Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS' survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (^HAP-1NP_DC+LND) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, ^HAP-1NP_DC+LND released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, ^HAP-1NP_DC+LND demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.

OBJECTIVES: To explore the mechanism of Qingda Granules (QDG) for alleviating brain damage in spontaneously hypertensive rats (SHRs). METHODS: Twelve 5-week-old SHRs were randomized into SHR control group and SHR+QDG group treated with QDG by gavage at the daily dose of 0.9 g/kg for 12 weeks. The control rats, along with 6 age-matched WKY rats, were treated with saline only. Blood pressure changes of the rats were monitored, and pathologies and neuronal apoptosis in the cerebral cortex were examined with HE staining and TUNEL staining. Cerebral cortical expressions of miR-124 and STAT3 mRNA were detected using RT-qPCR, and the protein expressions of NeuN, STAT3, Bcl-2, Bax, and cleaved caspase-3 were detected with immunohistochemistry and Western blotting. In a HT22 cell model of oxygen and glucose deprivation/reoxygenation (OGD/R), the effects of QDG on cell viability and apoptosis, expressions of miR-124 and STAT3 mRNA, and protein expressions of STAT3, Bcl-2, Bax, and cleaved caspase-3 were evaluated using CCK8 assay, Hoechst 33342 staining, RT-qPCR, and Western blotting. RESULTS: Compared with WKY rats, SHRs had significantly elevated systolic blood pressure, diastolic blood pressure and mean arterial pressure with significantly increased neuronal apoptosis in the cerebral cortex, reduced expressions of NeuN, miR-124 and Bcl-2, and enhanced expressions of STAT3, Bax and cleaved caspase-3 (P<0.05). All these changes in the SHRs were significantly ameliorated by treatment with QDG (P<0.05). In the HT22 cell model, QDG treatment obviously reduced OGD/R-induced cell apoptosis, increased the expressions of miR-124 and Bcl-2, and suppressed the elevation of protein expressions of STAT3, Bax and cleaved caspase-3. CONCLUSIONS QDG inhibits cerebral cortical neuronal apoptosis and thereby attenuates brain damage in SHR rats by modulating the miR-124/STAT3 signaling axis.
Animals ; Rats, Inbred SHR ; MicroRNAs/metabolism* ; STAT3 Transcription Factor/metabolism* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Rats ; Apoptosis/drug effects* ; Rats, Inbred WKY ; Male ; Hypertension

Objective:To explore the effects of deep hyperthermia on chemotherapy-related adverse effects and immune-inflammatory indicators in the patients undergoing postoperative adjuvant chemotherapy for colorectal cancer.Methods:This retrospective study included 52 patients who underwent surgery for colorectal cancer at the Affiliated Zhongshan Hospital of Dalian University from September 2021 to December 2023. The patients were divided into two groups based on treatment method: the combination group ( n=29) received postoperative adjuvant chemotherapy combined with deep hyperthermia, while the chemotherapy group ( n=23) received postoperative adjuvant chemotherapy alone. Both groups were treated with the XELOX regimen (oxaliplatin + capecitabine). The degree of bone marrow suppression during treatment was assessed by analyzing peripheral blood parameters, including hemoglobin, leukocyte count, neutrophil count, and platelet count. Immune-inflammatory indicators, including complement, procalcitonin (PCT), interleukin-6 (IL-6), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), were compared before and after treatment in both groups to evaluate the effects of deep hyperthermia on the immune-inflammatory response. Chi-square test or Fisher's exact test (two-tailed) was used to compare bone marrow suppression rates, and the immune-inflammatory indicators between the two groups were compared using t-tests or non-parametric tests, depending on whether the data conformed to a normal distribution. Results:In terms of myelosuppression, the incidence rates of moderate to severe decreases in leukocytes, neutrophils, platelets, and hemoglobin in the combination group were 31%, 31%, 21%, and 14%, respectively, compared to 52%, 61%, 48%, and 9% in the chemotherapy group. The change in PCT levels before and after treatment was significantly greater in the combination group than in the chemotherapy group ( P = 0.010). Both the combination group and the chemotherapy group showed significant reductions in SII, NLR and PLR after treatment, and the differences were statistically significant (all P < 0.05). The change in NLR before and after treatment was significantly greater in the combination group than in the chemotherapy group ( P = 0.031). Conclusions:Deep hyperthermia can alleviate chemotherapy-induced adverse effects such as thrombocytopenia and neutropenia in patients undergoing postoperative adjuvant chemotherapy for colorectal cancer. It also appears to improve the inflammatory response in these patients.

Objective:To investigate the clinicopathological and molecular genetic characteristics of diffuse gliomas with the features of polymorphous low-grade neuroepithelial tumor of the young (PLNTY) and their prognostic values.Methods:A retrospective analysis was performed on 14 cases of diffuse gliomas with PLNTY features diagnosed at the First Affiliated Hospital of Fujian Medical University, Fuzhou, China from June 2020 to August 2024. Their clinicopathological characteristics were examined, and their molecular genetic and epigenetic features were assessed using next-generation sequencing (NGS) and methylation analysis. Factors influencing prognosis were also analyzed.Results:Among the 14 patients, there were 8 males and 6 females, aged 3-62 years, median 29 (9, 50) years. All cases were initially diagnosed as low-grade diffuse gliomas histologically but exhibited the histological and immunohistochemical features of PLNTY. At the molecular level, all cases showed molecular abnormalities involving the mitogen-activated protein kinase pathway, including 5 cases with FGFR3-TACC3 (F3T3) fusion, 3 cases with FGFR2 fusion, 5 cases with BRAF V600E mutation, and 1 case with FGFR1 mutation. Among them, TERT promoter mutations were frequently observed in tumors with F3T3 fusion (5/5), while NCOR2 in-frame insertion mutations were prominent in tumors with non-F3T3 fusions. Clinical follow-up showed recurrence in 3 cases, all of which had F3T3 fusion and concurrent TERT promoter mutations. Prognostic analysis confirmed that F3T3 fusion with concurrent TERT promoter mutation was associated with poor prognosis.Conclusions:Diffuse gliomas with PLNTY features exhibit heterogeneity in clinicopathology and molecular genetics, with FGFR3/FGFR2 fusions and BRAF/FGFR1 mutations as the most common molecular alteration. They often have concurrent F3T3 fusion and TERT promoter mutations, which are related to poor prognosis. The possibility of molecular glioblastoma should be considered for these tumors. It is thus recommended to perform genetic testing on diffuse gliomas with PLNTY features in order to facilitate integrated diagnosis and provide molecular evidence for accurate evaluation of prognoses.

Objective:To investigate the impact of four registration methods on the accuracy of virtual occlusal records (VOR) in intraoral scanning for implant restorations with multiple missing teeth.Methods:A mandibular model simulating clinical conditions with multiple missing teeth (right first molar, left second premolar, left first molar, left second molar) and a maxillary compete dentition model were mounted on a semi-adjustable articulator. Subsequently, twelve 0.5 mm stainless steel spheres were adhered to reference positions (16, 46, 13, 43, 23, 33, 25, 35, 26, 36, 27, 37) as fiducial markers. Following this, a laboratory scanner generated reference datasets by digitizing the models in maximum intercuspation (MIP). Meanwhile, ten maxillary and mandibular scans were acquired using an intraoral scanner, with all nonarticulated scans duplicated four times to ensure data consistency. Forty VOR intraoral scans were performed in MIP using four registration protocols: left-side, right-side, anterior, and bilateral registration ( n=10 per group), randomized via a computer-generated pseudo-random sequence. For measurement, linear distances (D16-46, D13-43, D23-33, D25-35, D26-36, D27-37, D16-46 represented the single-tooth defect position, whereas D25-35, D26-36, D27-37 reflected positions in free-end edentulism areas) between opposing markers were measured in a reverse engineering software, with deviations (ΔD) from the reference scan calculated to assess accuracy. Specifically, negative ΔD values indicated vertical dimension underestimation. Given that non-normally distributed data were analyzed using medians [interquartile ranges (IQR)], trueness (median ΔD) and precision (IQR) were evaluated. The interaction effect between the registration method and the position of the measurement items was evaluated by using the generalized linear model. The accuracy was compared overall by the Kruskal-Wallis test with the two-sided significance level of α=0.05. For pairwise comparisons, post-hoc tests were conducted by Dunn′s t-test with the Bonferroni correction for the significance level. Results:The accuracy of VOR was affected by registration method ( P<0.05), with a significant position×registration method interaction observed ( P<0.05). In particular, in all four groups, only the bilateral registration group showed trueness of less than 0.1 mm for both free-end edentulism and the single tooth defect, with ΔD16-46, ΔD25-35, ΔD26-36, and ΔD27-37 being 0.059 (0.015), -0.082 (0.052), -0.065 (0.032), -0.070 (0.050) mm, respectively. Moreover, trueness in free-end edentulism showed negative values across all groups, with the largest negative deviations observed in the right-side registration group, with ΔD25-35, ΔD26-36 and ΔD27-37 being -0.410 (0.174), -0.442 (0.225), -0.439 (0.262) mm, respectively. Conclusions:In fully digital workflows of implant restorations for mandibular free-end edentulism with multiple missing teeth, registration method critically influences VOR accuracy. While four registration methods exhibited underestimation of occlusal vertical dimension, bilateral registration achieved the highest accuracy.

Objective To explore the objective characteristics of tongue in primary immune thrombocytopenia(ITP);To provide references for accurate syndrome differentiation.Methods Totally 112 patients with ITP were divided into groups according to their platelet count,TCM symptoms and drug treatment lines.Infrared thermal imager,hygrometer,colorimetry and image analysis software were used to detect the temperature,humidity,colorimetry and morphology of tongue body(TB),tongue coating(TC)and sublingual vessel(SV),and analyze their characteristics.The tongue was divided into five areas:tip of tongue(T),middle of tongue(M),behind of tongue(B),middle left of tongue(ML)and middle right of tongue(MR),and its temperature was measured.Humility(H)of tongue and tongue coating were measured by hygrometer.The images of tongue body,tongue coating and sublingual collaterals were taken,and the chromaticity indexes of R,G,B,L,a,b were analyzed by Adobe Photoshop 2023.The width,length and tortuosity of sublingual collaterals were under morphological analysis.Results ① Comparison of platelet count groups:compared with 30-50 platelet count group and more than 100 platelet count group,the TB-R of 51-100 platelet count group decreased(P<0.05,P<0.01),and compared with 30-50 platelet count group,the TB-a of 51-100 platelet count group decreased(P<0.01);compared with platelet<30 group and platelet 30-50 group,the TC-H of platelet>100 group increased(P<0.05,P<0.01);compared with platelet>100 group,the length of sublingual collaterals in platelet<30 group was longer(P<0.05).② Comparison of different TCM symptom groups:compared with the bleeding group and asymptomatic group,the M and SV-B in the fatigue group decreased(P<0.05,P<0.01);compared with the asymptomatic group,the TC-b in the anxious group was significantly higher(P<0.05).③ Comparison of administration groups:compared with the Danazol group and Chinese materia medica group,the TC-H in the glucocorticoid group was significantly higher(P<0.05,P<0.01).Conclusion There are differences in tongue characteristic indexes among ITP patients with different platelet counts,TCM symptoms and drug treatment lines,which can measure of tongue indexes to provide references for accurate syndrome differentiation of ITP.

Objective To explore the mechanism of Qingda Granules(QDG)for alleviating brain damage in spontaneously hypertensive rats(SHRs).Methods Twelve 5-week-old SHRs were randomized into SHR control group and SHR+QDG group treated with QDG by gavage at the daily dose of 0.9 g/kg for 12 weeks.The control rats,along with 6 age-matched WKY rats,were treated with saline only.Blood pressure changes of the rats were monitored,and pathologies and neuronal apoptosis in the cerebral cortex were examined with HE staining and TUNEL staining.Cerebral cortical expressions of miR-124 and STAT3 mRNA were detected using RT-qPCR,and the protein expressions of NeuN,STAT3,Bcl-2,Bax,and cleaved caspase-3 were detected with immunohistochemistry and Western blotting.In a HT22 cell model of oxygen and glucose deprivation/reoxygenation(OGD/R),the effects of QDG on cell viability and apoptosis,expressions of miR-124 and STAT3 mRNA,and protein expressions of STAT3,Bcl-2,Bax,and cleaved caspase-3 were evaluated using CCK8 assay,Hoechst 33342 staining,RT-qPCR,and Western blotting.Results Compared with WKY rats,SHRs had significantly elevated systolic blood pressure,diastolic blood pressure and mean arterial pressure with significantly increased neuronal apoptosis in the cerebral cortex,reduced expressions of NeuN,miR-124 and Bcl-2,and enhanced expressions of STAT3,Bax and cleaved caspase-3(P＜0.05).All these changes in the SHRs were significantly ameliorated by treatment with QDG(P＜0.05).In the HT22 cell model,QDG treatment obviously reduced OGD/R-induced cell apoptosis,increased the expressions of miR-124 and Bcl-2,and suppressed the elevation of protein expressions of STAT3,Bax and cleaved caspase-3.Conclusion QDG inhibits cerebral cortical neuronal apoptosis and thereby attenuates brain damage in SHR rats by modulating the miR-124/STAT3 signaling axis.

Objective:To investigate the impact of four registration methods on the accuracy of virtual occlusal records (VOR) in intraoral scanning for implant restorations with multiple missing teeth.Methods:A mandibular model simulating clinical conditions with multiple missing teeth (right first molar, left second premolar, left first molar, left second molar) and a maxillary compete dentition model were mounted on a semi-adjustable articulator. Subsequently, twelve 0.5 mm stainless steel spheres were adhered to reference positions (16, 46, 13, 43, 23, 33, 25, 35, 26, 36, 27, 37) as fiducial markers. Following this, a laboratory scanner generated reference datasets by digitizing the models in maximum intercuspation (MIP). Meanwhile, ten maxillary and mandibular scans were acquired using an intraoral scanner, with all nonarticulated scans duplicated four times to ensure data consistency. Forty VOR intraoral scans were performed in MIP using four registration protocols: left-side, right-side, anterior, and bilateral registration ( n=10 per group), randomized via a computer-generated pseudo-random sequence. For measurement, linear distances (D16-46, D13-43, D23-33, D25-35, D26-36, D27-37, D16-46 represented the single-tooth defect position, whereas D25-35, D26-36, D27-37 reflected positions in free-end edentulism areas) between opposing markers were measured in a reverse engineering software, with deviations (ΔD) from the reference scan calculated to assess accuracy. Specifically, negative ΔD values indicated vertical dimension underestimation. Given that non-normally distributed data were analyzed using medians [interquartile ranges (IQR)], trueness (median ΔD) and precision (IQR) were evaluated. The interaction effect between the registration method and the position of the measurement items was evaluated by using the generalized linear model. The accuracy was compared overall by the Kruskal-Wallis test with the two-sided significance level of α=0.05. For pairwise comparisons, post-hoc tests were conducted by Dunn′s t-test with the Bonferroni correction for the significance level. Results:The accuracy of VOR was affected by registration method ( P<0.05), with a significant position×registration method interaction observed ( P<0.05). In particular, in all four groups, only the bilateral registration group showed trueness of less than 0.1 mm for both free-end edentulism and the single tooth defect, with ΔD16-46, ΔD25-35, ΔD26-36, and ΔD27-37 being 0.059 (0.015), -0.082 (0.052), -0.065 (0.032), -0.070 (0.050) mm, respectively. Moreover, trueness in free-end edentulism showed negative values across all groups, with the largest negative deviations observed in the right-side registration group, with ΔD25-35, ΔD26-36 and ΔD27-37 being -0.410 (0.174), -0.442 (0.225), -0.439 (0.262) mm, respectively. Conclusions:In fully digital workflows of implant restorations for mandibular free-end edentulism with multiple missing teeth, registration method critically influences VOR accuracy. While four registration methods exhibited underestimation of occlusal vertical dimension, bilateral registration achieved the highest accuracy.

Objective To explore the objective characteristics of tongue in primary immune thrombocytopenia(ITP);To provide references for accurate syndrome differentiation.Methods Totally 112 patients with ITP were divided into groups according to their platelet count,TCM symptoms and drug treatment lines.Infrared thermal imager,hygrometer,colorimetry and image analysis software were used to detect the temperature,humidity,colorimetry and morphology of tongue body(TB),tongue coating(TC)and sublingual vessel(SV),and analyze their characteristics.The tongue was divided into five areas:tip of tongue(T),middle of tongue(M),behind of tongue(B),middle left of tongue(ML)and middle right of tongue(MR),and its temperature was measured.Humility(H)of tongue and tongue coating were measured by hygrometer.The images of tongue body,tongue coating and sublingual collaterals were taken,and the chromaticity indexes of R,G,B,L,a,b were analyzed by Adobe Photoshop 2023.The width,length and tortuosity of sublingual collaterals were under morphological analysis.Results ① Comparison of platelet count groups:compared with 30-50 platelet count group and more than 100 platelet count group,the TB-R of 51-100 platelet count group decreased(P<0.05,P<0.01),and compared with 30-50 platelet count group,the TB-a of 51-100 platelet count group decreased(P<0.01);compared with platelet<30 group and platelet 30-50 group,the TC-H of platelet>100 group increased(P<0.05,P<0.01);compared with platelet>100 group,the length of sublingual collaterals in platelet<30 group was longer(P<0.05).② Comparison of different TCM symptom groups:compared with the bleeding group and asymptomatic group,the M and SV-B in the fatigue group decreased(P<0.05,P<0.01);compared with the asymptomatic group,the TC-b in the anxious group was significantly higher(P<0.05).③ Comparison of administration groups:compared with the Danazol group and Chinese materia medica group,the TC-H in the glucocorticoid group was significantly higher(P<0.05,P<0.01).Conclusion There are differences in tongue characteristic indexes among ITP patients with different platelet counts,TCM symptoms and drug treatment lines,which can measure of tongue indexes to provide references for accurate syndrome differentiation of ITP.

Objective:To explore the effects of deep hyperthermia on chemotherapy-related adverse effects and immune-inflammatory indicators in the patients undergoing postoperative adjuvant chemotherapy for colorectal cancer.Methods:This retrospective study included 52 patients who underwent surgery for colorectal cancer at the Affiliated Zhongshan Hospital of Dalian University from September 2021 to December 2023. The patients were divided into two groups based on treatment method: the combination group ( n=29) received postoperative adjuvant chemotherapy combined with deep hyperthermia, while the chemotherapy group ( n=23) received postoperative adjuvant chemotherapy alone. Both groups were treated with the XELOX regimen (oxaliplatin + capecitabine). The degree of bone marrow suppression during treatment was assessed by analyzing peripheral blood parameters, including hemoglobin, leukocyte count, neutrophil count, and platelet count. Immune-inflammatory indicators, including complement, procalcitonin (PCT), interleukin-6 (IL-6), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), were compared before and after treatment in both groups to evaluate the effects of deep hyperthermia on the immune-inflammatory response. Chi-square test or Fisher's exact test (two-tailed) was used to compare bone marrow suppression rates, and the immune-inflammatory indicators between the two groups were compared using t-tests or non-parametric tests, depending on whether the data conformed to a normal distribution. Results:In terms of myelosuppression, the incidence rates of moderate to severe decreases in leukocytes, neutrophils, platelets, and hemoglobin in the combination group were 31%, 31%, 21%, and 14%, respectively, compared to 52%, 61%, 48%, and 9% in the chemotherapy group. The change in PCT levels before and after treatment was significantly greater in the combination group than in the chemotherapy group ( P = 0.010). Both the combination group and the chemotherapy group showed significant reductions in SII, NLR and PLR after treatment, and the differences were statistically significant (all P < 0.05). The change in NLR before and after treatment was significantly greater in the combination group than in the chemotherapy group ( P = 0.031). Conclusions:Deep hyperthermia can alleviate chemotherapy-induced adverse effects such as thrombocytopenia and neutropenia in patients undergoing postoperative adjuvant chemotherapy for colorectal cancer. It also appears to improve the inflammatory response in these patients.