Microglial functions are linked to Ca²⁺ signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer's disease (AD), but how ER Ca²⁺ receptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (Ryr2) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Ca²⁺ transients in controls and normalized Ca²⁺ transients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Ca²⁺ receptors in both homeostatic and AD microglia, providing insights into microglial Ca²⁺ malfunctions in AD.
Animals ; Microglia/pathology* ; Alzheimer Disease/pathology* ; Phagocytosis/drug effects* ; Ryanodine Receptor Calcium Release Channel/metabolism* ; Disease Models, Animal ; Mice ; Cell Movement/drug effects* ; Mice, Transgenic ; Calcium Signaling/physiology* ; Calcium/metabolism* ; Mice, Inbred C57BL ; Male ; Endoplasmic Reticulum/metabolism*

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The ubiquitin-specific peptidase 25 (USP25) protein has been reported to participate in the development of several cancers. However, few studies have reported its association with HCC. In this study, we aimed to investigate the function and mechanism of USP25 in the progression of HCC. METHODS: We analyzed USP25 protein expression in HCC based on The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database cohorts. Then, we constructed USP25-overexpressing and USP25-knockdown HepG2, MHCC97H, and L-O2 cells. We detected the biological function of USP25 by performing a series of assays, such as Cell Counting Kit-8 (CCK-8), colony formation, transwell, and wound healing assays. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were performed to detect the interaction between USP25 and the Wnt/β-catenin signaling pathway. The relationship between USP25 and tripartite motif-containing 21 (TRIM21) was assessed through mass spectrometry and co-immunoprecipitation (Co-IP) analysis. Finally, we constructed a mouse liver cancer model with the USP25 gene deletion to verify in vivo role of USP25. RESULTS: USP25 was highly expressed in HCC tissue and HCC cell lines. Importantly, high expression of USP25 in tissues was closely related to a poor prognosis. USP25 knockdown markedly reduced the proliferation, migration, and invasion of HepG2 and MHCC97H cells, whereas USP25 overexpression led to the opposite effects. In addition, we demonstrated that USP25 interacts with TRIM21 to regulate the expression of proteins related to epithelial-mesenchymal transition (EMT; E-cadherin, N-cadherin, and Snail) and the Wnt/β-catenin pathway (β-catenin, Adenomatous polyposis coli, Axin2 and Glycogen synthase kinase 3 beta) and those of their downstream proteins (C-myc and Cyclin D1). Finally, we verified that knocking out USP25 inhibited tumor growth and distant metastasis in vivo . CONCLUSIONS In summary, our data showed that USP25 was overexpressed in HCC. USP25 promoted the proliferation, migration, invasion, and EMT of HCC cells by interacting with TRIM21 to activate the β-catenin signaling pathway.
Animals ; Mice ; beta Catenin/genetics* ; Carcinoma, Hepatocellular/pathology* ; Cell Line, Tumor ; Cell Movement/genetics* ; Cell Proliferation/genetics* ; Epithelial-Mesenchymal Transition/genetics* ; Gene Expression Regulation, Neoplastic ; Liver Neoplasms/pathology* ; Ubiquitin Thiolesterase/metabolism* ; Wnt Signaling Pathway/genetics*

【Objective】 To evaluate the expression of GAB1 in ER-positive breast cancer and its effect on MCF-7 cells’ metastasis. 【Methods】 The expression of GAB1 in ER-positive breast cancer tissues was detected by immunohistochemistry. We analyzed the relationship of GAB1 expression with the patients’ clinicopathological features and prognosis. The invasion and metastasis abilities of MCF-7 cells after silencing GAB1 expression were observed by Transwell assay. The effect of GAB1 expression on the EMT of breast cancer cells was analyzed by Western blotting. 【Results】 Immunohistochemical staining showed that GAB1 expression had significant correlation with lymph node metastasis(P=0.014) and stage(P=0.011). Transwell results showed that shGAB1 significantly inhibited the migration and invasion of human breast cancer MCF-7 cells. Western blotting results showed that shGAB1 significantly increased E-cadherin expression and decreased Vimentin expression. Kaplan-Meier analysis revealed that ER-positive breast cancer patients with high GAB1 expression tumors had a significantly worse relapse-free survival rate than those with low GAB1 expression tumors(P<0.001). Multivariate analysis showed that stage and GAB1 expression were independent predictors of survival. 【Conclusion】 GAB1 is highly expressed in ER-positive breast cancer. ShGAB1 expression can inhibit the migration, invasion and EMT of breast cancer cells. GAB1 might be used as one of the valuable markers for prognosis in patients with ER-positive breast cancer.

Objectives: To explore and summarize the beneficial effects of a traditional Chinese medicine prepara-tion, Tripterygium glycosides tablets (TGT), in rheumatoid arthritis (RA) animal models of neo-vascularization, and to provide a reference for future clinical applications and research on its pharmacologic mechanism.Methods: We searched the databases PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, VIP, Wan Fang and SinoMed (China Biomedical Document Service System) to identify studies of TGT with outcome indicators of angiogenesis-related factors that were published before April 2020. Subgroup analysis and meta-regression were performed for dosage and duration of TGT. Statistical tests and subgroup analysis were conducted using RevMan 5.3, and meta-regression and sensitivity analysis were conducted using STATA/SE 15.0. Results: Fourteen studies of TGT in RA rats were included in this analysis. Treatment with TGT signifi-cantly reduces synovial microvessel density and the expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, hypoxia inducible factor α, c-Fos, c-Jun, angiopoietin-1 and angiopoietin-2 compared with control groups (P < .05). Subgroup analysis did not show a significant association of the mRNA levels of VEGF in synovium, assessed using quantitative real-time PCR, with duration or dosage of TGT. Meta-regression analysis also indicated that the effects of dosage and duration were not significantly associated with differences in VEGF mRNA levels. Sensitivity analysis on VEGF mRNA levels did not fundamentally change the results. Conclusions: TGT can reduce synovial neovascularization by decreasing synovial microvessel density and expression of VEGF, VEGF receptor 2, hypoxia-inducible factorα, c-Fos, c-Jun, Ang-1 and Ang-2, thereby suppressing pannus formation and bone destruction in rat models of RA. Additional well-designed studies are required to confirm these findings.

Objective To observe the efficacy and safety of apatinib combined with docetaxel in the third line and above treatment of advanced serum alpha-fetoprotein-positive gastric cancer(AFPGC). Methods A total of 41 patients with AFPGC from February 2015 to April 2018 in Suining Central Hospital of Sichuan Province were retrospectively analyzed. The patients were divided into experimental group and control group according to different treatment methods,15 patients in the experimental group received with apatinib combined with docetaxel,and 26 patients in the control group received chemotherapy alone or optimal nutritional support. The short-term efficacy,long-term efficacy and adverse reactions were evaluated by Response Evaluation Criteria in Solid Tumours(RECIST)version 1. 1,progression-free survival(PFS),overall survival(OS)and National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE)version 4. 0. Results After 2 cycles of treatment,no complete remission( CR)was achieved in either group,4 partial remission (PR),7 stable disease(SD),4 progressive disease(PD)in the experimental group,and 2 PR,7 SD,17 PD in the control group. The objective response rate(ORR)was 26. 67％(4 / 15)and 7. 69％(2 / 26)respective-ly in the experimental group and the control group,with no significant difference(χ2 = 1. 433,P = 0. 231). The disease control rate(DCR)was 73. 33％(11 / 15)and 34. 62％(9 / 26)respectively in the two groups, with significant difference(χ2 = 5. 707,P = 0. 017). The median PFS of the experimental group and the control group were both 3. 0 months,and there was no significant difference between the two groups(χ2 = 4. 425,P =0. 350). The median OS were 6. 0 months and 4. 0 months respectively,and the difference was statistically sig-nificant(χ2 = 5. 727,P = 0. 017). The occurrence rates of leukopenia of the experimental group and the control group were 73. 33％(11 / 15)and 30. 77％(8 / 26),the occurrence rates of hypertension were 40. 00％(6 /15)and 0(0 / 26),the occurrence rates of proteinuria were 26. 67％(4 / 15)and 0(0 / 26),the occurrence rates of poor appetite were 80. 00％(12 / 15)and 38. 46％(10 / 26),and the occurrence rates of hemorrhage were 33. 33％(5 / 15)and 3. 85％(1 / 26). The occurrence rates of the above adverse reactions in the experi-mental group were significantly higher than those in the control group(χ2 = 6. 930,P = 0. 008;χ2 = 9. 191, P = 0. 002;χ2 = 4. 953,P = 0. 026;χ2 = 6. 600,P = 0. 010;χ2 = 4. 471,P = 0. 034),and the differences were statistically significant. There was no significant difference in the incidence of thrombocytopenia,anemia, nausea and vomiting,diarrhea,fatigue and hand-foot syndrome between the two groups( all P > 0. 05). Conclusion The DCR of apatinib combined with docetaxel in the third-line and above treatment of advanced AFPGC patients is higher. This scheme can prolong survival period,and the adverse reactions are more serious,but they are basically tolerable.

Sepsis is frequently associated with multi-system organ dysfunction and refractory hypotension,leading to a high mortality and poor prognosis.As an antioxidant,ascorbic acid (vitamin C) is an important auxiliary factor for many enzymes in the organism.Numerous studies have revealed that vitamin C can attenuate the inflammatory response,improve microcirculatory and hypotension in sepsis,and also can enhance the role of catecholamine in central nervous system,to prevent sepsis-induced organ failure and improve prognosis of patients.

Objective To investigate the clinical value of serum endocan and procalcitonin (PCT) in early diagnosis and prognosis evaluation of sepsis.Methods The patients with systemic inflammatory response syndrome (SIRS,n = 26) and sepsis (n = 78) admitted to intensive care unit (ICU) of the Third Hospital of Hebei Medical University from December 2014 to December 2016 were enrolled. According to the severity of disease, the sepsis patients were divided into general sepsis group (n = 20), severe sepsis group (n = 24), and septic shock group (n = 34). The cases were divided into survival group (n = 55) and non-survival group (n = 23) according to 28-day mortality. The serum endocan, PCT, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, and sequential organ failure assessment (SOFA) score were recorded when the patients were admitted into ICU. The differences in endocan, PCT, APACHE Ⅱ, SOFA score between SIRS and sepsis groups and within sepsis subgroups were compared. Spearman correlation analysis was used to analyze the correlation between the indexes of sepsis patients. Receiver operation characteristic curve (ROC) was used to evaluate the value of endocan and PCT for the diagnosis and prognosis of sepsis.Results ① Serum endocan, PCT, APACHE Ⅱ, SOFA score and 28-day mortality in the sepsis group were significantly higher than those in the SIRS group [endocan (μg/L): 4.28 (10.64) vs. 1.03 (0.69), PCT (μg/L): 3.94 (10.75) vs. 0.43 (0.39), APACHE Ⅱ:18.81±9.17 vs. 9.35±3.78, SOFA: 9.00 (7.20) vs. 4.50 (1.50), 28-day mortality: 29.49% vs. 11.54%, allP < 0.01]. The area under the ROC curve (AUC) of endocan, PCT, APACHE Ⅱ, SOFA score for sepsis diagnosis were 0.887, 0.842, 0.822, 0.835, respectively. When the cut-off value of endocan was 1.26μg/L, the sepsis diagnostic sensitivity was 87.2% and specificity was 81.8%. When the cut-off value of PCT was 0.75μg/L, the sepsis diagnostic sensitivity was 85.9% and specificity was 81.8%. ② With the severity of the disease increased, the index showed an increasing trend in patients with sepsis. Serum endocan, PCT, APACHE Ⅱ, SOFA score and 28-day mortality in septic shock group were significantly higher than those in severe sepsis group or general sepsis group [endocan (μg/L): 13.02 (6.70) vs. 3.33 (3.05), 1.60 (0.98); PCT (μg/L): 8.10 (17.68) vs. 5.47 (8.92), 1.57 (2.78); APACHE Ⅱ: 25.00 (9.50) vs. 18.00 (9.00), 9.50 (5.75); SOFA: 13.00 (4.50) vs. 8.00 (3.00), 5.00 (3.50); 28-day mortality: 52.94% vs. 20.83%, 0%; allP < 0.01]. There was a significantly positive correlation between endocan, PCT, APACHE Ⅱ, SOFA, indicating that the endocan and PCT can be used to assess the severity of sepsis. ③ Serum endocan, PCT, APACHE Ⅱ and SOFA score in non-survival group were significantly higher than those in the survival group [endocan (μg/L): 15.05 (9.23) vs. 2.32 (4.81), PCT (μg/L):18.40 (16.99) vs. 3.10 (6.67), APACHE Ⅱ: 28.13±7.56 vs. 14.91±6.64, SOFA: 14.70±3.65 vs. 7.38±3.26, allP < 0.01]. The AUC of endocan, PCT, APACHE Ⅱ, SOFA score for the prediction of non-survival sepsis were 0.915, 0.763, 0.899, 0.930. When the cut-off value of endocan was 4.37μg/L, the septic death prediction sensitivity was 95.7% and specificity was 70.9%. When the cut-off value of PCT was 7.68μg/L, the septic death prediction sensitivity was 65.2% and specificity was 78.2%.Conclusions Serum endocan is more clinically valuable than PCT in early diagnosis and prognosis assessment of sepsis.

This study was aimed to analyze the application of non-pharmacotherapy in treating cervical radiculopathy (CR) in real-world,and to provide clinical reference for CR non-pharmacotherapy.The clinical real-world data of CR was extracted by using information sharing system of traditional Chinese medicine (TCM) and clinical research.Six hundred and twenty-eight inpatients and outpatients with CR were enrolled from December 2012 to July 2014 in the information system database of Wangjing Hospital.Basic characteristics of the non-pharmacotherapy groups were analyzed by statistical description method.The node degree and mutual information value were recorded for non-pharmacotherapy application of all patients by using liquorice software.Complex network diagrams were generated.The results showed that 47％ of CR patients received non-pharmacotherapy (294/628),including 67 males and 227 females.The average age of patients was 49 years old,and the prevalence of the disease was the highest from 45 to 65 years old.In all patients,the usage of manipulation and cervical traction was higher,and the combination of manipulation and acupuncture was the most.Within outpatients,the proportion of cervical traction was higher,and the combination of manipulation and acupuncture was the most frequently.Within inpatients,the proportion of manipulation and cervical traction was higher,and the combination of comprehensive physical therapy and exercise therapy was the most frequently.It was concluded that non-pharmacotherapy has been commonly used in clinical treatment of CR.Cervical traction and manipulation was the widest applications.The combination treatment was in wide application.Future studies should increase the sample size of CR patients from different regions,and enhance gradually the level of evidence of clinical research for non-pharmacotherapy treating CR.

Objective: To categorize and summarize the clinical and mechanism studies of the past 30 years on the treatment of Hashimoto’s thyroiditis (HT) with moxibustion, moxibustion plus medication, and acupuncture plus medication, etc., and to analyze the current problems. Methods: The clinical and laboratory studies related to the treatment of HT with acupuncture-moxibustion therapies published before June 2015 were retrieved from MEDLINE, Excerpta Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI), Wanfang Academic Journal Full-text Database (Wanfang) and Chongqing VIP Database (CQVIP). Results:Moxibustion, moxibustion plus medication, and acupuncture plus medication can produce certain therapeutic effects in treating HT. Conclusion:The research on the treatment of HT with acupuncture-moxibustion therapies is rather limited in the amount and content. In the future, standardization should be fortified, specific moxibustion research needs deepening, and the action mechanism of moxibustion should be emphasized.