BACKGROUND:Prolyl hydroxylase domain 2(PHD2)inhibitors can regulate bone metabolism and relieve osteoporosis in ovariectomized rats.cpd17 is a small molecule oral PHD2 inhibitor newly developed by China Pharmaceutical University.It is effective in the treatment of renal anemia with few side effects,but its effect on bone formation and bone resorption is still unclear. OBJECTIVE:To investigate the effects of cpd17 on mouse osteogenic precursor cells. METHODS:Osteogenic precursor cells were treated with cpd17.Alkaline phosphatase activity and extracellular matrix mineralization were measured,and the expression levels of osteogenesis-and osteoclastogenesis-related markers,as well as PHD2 and hypoxia-inducible factor 1α,were detected.After inhibition of the hypoxia-inducible factor 1α pathway using LW6(a hypoxia-inducible factor 1α pathway inhibitor),alkaline phosphatase activity and extracellular matrix mineralization were detected again,as well as the expression levels of osteogenesis-and osteoclastogenesis-related markers,PHD2 and hypoxia-inducible factor 1α. RESULTS AND CONCLUSION:cpd17 significantly enhanced alkaline phosphatase activity and extracellular matrix mineralization,up-regulated the expression of osteogenesis-related markers,down-regulated the expression of osteoclastogenesis-related markers,up-regulated the expression of hypoxia-inducible factor 1α,down-regulate the expression of PHD2.However,cpd17's effects were significantly attenuated by LW6.To conclude,the PHD2 inhibitor cpd17 promotes osteogenic differentiation and inhibits osteoclastic differentiation through activation of the hypoxia-inducible factor 1α signaling pathway.

BACKGROUND:The capability of repairing articular cartilage damage is very limited,and tissue engineering technology provides new therapeutic options for repairing damaged cartilage,in which the interaction and induction between chondrocytes,bone marrow mesenchymal stem cells,and synovial mesenchymal stem cells is the basis of autologous healing of cartilage damage. OBJECTIVE:To construct the chondrocyte-bone marrow mesenchymal stem cell-synovial mesenchymal stem cell co-culture system to simulate the in vitro microenvironment of chondrocytes,and to explore the optimal cell inoculation ratio,meanwhile to observe the effects of icariin-containing serum on the proliferation of chondrocytes and the chondrogenic differentiation of stem cells in the system. METHODS:Rat knee chondrocytes,bone marrow mesenchymal stem cells and synovial mesenchymal stem cells were extracted,cultured and identified,and a chondrocyte-bone marrow mesenchymal stem cell-synovial mesenchymal stem cell non-contact co-culture system was constructed according to different cell inoculation ratios.After 72 hours of co-culturing,the chondrocyte proliferative activity and phenotypic ability were observed,and the co-culture system with the best overall effect was selected.New Zealand white rabbits were gavaged with icariin solution(0.25 mg/mL)to prepare icariin-containing serum,and cultured in conventional complete medium(high sugar DMEM culture medium containing 10%fetal bovine serum and 1%double antibody by volume)as the control group,while the experimental group was intervened by adding 10%icariin-containing serum by volume on the basis of above.The proliferative activity of chondrocytes and the expression of collagen type II were tested for the two groups after 24 and 48 hours.The differentiation of bone marrow mesenchymal stem cells and synovial mesenchymal stem cells into chondrocytes in the co-culture system was tested by immunofluorescence staining after 14 days. RESULTS AND CONCLUSION:(1)The three kinds of cells grew normally adherently to the wall in different ratios of co-culture,where chondrocytes showed the best proliferative activity and phenotypic ability in the co-culture system when chondrocytes:bone marrow mesenchymal stem cells:synovial mesenchymal stem cells=2:1:1.(2)Compared with the control group,the proliferative activity and type II collagen expression of chondrocytes in the experimental group were significantly increased after 24 hours(P<0.01),and the two groups still had difference after 48 hours(P<0.05).The two groups showed obvious chondrogenic differentiation of bone marrow mesenchymal stem cells and synovial mesenchymal stem cells after 14 days(P<0.01),and some of the cells appeared round or oval,and the cytoplasmic type II collagen immunofluorescence staining was positive.The fluorescence intensity of the experimental group was significantly higher than that of the control group(P<0.01).(3)The results showed that the chondrocyte-bone marrow mesenchymal stem cell-synovial mesenchymal stem cell co-culture system could be successfully established by the non-contact co-culture method,and the best chondrocyte proliferative activity and phenotypic ability could be obtained when the cell ratio was 2:1:1.Icariin-containing serum had the promoting effect on chondrocyte proliferation,and chondrogenic differentiation of bone marrow mesenchymal stem cells and synovial mesenchymal stem cells in the system.

BACKGROUND:Osteosarcoma has a complex pathogenesis and a poor prognosis.While advancements in medical technology have led to some improvements in the 5-year survival rate,substantial progress in its treatment has not yet been achieved. OBJECTIVE:To screen key molecular markers in osteosarcoma,analyze their relationship with osteosarcoma treatment drugs,and explore the potential disease mechanisms of osteosarcoma at the molecular level. METHODS:GSE99671 and GSE284259(miRNA)datasets were obtained from the Gene Expression Omnibus database.Differential gene expression analysis and Weighted Gene Co-expression Network Analysis(WGCNA)on GSE99671 were performed.Functional enrichment analysis was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes separately for the differentially expressed genes and the module genes with the highest positive correlation to the disease.The intersection of these module genes and differentially expressed genes was taken as key genes.A Protein-Protein Interaction network was constructed,and correlation analysis on the key genes was performed using CytoScape software,and hub genes were identified.Hub genes were externally validated using the GSE28425 dataset and text validation was conducted.The drug sensitivity of hub genes was analyzed using the CellMiner database,with a threshold of absolute value of correlation coefficient|R|>0.3 and P<0.05. RESULTS AND CONCLUSION:(1)Differential gene expression analysis identified 529 differentially expressed genes,comprising 177 upregulated and 352 downregulated genes.WGCNA analysis yielded a total of 592 genes with the highest correlation to osteosarcoma.(2)Gene Ontology enrichment results indicated that the development of osteosarcoma may be associated with extracellular matrix,bone cell differentiation and development,human immune regulation,and collagen synthesis and degradation.Kyoto Encyclopedia of Genes and Genomes enrichment results showed the involvement of pathways such as PI3K-Akt signaling pathway,focal adhesion signaling pathway,and immune response in the onset of osteosarcoma.(3)The intersection analysis revealed a total of 59 key genes.Through Protein-Protein Interaction network analysis,8 hub genes were selected,which were LUM,PLOD1,PLOD2,MMP14,COL11A1,THBS2,LEPRE1,and TGFB1,all of which were upregulated.(4)External validation revealed significantly downregulated miRNAs that regulate the hub genes,with hsa-miR-144-3p and hsa-miR-150-5p showing the most significant downregulation.Text validation results demonstrated that the expression of hub genes was consistent with previous research.(5)Drug sensitivity analysis indicated a negative correlation between the activity of methotrexate,6-mercaptopurine,and pazopanib with the mRNA expression of PLOD1,PLOD2,and MMP14.Moreover,zoledronic acid and lapatinib showed a positive correlation with the mRNA expression of PLOD1,LUM,MMP14,PLOD2,and TGFB1.This suggests that zoledronic acid and lapatinib may be potential therapeutic drugs for osteosarcoma,but further validation is required through additional basic experiments and clinical studies.

ObjectiveTo explore the dose-effect relationship and safety of high， medium， and low doses of raw Astragali Radix in the modified Huangqi Chifengtang （MHCD） for treating proteinuria in immunoglobulin A （IgA） nephropathy， and to provide scientific evidence for the clinical use of high-dose Astragali Radix in the treatment of proteinuria in IgA nephropathy. MethodsA total of 120 patients with IgA nephropathy， diagnosed with Qi deficiency and blood stasis combined with wind pathogen and heat toxicity， were randomly divided into a control group and three treatment groups. The control group received telmisartan combined with a Chinese medicine placebo， while the treatment groups were given telmisartan combined with MHCD containing different doses of raw Astragali Radix （60， 30， 15 g）. Each group contained 30 patients， and the treatment period was 12 weeks. Changes in 24-hour urinary protein （24 hUTP）， traditional Chinese medicine （TCM） syndrome scores， effective rate， and renal function were observed before and after treatment. Safety was assessed by monitoring liver function and blood routine. ResultsAfter 12 weeks of treatment， 24 hUTP significantly decreased in the high， medium， and low-dose groups， as well as the control group （P<0.05， P<0.01）. The TCM syndrome scores in the high， medium， and low-dose groups also significantly decreased （P<0.01）. Comparisons between groups showed that the 24 hUTP in the high-dose group was significantly lower than in the medium， low-dose， and control groups （P<0.05， P<0.01）， and the 24 hUTP in the medium-dose group was significantly lower than in the control group （P<0.05）. The TCM syndrome scores in the high and medium-dose groups were significantly lower than in the low-dose and control groups （P<0.05， P<0.01）. The total effective rates for proteinuria in the high， medium， low-dose， and control groups were 92.59% （25/27）， 85.19% （23/27）， 60.71% （17/28）， and 57.14% （16/28）， respectively. The effective rates in the high and medium-dose groups were significantly higher than in the low-dose and control groups （χ²=13.185， P<0.05， P<0.01）. The effective rates for TCM syndrome scores in the high， medium， low-dose， and control groups were 88.89% （24/27）， 81.48% （22/27）， 71.43% （20/28）， and 46.43% （13/28）， respectively. The efficacy of TCM syndrome scores in the high and medium-dose groups was significantly higher than in the control group （χ²=14.053， P<0.01）. Compared with pre-treatment values， there was no statistically significant difference in eGFR and serum creatinine in the high and medium-dose groups. However， eGFR significantly decreased in the low-dose and control groups after treatment （P<0.05）， and serum creatinine levels increased significantly in the control group （P<0.05）. No statistically significant differences were observed in urea nitrogen， uric acid， albumin， total cholesterol， triglycerides， liver function， and blood routine before and after treatment in any group. ConclusionThere is a dose-effect relationship in the treatment of IgA nephropathy with high， medium， and low doses of raw Astragali Radix in MHCD. The high-dose group exhibited the best therapeutic effect and good safety profile.

Alzheimer's disease （AD）， a degenerative disease of the central nervous system， is characterized by progressive degradation of learning， memory， and cognitive functions. Currently， few drugs are available for treating AD， and their effects are limited. Berberine （BBR） is a natural isoquinoline （quaternary ammonium-like） with a wide range of pharmacological effects. Studies have proven that BBR has good potential in the treatment of AD. Specifically， BBR can inhibit the generation， aggregation， and neurotoxicity of amyloid-β and the hyperphosphorylation of Tau protein， promote the clearance of phosphorylated Tau protein， reduce the cholinesterase activity， neuroinflammation， and oxidative stress， regulate neuronal apoptosis， improve the mitochondrial function and glucose and lipid metabolism， suppress the monoamine oxidase activity， and modulate gut microbiota. In addition， researchers have ameliorated the low bioavailability of BBR. Probing into the potential targets is hoped to provide a reference for further research on the prevention and treatment of AD by BBR.

Huopo Xialingtang is a famous classical formula for treating dampness and warmth， which is included in the Catalogue of Ancient Famous Classical Formulas（The First Batch）. In this paper， bibliometric methods was used to collect the literature related to Huopo Xialingtang， and 16 items of related literature were retrieved， involving five medical books， which were used to textual research on the origin， name， composition， drug dosage， preparation method， processing and main treatment symptoms of this formula. The results indicated that Huopo Xialingtang was originated from Yiyuan written by Shi Funan in the Qing dynasty， and and was later named and extended by He Lianchen. The composition of the proposed formula was consistent with the record of Yiyuan， and the origin of each Chinese materia medica was basically clear. Houpo was the dried bark and root bark of Magnolia officinalis， Zexie was the dried tubers of Alisma orientale， Kuxingren was the dried mature seeds of Prunus armeniaca， Doukou was the dried mature fruits of Amomum kravanh， the origin of Tuhuoxiang was consistent with the 2018 edition of Shanghai Standards of Processing Chinese Crud Drugs， and the origins of the remaining Chinese medicines were consistent with the 2020 edition of Chinese Pharmacopoeia. The converted dose of each Chinese medicine was 7.46 g for Agastache rugosa， 3.73 g for Magnoliae Officinalis Cortex， 8.39 g for Pinelliae Rhizoma Praeparatum cum Zingibere et Alumine， 11.19 g for Poria， 11.19 g for Armeniacae Semen Amarum， 14.92 g for Coicis Semen， 2.61 g for Amomi Fructus Rotundus， 5.60 g for Polyporus， 5.60 g for Alismatis Rhizoma， 14.92 g for Tetrapanacis Medulla. Huopo Xialingtang was initially used for the treatment of dampness and warmth at the beginning of the disease， and was later expanded to treat dampness obstruction， dampness-warming dysentery and so on， but always with the dampness-heat in the lungs and spleen as the pathogenesis. In modern times， the clinical application is more extensive， used in digestive， respiratory， endocrine， nervous system and other types of diseases， especially for chronic gastritis， stomach pain and fever. By combing the ancient literature of Huopo Xialingtang， we verified the origin of the formula and determined the key information of the prescription， which can provide literature reference for the clinical application and drug development of this formula.

GPR126, also known as ADGRG6, is one of the most deeply studied aGPCRs. Initially, GPR126 was thought to be a receptor associated with muscle development and was primarily expressed in the muscular and skeletal systems. With the deepening of research, it was found that GPR126 is expressed in multiple mammalian tissues and organs, and is involved in many biological processes such as embryonic development, nervous system development, and extracellular matrix interactions. Compared with other aGPCRs proteins, GPR126 has a longer N-terminal domain, which can bind to ligands one-to-one and one-to-many. Its N-terminus contains five domains, a CUB (complement C1r/C1s, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a SEA (Sperm protein, Enterokinase, and Agrin) domain, a hormone binding (HormR) domain, and a conserved GAIN domain. The GAIN domain has a self-shearing function, which is essential for the maturation, stability, transport and function of aGPCRs. Different SEA domains constitute different GPR126 isomers, which can regulate the activation and closure of downstream signaling pathways through conformational changes. GPR126 has a typical aGPCRs seven-transmembrane helical structure, which can be coupled to Gs and Gi, causing cAMP to up- or down-regulation, mediating transmembrane signaling and participating in the regulation of cell proliferation, differentiation and migration. GPR126 is activated in a tethered-stalk peptide agonism or orthosteric agonism, which is mainly manifested by self-proteolysis or conformational changes in the GAIN domain, which mediates the rapid activation or closure of downstream pathways by tethered agonists. In addition to the tethered short stem peptide activation mode, GPR126 also has another allosteric agonism or tunable agonism mode, which is specifically expressed as the GAIN domain does not have self-shearing function in the physiological state, NTF and CTF always maintain the binding state, and the NTF binds to the ligand to cause conformational changes of the receptor, which somehow transmits signals to the GAIN domain in a spatial structure. The GAIN domain can cause the 7TM domain to produce an activated or inhibited signal for signal transduction, For example, type IV collagen interacts with the CUB and PTX domains of GPR126 to activate GPR126 downstream signal transduction. GPR126 has homology of 51.6%-86.9% among different species, with 10 conserved regions between different species, which can be traced back to the oldest metazoans as well as unicellular animals.In terms of diseases, GPR126 dysfunction involves the pathological process of bone, myelin, embryo and other related diseases, and is also closely related to the occurrence and development of malignant tumors such as breast cancer and colon cancer. However, the biological function of GPR126 in various diseases and its potential as a therapeutic target still needs further research. This paper focuses on the structure, interspecies differences and conservatism, signal transduction and biological functions of GPR126, which provides ideas and references for future research on GPR126.

ObjectiveTo systematically analyze the global policy framework, standard systems and application technology models of digital rehabilitation within the framework of the World Health Organization (WHO) Global Digital Health Strategy and propose policy recommendations for the future development of digital rehabilitation. MethodsBased on the policies on digital health and rehabilitation development issued by the WHO, focusing on the Global Digital Health Strategy, Rehabilitation 2030 Initiative, Rehabilitation in Health Systems, Rehabilitation in Health Systems: A Guide for Action, and World Report on Disability, a systematic review was conducted, to explore the policy architecture and core content of digital rehabilitation, the standard system for digitalizing rehabilitation, and key technological models for the development of digital rehabilitation. ResultsIn the context of global health and digital transformation, the development of digital rehabilitation services was an essential component of the global digital health strategy. Building a comprehensive policy framework and content system for digital rehabilitation was critical for strengthening rehabilitation data governance, enhancing data utilization efficiency, and ensuring data privacy and security. Empowering rehabilitation with digital technology was vital for improving the standardization, effectiveness, coverage, quality and safety of rehabilitation services. International digital rehabilitation policies primarily involved the following areas: policy and governance, digital standard systems, data privacy, security and ethics, digital talent cultivation and capacity building, and monitoring, evaluation and continuous improvement of digitally empowered rehabilitation services. The standard system for rehabilitation digitization covered the three major reference classifications of the WHO Family of International Classifications, including International Classification of Diseases Eleventh Revision (ICD-11), International Classification of Functioning, Disability and Health (ICF), and International Classification of Health Interventions (ICHI), especially ICF. It also included international data interoperability standards, data security and privacy protection standards, data quality and certification standards, and health information standards, etc. The application technology models of digital rehabilitation primarily included data-driven service models, artificial intelligence -enabled models, and remote rehabilitation models combined with virtual reality, augmented reality technologies, and Internet of Things support. ConclusionThe establishment and implementation of comprehensive policies, standards and technological models for digital rehabilitation are crucial for driving the digital transformation and development of global rehabilitation services. Under the framework of the WHO Global Digital Health Strategy, it is necessary to build adaptive digital rehabilitation policy frameworks, and enhance digital governance capabilities and levels, establishing and improving digital rehabilitation standard systems, and promoting the interoperability and integration of rehabilitation data with other health big data. Meanwhile, it is essential to actively develop data-driven technological models for rehabilitation services to comprehensively improve the accessibility, availability, quality and safety of rehabilitation services.

ObjectiveTo systematically evaluate the effect of art therapy on the mental health of older adults with mild cognitive impairment (MCI), based on International Classification of Functioning, Disability and Health. MethodsLiterature on art therapy for mental health of MCI older adults was retrieved from databases of CNKI, VIP, Wanfang Data, PubMed, ProQuest and Web of Science, between 2014 and 2024, and selected according to inclusion and exclusion criteria. The quality of the literature was assessed using PEDro scale, and a systematic review was conducted following the PRISMA guideline. ResultsA total of nine researches were included from China, Tanzania, Spain, Malaysia and Singapore, involving 763 individuals with MCI aged 60 or more (average 71.23). The types of art therapy interventions were visual arts therapy (painting, collage, paper-cutting, sculpture and modeling, etc.), expressive arts therapy (encompassing dance and music) and creative arts therapy (narrative creation), 30 to 120 minutes a time (majority of 60 minutes), one to four times a week (majority of two to four times), for six to 36 weeks (majority of six to twelve weeks). Health outcomes predominantly focused on mental health, such as anxiety and depression. ConclusionMost researches support that art therapy is effective on mental health of older adults with MCI, but there are disagreements in some researches, and more researches are needed.

ObjectiveTo analyze the research hotspot and future trend of non-invasive brain stimulation (NIBS) in Alzheimer's disease. MethodsRelevant literature on application of NIBS in Alzheimer's disease from January, 2014 to October, 2024 was retrieved from the Web of Science Core Collection database. CiteSpace 6.4.R1 was used to perform a bibliometric analysis and to create knowledge maps, including annual publication volume, countries, institutions, authors, keywords and co-cited references. ResultsA total of 731 articles were included, showing an increasing trend in annual publication volume. The United States was the leading country in publication volume, Harvard University was the most productive institution, and Giacomo Koch was the most prolific author. Brain Stimulation was the most frequently cited journal. Highly focused keywords included cognitive impairment, memory, dementia, transcranial magnetic stimulation and transcranial direct current stimulation. Bursting keywords in the past two years included transcranial alternating current stimulation, functional magnetic resonance imaging, brain-derived neurotrophic factor and oxidative stress. ConclusionResearch interest in NIBS within the field of Alzheimer's disease has been steadily increasing. The research hotspots include the effect and mechanism of NIBS on cognitive function and the impact of stimulating different brain regions on cognitive outcome. Future research may focus on integrating NIBS with techniques such as functional magnetic resonance imaging to achieve individualized and precise stimulation.