentong method (aromatic warm and unblocking method). Association rule analysis identified four strong herb pairings, with high support for "musk-aconite," "cinnamon-dried ginger," "dried ginger-aconite," and "shallot-trichosanthes" (confidence ≥ 90%). Factor analysis extracted four common factors, reflecting the historical TCM treatment philosophy of Fangxiang Wentong method. The four core herb pairs might alleviate cardiac aging by modulating inflammatory signaling pathways, which were correlated with the relatively high proportion of inflammatory markers in cardiac aging. Molecular docking of the "musk-aconite" pair revealed good binding ability and stability between key targets and their corresponding active ingredients. (2) Cell counting kit-8 assay results indicated that the "musk-aconite" pair exhibited high cellular compatibility with drug-containing serum. Western blot analysis revealed that compared with the control group, intervention with tumor necrosis factor α significantly induced phosphorylation of the nuclear factor κB inhibitor protein, leading to the release of the nuclear factor κB dimer (p65/p50) into the cell nucleus, thereby confirming the successful establishment of the inflammatory injury model. However, low- and high-dose musk-aconite drug pair-containing serum intervention significantly inhibited the upregulation of nuclear factor κB inhibitor protein and nuclear factor κB (p65/p50) in the cell nucleus induced by tumor necrosis factor α. To conclude, in traditional Chinese medicine, the treatment of cardiac aging primarily follows the principle of Fangxiang Wentong method, with the musk-aconite pair as the core. This herbal combination may slow the progression of cardiac aging by inhibiting inflammatory signals. Figures and Tables | References | Related Articles | Metrics

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Revealing the regulatory targets of plasma proteins in rheumatoid arthritis from the perspective of genomics Cheng Yuebin, Wang Baojian, Dai Wenkang, Yin Yueshan, Sun Zhiqiang, Peng Zhiyun, Shang Yuhang, Ma Yufeng 2026, 30 (17):  4498-4507.  doi: 10.12307/2026.136 Abstract ( 86 )   PDF (1933KB) ( 11 )   Save BACKGROUND: Rheumatoid arthritis is a complex autoimmune disease, which involves the interaction of many factors including heredity, environment and immunity. Traditional research focuses on the relationship between individual protein and rheumatoid arthritis, but lacks systematic evaluation of the causal relationship between large-scale plasma proteins and rheumatoid arthritis. Mendelian randomization, as an innovative causal inference method, uses genetic variation as a tool variable, which avoids the interference of confounding factors in traditional epidemiological research and provides a new way to reveal the causal relationship between plasma protein and rheumatoid arthritis. OBJECTIVE: To study the potential relationship between human plasma protein and rheumatoid arthritis, and to explore the possible biological pathways involved in the pathogenesis of rheumatoid arthritis. METHODS: The public data of plasma protein (exposure factor) and rheumatoid arthritis (outcome factor) were collected. Among them, the data of 4 907 types of plasma proteins came from genome-wide association studies published in the journal Nature Genetics in 2022, which is now included in the Icelandic deCODE Genetics database. The study covered 35 559 Icelanders and found 18 084 protein quantitative trait loci. Genome-wide association study data of rheumatoid arthritis came from FinnGen database (R11 version), including 14 818 cases of rheumatoid arthritis and 287 796 cases in the control group. All participants were from the European population. The potential causal relationship between plasma protein and rheumatoid arthritis was evaluated by two-way Mendelian randomized analysis. Mendelian randomized analysis included five analysis methods: inverse variance weighted method, MR-Egger regression method, weighted median method, weighted model method and simple model method. Heterogeneity test, horizontal pleiotropy test and leave-one-out analysis were used to test whether the results of Mendelian randomized analysis are reliable. Reverse Mendelian randomization analysis took the plasma protein that met the screening conditions in the positive Mendelian randomization analysis as the outcome for effect analysis and sensitivity analysis. RESULTS AND CONCLUSION: (1) The results of inverse variance weighting method showed that plasma proteins CRAT and LYG1 were directly and positively correlated with rheumatoid arthritis. Plasma proteins FAM177A1, JPH4 and SPAG11B had a direct negative causal relationship with rheumatoid arthritis. (2) Reverse Mendelian randomization results showed that rheumatoid arthritis had a direct positive causal relationship with LYG1. (3) No heterogeneity or horizontal pleiotropy was found in two-way sensitivity analysis. (4) With plasma proteins as the exposure and rheumatoid arthritis as the outcome, two plasma proteins CRAT and LYG1 were positively correlated with rheumatoid arthritis, and three plasma proteins FAM177A1, JPH4 and SPAG11B were negatively correlated with rheumatoid arthritis. With rheumatoid arthritis as the exposure and plasma proteins CRAT, LYG1, FAM177A1, JPH4, SPAG11B as the outcome, rheumatoid arthritis had a positive causal relationship with the plasma protein LYG1. The above results suggest that there may be causal relationship between these five plasma proteins and rheumatoid arthritis, which will help the development of potential therapeutic and monitoring targets for rheumatoid arthritis in the future. Although the protein targets found in European databases need to be verified in the China population, the preliminary evidence of such causal associations can guide domestic research to give priority to related protein pathways and accelerate targeted drug research and development. At the same time, it calls for strengthening the construction of a local multi-center biological sample bank and a proteomics-genome-wide association studies integrated platform to overcome the limitations of European databases and promote precision medical research based on Asian populations. Figures and Tables | References | Related Articles | Metrics

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Preventive effect of lipid-lowering drug targets on the risk of osteonecrosis: genetic information analysis based on the FinnGen and GLGC databases Li Wei, Chai Jinlian, Zhang Bochun, Li Guangzheng, Liu Xiaochen, Wei Chuanfu, Chen Ning, Luo Di, Li Gang, Liang Xuezhen 2026, 30 (17):  4508-4516.  doi: 10.12307/2026.090 Abstract ( 80 )   PDF (3057KB) ( 23 )   Save BACKGROUND: Osteonecrosis is a common and refractory disease in clinical practice, which brings great distress to the patients' lives and also imposes a heavy burden on the medical system. Some observational studies have shown that lipid-lowering drugs may have a certain promoting effect on the prognosis of osteonecrosis. However, the causal relationship between the specific targets of lipid-lowering drugs and osteonecrosis remains unknown. OBJECTIVE: To explore the causal relationships between low-density lipoprotein, lipid-lowering drugs [3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors] and osteonecrosis through Mendelian randomization and Meta-analysis. METHODS: (1) The study first downloaded the HMGCR gene (Chromosome 5: 74632154-74657929), PCSK9 gene (Chromosome 1: 55505221-55530525), and NPC1L1 gene (Chromosome 7: 44552134-44580914) from the Global Lipids Genetics Consortium (GLGC) database as instrumental variables for lipid-lowering drug exposure. Osteonecrosis-related data were obtained from the FinnGen database, including Version R9 (with a total sample size of 359 399: 1 385 cases and 358 014 controls), Version R10 (with a total sample size of 392 580: 1 543 cases and 391 037 controls), and Version R11 (with a total sample size of 431 369: 1 543 cases and 429 826 controls). Meanwhile, low-density lipoprotein was selected as the biomarker for this study. (2) The two-sample Mendelian randomization analysis method was used to evaluate the causal relationship between lipid-lowering drug exposure and osteonecrosis. And LDlink was used to remove confounding factors that might affect the pathogenesis of osteonecrosis. (3) Four methods, namely MR-Egger, weighted median, inverse-variance weighting (IVW), and weighted mode, were employed to detect the causal relationship between lipid-lowering drug exposure and osteonecrosis. The IVW method was used as the primary analysis method. (4) To comprehensively and comprehensively evaluate the association between lipid-lowering drugs and osteonecrosis, a meta-analysis was further conducted on the odds ratio (OR) values obtained from the IVW method. (5) Finally, to ensure the robustness and reliability of the research results, this study used the Q test to evaluate heterogeneity, MR-Egger regression to evaluate horizontal pleiotropy, and Bayesian colocalization analysis for positive results. (6) The study also selected coronary heart disease as a positive control. By conducting Mendelian randomization analysis with it as the outcome factor, the reliability of the instrumental variables was determined. RESULTS AND CONCLUSION: (1) The results of the Mendelian randomization analysis showed that the relationship between HMGCR inhibitors and osteonecrosis exhibited diverse characteristics across different versions of osteonecrosis data. In the R9 version data, HMGCR inhibitors were significantly effective in reducing the risk of osteonecrosis (IVW: OR=0.24, 95% confidence interval [CI]: 0.08-0.71; P=0.009). Similar conclusions were drawn from the R10 version data (IVW: OR=0.29, 95% CI: 0.10-0.86; P=0.025). However, in the R11 version data, there was no obvious causal relationship between them (P=0.09 > 0.05). (2) Neither NPC1L1 inhibitors, PCSK9 inhibitors, nor low-density lipoprotein showed an obvious causal relationship with osteonecrosis in the R9, R10, and R11 version data of osteonecrosis. The meta-analysis of the IVW results for HMGCR inhibitors further confirmed that they could significantly reduce the risk of osteonecrosis (OR=0.3, 95% CI: 0.16-0.56). (3) The sensitivity analysis did not find statistical evidence of heterogeneity or genetic confounding bias. The Bayesian colocalization analysis showed that the posterior probability of H4/(H4+H3) exceeded 90%, indicating that the causal relationship between HMGCR inhibitors and osteonecrosis was not accidental. (4) This study, through Mendelian randomization and meta-analysis, confirmed that there was a significant causal association between HMGCR inhibitors and the reduction of the risk of osteonecrosis. This suggests that existing HMGCR inhibitors are expected to become key targets for the prevention and treatment of osteonecrosis, bringing new treatment options for many patients with osteonecrosis. However, further in-depth clinical studies are still needed for verification. Figures and Tables | References | Related Articles | Metrics

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Dandeng Tongnao soft capsules against ischemic stroke: fingerprinting and network pharmacological analysis of efficacy and mechanism of action Wu Xue, Zhang Linao, Luo Shifang, Liu Feifan, Wan Yan, Bai Yuanmei, Cao Julin, Xie Yuhuan, Guo Peixin 2026, 30 (17):  4517-4528.  doi: 10.12307/2026.100 Abstract ( 99 )   PDF (21845KB) ( 15 )   Save BACKGROUND: The Chinese medicine Compound Dandeng Tongnao Soft Capsule is characterized by the synergistic effect of multiple components, but traditional research methods are difficult to systematically reveal its complex mechanism of action. This experiment innovatively integrates high-performance liquid chromatography fingerprinting and network pharmacology methods. This integrated strategy can not only achieve a comprehensive evaluation of the material basis of traditional Chinese medicine, but also further elucidate the targets of traditional Chinese medicine, clarify its pathways and mechanisms, and provide a new research paradigm for elucidating the “multi-component-multi-target-multi-pathway” mechanism of traditional Chinese medicine prescriptions. OBJECTIVE: To investigate the material basis and mechanism of action of Dandeng Tongnao Soft Capsules against ischemic stroke based on HPLC fingerprinting and network pharmacology.  METHODS: The fingerprints of 10 batches of Dandeng Tongnao Soft Capsules were determined by high-performance liquid chromatography, and the common peaks in the fingerprints of Dandeng Tongnao Soft Capsules were identified by LCMS-IT-TOF technique. Common peak component targets of Dandeng Tongnao Soft Capsules were predicted by SwissTargetPrediction database (developed by Swiss Institute of Bioinformatics; function: prediction of potential targets based on the structure of compounds). Ischemic stroke-related targets were collected through the OMIM database (maintained by Johns Hopkins University, USA; function: to include human genetic diseases and disease-causing genes) and the GeneCards database (developed by the Weizmann Institute of Science, Israel; function: to integrate information on gene functions, disease associations and pathways). Drug-disease intersection targets were screened using the Venny 2.1.0 online tool to draw Venn diagrams. Cytoscape 3.10.1 software was used to construct a “drug-compound-target” interaction network to screen the potential components of Dandeng Tongnao Soft Capsules against ischemic stroke. Protein-protein interaction network analysis was performed through the STRING database (jointly developed by the European Molecular Biology Laboratory and other institutions, function: analysis of protein interaction networks and core targets) to obtain core targets. DAVID database (developed by National Institute of Allergy and Infectious Diseases, Function: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis) was used to analyze the biological functions and pathways of the core targets of Dandeng Tongnao Soft Capsules against ischemic stroke, and ultimately to build a multi-dimensional network of “drug-component-target-pathway-disease.” RESULTS AND CONCLUSION: (1) The fingerprint pattern of Dandeng Tongnao Soft Capsules was established, 24 common peaks were calibrated, the peaks were well separated, and the similarity between samples was greater than 0.9. Twenty-four peaks in Dandeng Tongnao Soft Capsule were identified. A total of 508 intersecting targets of components and diseases in Dandeng Tongnao Soft Capsule were obtained. (2) Protein-protein interaction analysis, GO function enrichment and KEGG pathway enrichment analysis revealed that Dandeng Tongnao Soft Capsules may exert anti-ischemic stroke effects through its active ingredients, geranodendronin, danshenone I, tanshenone IIA, ethyl ferulate, and tanshenaldehyde, which act on glyceraldehyde-3-phosphate dehydrogenase, serine/threonine protein kinase 1, and tumor necrosis factor, non-receptor tyrosine kinase, to regulate hypoxia-inducible factor-1 signaling pathway, advanced glycosylation end product-receptor signaling pathway, and phosphatidylinositol 3-kinase protein kinase B signaling pathway. To conclude, the organic integration of chemical analysis and bioinformatics prediction systematically explains the multidimensional mechanism of action of Dandeng Tongnao Soft Capsules. It not only provides a scientific basis for its clinical efficacy, but also, more importantly, establishes an integrated research framework of “fingerprinting-network pharmacology,” which provides a general methodological reference for the comprehensive evaluation of the material basis of traditional Chinese medicines and the analysis of their mechanism of action, and has important theoretical and practical value for the modernization of traditional Chinese medicines. Figures and Tables | References | Related Articles | Metrics

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Visual analysis of cuproptosis research: global landscape of hotspots and frontiers Li Ruiying, Xia Hong 2026, 30 (17):  4529-4541.  doi: 10.12307/2026.139 Abstract ( 122 )   PDF (2772KB) ( 43 )   Save BACKGROUND: Cuproptosis, as an emerging form of cell death, has garnered widespread attention in recent years. However, there is a lack of systematic understanding of the global research dynamics of cuproptosis, especially the research priorities and trends in different countries and academic communities. A multi-database, multi-faceted bibliometric analysis is urgently needed to provide a more comprehensive understanding of the research progress in the field of cuproptosis. OBJECTIVE: To systematically analyze the research status, hotspots, and development trends in the field of cuproptosis using bibliometric methods. METHODS: Using bibliometric methods combined with CiteSpace and VOSviewer visualization and analysis tools, we retrieved and analyzed 1 378 cuproptosis-related literature published from 2022 to 2024 in the international authoritative Web of Science core collection database and the China Knowledge Network database (CNKI). This analysis included annual publication volume, research cooperation network, keyword co-occurrence, clustering and hotspot change characteristics, and highly cited literature. By comparing and analyzing the data from these two databases, we aim to reveal the overall landscape of cuproptosis research from a global perspective. RESULTS AND CONCLUSION: Cuproptosis research has shown a rapid growth trend, with China leading in the number of publications, where institutions such as Shanghai Jiao Tong University and Central South University serve as the core institutions. The research theme focuses on the mechanism of cuproptosis, tumor therapeutic application (chemokinetic therapy) and cross-regulation with ferroptosis. The keyword emergence analysis showed that "immune microenvironment" and "tumor therapy" are the research hotspots. Machine-learning gene prediction models and single-cell sequencing technologies are driving the development of precision medicine. Most of the English studies focus on the exploration of mechanisms and application of technologies. Their research methods, technical routes and hot directions are of great significance to the cuproptosis research in China, which is in the rapid development period. In particular, interdisciplinary cooperation and multi-center clinical translational research in the field of tumor treatment and other major diseases are expected to provide more targeted and effective new strategies for the diagnosis and treatment of malignant tumors and other major diseases, including the Chinese population. Funding: the National Research Association of Computer Basic Education in Colleges and Universities of China, No. 2024-AFCEC-105 (to XH); the Scientific Research and Innovation Project of Capital Medical University, No. XSKY2024160 (to XH) Figures and Tables | References | Related Articles | Metrics

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Bidirectional causal interplay between Epstein-Barr virus and ankylosing spondylitis: data analysis based on the UK Biobank and FinnGen databases Liu Enxu, Sun Yu, Duan Jiahao, Yang Lei, Jiang Haobo, Yang Shaofeng 2026, 30 (17):  4542-4547.  doi: 10.12307/2026.122 Abstract ( 112 )   PDF (1340KB) ( 14 )   Save BACKGROUND: Epstein-Barr virus (EBV), a human herpesvirus, exhibits widespread prevalence in the global population. Previous observational studies have suggested an association between EBV infection and ankylosing spondylitis; however, conventional methodologies are limited by confounding factors and reverse causation bias, precluding definitive causal inference. Elucidating the causal relationship between EBV and ankylosing spondylitis is critical for uncovering the immune pathogenesis of ankylosing spondylitis and establishing a theoretical foundation for EBV-targeted preventive strategies. OBJECTIVE: To investigate the bidirectional causal relationship between EBV infection and ankylosing spondylitis using bidirectional Mendelian randomization (MR) analysis. METHODS: Bidirectional two-sample MR analysis was conducted using European population-wide genome-wide association study (GWAS) summary statistics. The generalized summary data MR approach was integrated with conventional methods, including inverse-variance weighted, MR-Egger, and weighted median estimators, to assess bidirectional causality between EBV infection and ankylosing spondylitis. EBV antibody data (EA-D, EBNA-1, VCA p18, and ZEBRA) were sourced from the UK Biobank, while ankylosing spondylitis data were obtained from FinnGen. Instrumental variables were selected based on genome-wide significance (P < 5×10⁻⁶), with exclusion of linkage disequilibrium and confounding single-nucleotide polymorphisms associated with smoking, rheumatoid arthritis, or psoriasis. Statistical significance was determined using Bonferroni correction (threshold: P=6.3×10-3), supplemented by sensitivity analyses for heterogeneity (Cochran’s Q), pleiotropy (MR-Egger intercept, MR-PRESSO), and robustness (leave-one-out analysis). The generalized summary data MR approach further applied HEIDI-outlier testing (P < 0.01) to eliminate pleiotropic single-nucleotide polymorphisms, ensuring causal inference validity. RESULTS AND CONCLUSION: (1) Bidirectional MR revealed that EBV infection significantly increased the risk of ankylosing spondylitis: Elevated EBNA-1 antibody levels showed a positive association with ankylosing spondylitis [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.14–1.76, P = 0.002], while ZEBRA antibodies demonstrated a stronger effect (OR = 1.56, 95% CI: 1.31–1.85, P = 5.4×10⁻⁷), suggesting both latent (EBNA-1) and lytic (ZEBRA) EBV phases may drive ankylosing spondylitis pathogenesis via cross-reactive immune responses. (2) Reverse MR analysis indicated an inverse correlation between ankylosing spondylitis and EBV lytic-phase EA-D antibodies (OR=0.96, 95% CI: 0.94–0.98, P=3.25×10⁻⁴), indicating that ankylosing spondylitis-associated immune profiles may suppress EBV reactivation. (3) All results remained robust in heterogeneity, pleiotropy, and sensitivity analyses, with no detectable bias. (4) This study is the first to confirm EBV infection as an independent causal risk factor for ankylosing spondylitis based on international databases and European population data. Although genetic heterogeneity exists across populations, these findings in European populations provide critical insights into shared immune mechanisms underlying ankylosing spondylitis. Future validation in Chinese cohorts is warranted to characterize EBV-ankylosing spondylitis molecular interactions specific to this population. Furthermore, the generalized summary data MR framework exemplifies the utility of public GWAS data for causal inference, offering a paradigm for efficient risk factor discovery and helping the development of precision medicine.  Figures and Tables | References | Related Articles | Metrics

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Genetic structure of co-morbidity between frailty and rheumatoid arthritis: a genome-wide association analysis Han Jie, Yao Guojun, Huang Yebao, Xu Zhiwei, Shao Weigang, Shang Kebin, Wu Yachao, Liao Zhen 2026, 30 (17):  4548-4556.  doi: 10.12307/2026.110 Abstract ( 64 )   PDF (2503KB) ( 15 )   Save BACKGROUND: Frailty and rheumatoid arthritis are both chronic diseases that seriously impact health. With the accelerating aging population in China, the prevalence of chronic diseases such as frailty and rheumatoid arthritis continues to rise. Existing studies have suggested an association between the two, but their shared genetic basis is still unclear. Therefore, further in-depth exploration of the comorbid genetic structure of frailty and rheumatoid arthritis is necessary to provide insights into co-morbid prevention and treatment of the two diseases. OBJECTIVE: To explore the possible shared genetic structure and potential biological links between frailty and rheumatoid arthritis, and to provide a scientific basis for co-morbidity prevention and treatment. METHODS: We utilized whole-genome sequencing data for frailty from the GWAS Catalog database and rheumatoid arthritis data from the FinnGen R11. Linkage disequilibrium score regression analysis, Bayesian analysis, and stratified linkage disequilibrium score regression analysis were employed to assess the genetic correlation between frailty and rheumatoid arthritis. Multi-trait analysis and cross-trait meta-analysis were used to identify shared risk single nucleotide polymorphisms. Gene and gene-set association analysis tools and stratified linkage disequilibrium score regression analysis were applied for tissue-specific enrichment analysis. Finally, two-sample Mendelian randomization analysis based on generalized summary data was conducted to investigate potential bidirectional causal relationships between frailty and rheumatoid arthritis. RESULTS AND CONCLUSION: Frailty and rheumatoid arthritis exhibited significant positive genetic correlation (rg=0.28, P=4.54×10-35), particularly in specific loci at 6p21.32-21.33 (chr6:31571218-33236497). Through integrating multiple analytical methods, we successfully identified four single nucleotide polymorphisms (rs111294540, rs560607175, rs9277362, rs144112342) that shared risk between frailty and rheumatoid arthritis, located in the HLA-DQA1, HLA-DPA1, and TAP2 genes. Functional element analysis revealed 12 significant elements associated with both frailty and rheumatoid arthritis. Combined with gene expression data, tissue-specific enrichment analysis showed that single nucleotide polymorphisms associated with both frailty and rheumatoid arthritis were specifically enriched in the spleen. Furthermore, Mendelian randomization validated the bidirectional causal relationship between frailty and rheumatoid arthritis. This study elucidated the shared genetic basis between frailty and rheumatoid arthritis, revealing significant genetic correlation and common risk genes for both diseases, and validating their bidirectional causal relationship. These findings provide a reference for the future exploration of the comorbidity mechanisms and therapeutic targets for the two conditions. Although this research utilized data from European populations, it holds valuable implications for the prevention and treatment of chronic diseases in the context of the increasingly aging population in China. Figures and Tables | References | Related Articles | Metrics