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.

ObjectiveTo investigate the protective effect of Xielitang on dextran sulfate sodium （DSS）-induced ulcerative colitis （UC） mice and its possible mechanism. MethodsDSS was used to establish UC model. Sixty mice were randomly divided into a normal group， a model group， a sulfasalazine group （0.6 g·kg^-1）， and low-， medium-， and high-dose Xielitang groups （1.67， 3.34， 6.68 g·kg^-1）. After treatment for 42 d， the colon length was recorded， and the disease activity index （DAI） score was calculated. Enzyme-linked immunosorbent assay （ELISA） was used to detect the serum levels of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and interleukin-10 （IL-10）. Hematoxylin-eosin （HE） staining was used to observe the pathomorphological changes of colon. Western blot was used to detect the protein expression of farnesoid X receptor （FXR）， small heterodimer partner （SHP）， liver receptor homolog-1 （LRH-1）， cholesterol 7α-hydroxylase （CYP7A1）， and fibroblast growth factor receptor 4 （FGFR4） in liver and FXR， sodium-dependent bile acid transporter （ASBT）， and fibroblast growth factor 15 （FGF15） in ileum. 16S rRNA sequencing was used to analyze the intestinal flora. Moreover， ultra-high performance liquid chromatography–tandem mass spectrometry was used to detect the bile acid content. ResultsCompared with the normal group， the model group showed significantly decreased colon length， IL-10 content， α-diversity index， abundance of Firmicutes and Lactobacillus， and content of deoxycholic acid （DCA） and lithocholic acid （LCA） （P<0.01）， significantly increased DAI score， IL-6 and TNF-α content， abundance of Bacteroidetes， and the content of cholic acid （CA）， chenodeoxycholic acid （CDCA）， and taurocholic acid （TCA） （P<0.05， P<0.01）， significantly down-regulated protein expression of FXR， SHP， and FGFR4 in liver and FXR， ASBT， and FGF15 in ileum （P<0.01）， and significantly up-regulated protein expression of LRH-1 and CYP7A1 in liver （P<0.01）. In addition， the structure of colonic mucosa was destroyed， and inflammatory cells infiltrated in the model group. Compared with the model group， Xielitang could significantly increase the colon length， IL-10 content， α-diversity index， the abundance of Firmicutes and Lactobacillus， and DCA and LCA content （P<0.05， P<0.01）， decrease DAI score， abundance of Bacteroidetes， and the content of IL-6， TNF-α， CA， CDCA， and TCA （P<0.01）， up-regulate the protein expression of FXR， SHP， and FGFR4 in liver and FXR， ASBT， and FGF15 in ileum （P<0.01）， and down-regulate the protein expression of LRH-1 and CYP7A1 in liver （P<0.01）. The pathological damage of colonic mucosa was obviously alleviated. ConclusionXielitang protects against UC probably by regulating the "intestinal microbiota-bile acid" axis， regulating intestinal flora imbalance， and maintaining bile acid homeostasis.

Objective: To explore the cross sectional and longitudinal associations between 24 hour movement behaviors and physical fitness in preschool children, and to adopt the method of equal time substitution analysis to evaluate the impact of time redistribution of different activity behaviors on physical fitness scores,so as to provide a scientific basis for promoting the health of preschool children. Methods: A total of 193 preschool children aged 3-6 years were selected from three Shanghai districts (Jing an, Baoshan, Jiading) from October to December 2023 by the stratified cluster random sampling method. The 24 hour movement behaviors were monitored via 7 day accelerometry, and physical fitness was measured according to the National Physical Fitness Measurement Standards (Revised 2023, preschool section). From October to December 2024, the follow up of physical fitness among preschool children used the same testing method. The comparison between groups was conducted by t-test. Compositional regression analyses evaluated the relationship of 24 hour movement behaviors and physical fitness among preschool children. Results: At baseline, moderate to vigorous physical activity (MVPA) time was significantly higher in boys [(84.10±25.78)min/d] than in girls [( 70.44± 25.98)min/d]; the composite physical fitness score was significantly higher in boys (71.65±8.69) than in girls (68.84±9.89), and the differences were statistically significant ( t =3.65, 2.10, both P <0.01). After adjusting for gender, age and body mass index, the results of component multiple linear regression analysis showed that MVPA time proportion was positively correlated with the composite physical fitness score at baseline among preschool children ( β =6.61), but was negatively correlated with two legged continuous hopping time at 1 year ( β =-1.12) (both P <0.05). Light physical activity (LPA) time proportion was negatively correlated with walking on the balance beam time at 1 year ( β =-4.44), and sedentary behavior (SB) time proportion was negatively correlated with the composite score of physical fitness at baseline ( β =-6.55) (both P <0.05). Isotemporal substitution analysis revealed that replacing 10 minutes of sleep (SP), SB, and LPA with MVPA increased the baseline physical fitness composite score by 0.750, 0.689 and 0.575 units, respectively; at 1 year follow up, the composite score increased by 1.440, 1.419 and 1.430 units, respectively (all P <0.05). Conversely, replacing MVPA with 10 minutes of SP, SB, and LPA,resulted in decreases in baseline physical fitness composite scores of 0.836, 0.777 and 0.669 units, and reductions of 1.613, 1.592 and 1.598 units at 1 year follow up (all P < 0.05 ). Conclusions Preschool children s 24 hour movement behaviors, especially MVPA, are closely related to physical health. Implementing appropriate strategies to increase physical activity and reduce sedentary time may improve the physical fitness of preschoolers.

BACKGROUND: The combination of immune checkpoint inhibitors and chemotherapy (ICI + Chemo) shows promise in treatment of recurrent or metastatic nasopharyngeal carcinoma (RM-NPC), but some patients received limited benefit and the prognostic factors of the treatments remain unclear. Furthermore, ICIs efficacy in subsequent treatments needs further evaluation. METHODS: A systematic search on PubMed, Embase, the Cochrane Library, and major conference proceedings was conducted to identify relevant studies for meta-analysis. The study was designed to compare ICI + Chemo with chemotherapy in first-line treatment and identify efficacy predictors, and to evaluate ICIs alone in subsequent-line treatment for RM-NPC, with a focus on progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (AEs). RESULTS: Fifteen trials involving 1928 patients were included. Three trials compared ICI + Chemo with chemotherapy as a first-line treatment, while 12 trials evaluated ICIs alone in subsequent-line treatment of RM-NPC patients. First-line ICI + Chemo showed superior PFS (hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.43-0.63; P <0.001) and ORR (risk ratio [RR] = 1.14, 95% CI, 1.05-1.24; P <0.001) compared to chemotherapy, without increased AEs (RR = 1.01, 95% CI, 0.99-1.03; P = 0.481). Neither programmed death-ligand 1 (PD-L1) nor other factors predicted the efficacy of ICI + Chemo vs . chemotherapy. Subsequent-line ICIs alone had a median PFS of 4.12 months (95% CI, 2.93-5.31 months), an ORR of 24% (95% CI, 20-28%), with grade 1-5/grade 3-5 AEs at 79%/14%. However, ICIs alone were associated with significantly shorter PFS (HR = 1.31, 95% CI, 1.01-1.68; P = 0.040) than chemotherapy alone. CONCLUSIONS ICI + Chemo confers superior survival benefits compared to chemotherapy in first-line RM-NPC treatment, independent of PD-L1 expression or other factors. However, ICIs alone demonstrate a manageable safety profile but do not surpass chemotherapy in efficacy for subsequent-line treatment.
Humans ; Immune Checkpoint Inhibitors/adverse effects* ; Nasopharyngeal Carcinoma/drug therapy* ; Nasopharyngeal Neoplasms/drug therapy* ; Neoplasm Recurrence, Local/drug therapy*

OBJECTIVES: To investigate the effects of dihydroartemisinin (DHA) combined with doxorubicin (DOX) on proliferation and apoptosis of triple-negative breast cancer cells and explore the underlying molecular mechanism. METHODS: MDA-MB-231 cells were treated with 50, 100 or 150 μmol/L DHA, 0.5 μmol/L DOX, or with 50 μmol/L DHA combined with 0.5 μmol/L DOX. The changes in proliferation and survival of the treated cells were examined with MTT assay and colony-forming assay, and cell apoptosis was analyzed with flow cytometry. Western blotting was performed to detect the changes in protein expression levels of PCNA, cleaved PARP, Bcl-2, Bax, STAT3, p-STAT3, HIF-1α and survivin. RESULTS: The IC₅₀ of DHA was 131.37±29.87 μmol/L in MDA-MB-231 cells. The cells with the combined treatment with DHA and DOX showed significant suppression of cell proliferation. Treatment with DHA alone induced apoptosis of MDA-MB-231 cells in a dose-dependent manner, but the combined treatment produced a much stronger apoptosis-inducing effect than both DHA and DOX alone. DHA at 150 μmol/L significantly inhibited clone formation of MDA-MB-231 cells, markedly reduced cellular expression levels of PCNA, p-STAT3, HIF-1α and survivin proteins, and obviously increased the expression level of cleaved PARP protein and the Bax/Bcl-2 ratio, and the combined treatment further reduced the expression level of p-STAT3 protein and increased the Bax/Bcl-2 ratio. CONCLUSIONS DHA combined with DOX produces significantly enhanced effects for inhibiting cell proliferation and inducing apoptosis in MDA-MB-231 cells possibly as result of DHA-mediated negative regulation of the STAT3/HIF-1α pathway.
Humans ; STAT3 Transcription Factor/metabolism* ; Apoptosis/drug effects* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Doxorubicin/pharmacology* ; Triple Negative Breast Neoplasms/metabolism* ; Cell Line, Tumor ; Artemisinins/pharmacology* ; Female ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Survivin

Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues. Dimethyl fumarate (DMF) has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions. Here, we investigated for the first time the therapeutic effect of DMF on periodontitis. In vivo studies showed that DMF significantly inhibited periodontal destruction, enhanced mitophagy, and decreased the M1/M2 macrophage ratio. In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages, with improved mitochondrial function, inhibited oxidative stress, and increased mitophagy in RAW 264.7 cells. Furthermore, DMF increased intracellular mitochondrial Tu translation elongation factor (TUFM) levels to maintain mitochondrial homeostasis, promoted mitophagy, and modulated macrophage polarization, whereas TUFM knockdown decreased the protective effect of DMF. Finally, mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway. Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages, resulting in a shift in the balance of macrophage polarization, thereby attenuating periodontitis. Importantly, this study provides new insights into the prevention of periodontitis.
Dimethyl Fumarate/pharmacology* ; Mitophagy/drug effects* ; Animals ; Mice ; Macrophages/metabolism* ; Periodontitis/prevention & control* ; RAW 264.7 Cells ; Oxidative Stress/drug effects* ; Peptide Elongation Factor Tu/metabolism* ; Mice, Inbred C57BL ; Male ; Mitochondria/drug effects*

Objective To investigate the effects of adiponectin(APN)on the proliferation,migration,and invasion of ovarian cancer cells and its potential association with the phosphatidylinositol 3-kinase(PI3K)/pro-tein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling pathway.Methods A2780 and SK-OV3 cell lines were selected.AdipoR1 mRNA expression was detected by real-time polymerase chain reaction(RT-PCR).The CCK-8 assay was employed to evaluate APN-induced proliferation,while scratch wound heal-ing and Transwell assays were conducted to assess migration and invasion capabilities.Western blot analysis was performed to measure the expression levels of PI3K,Akt,mTOR,and their phosphorylated forms(p-Akt,p-mTOR)at different time points(0-60 min)after APN treatment and across intervention groups(APN,LY294002,APN+LY294002).Results Both A2780 and SKOV3 cells expressed AdipoR1 mRNA.Compared with the control group,APN significantly enhanced the proliferation,migration,and invasion of o-varian cancer cells(P＜0.05).Under the stimulation of APN,the expression levels of p-Akt and p-mTOR in A2780 and SKOV3 cells showed a significant upward trend.The peak expression of p-Akt and p-mTOR in A2780 cells was observed at 30 minutes,while in SKOV3 cells,it occurred at 60 minutes.The expression lev-els of p-Akt and p-mTOR were significantly reduced in the LY294002 group and APN+LY294002 group(P＜0.001).Conclusion APN enhances the proliferation,migration,and invasion behavior of ovarian cancer cells by activating the PI3K/Akt/mTOR signaling pathway,and its effect can be reversed by PI3K inhibitors,providing a theoretical basis for targeted intervention in ovarian cancer progression.

Objective:To understand trends and hotspots of TCM research papers published in journals with high IF basing on a bibliometric analysis.Methods:TCM research papers published between January 1, 2014 and December 31, 2024 from 80 journals with IF higher than 16.0 were retrieved from medical, life sciences and comprehensive journals in Journal Citation Reports of 2024. CiteSpace 6.3.R1 and Excel 2021 were used to analyze and visualize annual publication volume, research fields, features of clinical study, institutes, funds and keywords.Results:A total of 51 papers were included, showing an increasing trend in annual publication volume; the main research areas were pharmacology, acupuncture&moxibustion and internal medicine. Multi-center randomized controlled trials were the main clinical studies; China Academy of Chinese Medical Sciences was the leading institute in terms of publication volume; 84 funds were involved, including National Natural Science Foundation of China. Keywords that appeared most frequently were TCM, efficacy, double blind, electroacupuncture, stimulation and management.Conclusion:The number and quality of TCM research papers are improved simultaneously; future research needs to deepen international cooperation, and pay attention to the integration of TCM diagnosis and treatment characteristics and modern scientific research methods.

Objective To investigate the clinical application of three-dimensional magnetic resonance(MR)visualization in difficult laparoscopic cholecystectomy.Methods A total of 100 patients with gallstones who were admitted to the Second People's Hospital of Shantou from January 2022 to December 2023 were selected as research objects.The patients met the criteria of"difficult gallbladder"and were assigned to two groups according to random number table.The control group(n=50)were treated with routine laparoscopic cholecystectomy.In the observation group(n=50),laparoscopic cholecystectomy was assisted by MR 3D visualization model.Surgical indexes,pain within 1 day after surgery,risk of intraoperative trauma,and incidence of postoperative complications were compared between the two groups.Results Surgical indexes and recovery indexes in the observation group were superior to those in the control group(P<0.05).The visual analogue scale(VAS)score within 1 d after operation was significantly lower than that before operation in both groups,and the improvement of VAS score in the observation group was better than that in the control group(P<0.05).The incidence of gallbladder rupture(0.00%vs 10.00%)and liver margin injury(0.00%vs 8.00%)in the observation group were lower than those in the control group(P<0.05).The incidence of complications in the observation group was significantly lower than that in the control group(2.00%vs 14.00%,P<0.05).Conclusion The construction of MR 3D visualization model can provide clearer surgical field for laparoscopic cholecystectomy,and enable the operator to clarify the anatomical structure of the gallbladder,avoid surgical trauma,improve the postoperative recovery,alleviate postoperative pain,and reduce the risk of complications.

Objective To explore the influencing factors of liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease(MAFLD)complicated with chronic hepatitis B(CHB),and to find clinically convenient predictive parameters for assessing liver fibrosis risk.Methods A retrospective analysis was conducted on 221 cases of MAFLD with CHB diagnosed and treated at the Second Hospital of Lanzhou University between January 2015 and August 2022.Patients were divided into low-risk(FIB-4<1.30,n=84),medium-risk(1.30≤FIB-4≤2.67,n=94)and high-risk(FIB-4>2.67,n=43)liver fibrosis groups based on the Fibrosis-4(FIB-4)index.General clinical data,laboratory indicators and composite indicators were compared among the three groups.Variables were screened using forward stepwise regression,and binary logistic regression analysis was performed to determine independent predictors of liver fibrosis.A prediction model was constructed and evaluated using receiver operating characteristic(ROC)curve analysis.Results Age,AST and Triglyceride-glucose index(TyG)were independent risk factors for liver fibrosis in patients with MAFLD combined with CHB,while platelet-to-lymphocyte ratio(PLR)was an independent protective factor(all P<0.05).ROC curve analysis showed that the area under the curve(AUC)for age,AST,TyG,PLR,age-AST and AST-TyG in predicting liver fibrosis were 0.668,0.764,0.680,0.738,0.856 and 0.805,respectively.At the optimal cut-off values,the sensitivities were 86.0%,67.4%,93.0%,62.8%,86.0%and 79.1%,and the specificities were 43.3%,82.0%,51.7%,86.0%,71.3%and 70.2%.Conclusion Age,AST,TyG and PLR are influencing factors of liver fibrosis in MAFLD combined with CHB patients.The parameters established based on these factors may predict the risk of liver fibrosis,and combined prediction can improve predictive efficacy.