Sodium-glucose cotransporter 2 inhibitor was initially developed and marketed as a novel oral hypoglycemic agent.Currently,it has been recommended as one of the main therapeu-tic agents for chronic heart failure by national and international guidelines,and it has a significant cardioprotective effect on heart failure with reduced ejection fraction,heart failure with im-proved ejection fraction,heart failure with mildly reduced ejec-tion fraction,and heart failure with preserved ejection fraction.However,cardiac tissues do not express sodium-glucose cotrans-porter 2,and the underlying mechanisms of clinical cardiovascu-lar benefits of sodium-glucose cotransporter 2 inhibitors remain unclear.This review intends to summarize the cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors in clinical trials and the recommendations suggested by national and inter-national heart failure guidelines and to elucidate further the po-tential mechanisms of sodium-glucose cotransporter 2 inhibitor-mediated cardioprotective effects.

Objective To explore the molecular mechanism by which SOS Ras/Rac guanine nucleotide exchange factor 1-intronic transcript 1(SOS1-IT1)affects enhancer of zeste homolog 2(EZH2)protein expression in endometrial cancer cells Ishikawa and RL95-2.Methods Lentiviral transfection of short hairpin RNA(shRNA)and overexpression plasmid were used in Ishikawa and RL95-2 cell lines to knock down and overexpress SOS1-IT1.The mechanism of EZH2 expression regulation was studied using Real-time PCR,Western blotting,and chromatin immunoprecipitation.Results The expression of SOS1-IT1 and EZH2 genes was positively correlated in endometrial cancer tissues.Knocking down SOS1-IT1 significantly reduces the expression of EZH2,inhibited the proliferation and migration of Ishikawa and RL95-2 cells,and could reduced the acetylation of histone H3 at position 27(H3K27)and the enrichment of CREB binding protein(CBP)in the EZH2 gene promoter region.Overexpression of SOS1-IT1 could increased the expression of EZH2 and enhance the acetylation of H3K27 and the enrichment of CBP.CBP could bind to SOS1-IT1 RNA,and this binding ability was weakened when CBP was knocked down.Conclusion SOS1-IT1 can promote the expression level of EZH2 in endometrial cancer cells Ishikawa and RL95-2 by regulating the acetylation modification level of the EZH2 gene promoter region,thereby affecting the proliferation and migration ability of endometrial cancer cells.

Sodium-glucose cotransporter 2 inhibitor was initially developed and marketed as a novel oral hypoglycemic agent.Currently,it has been recommended as one of the main therapeu-tic agents for chronic heart failure by national and international guidelines,and it has a significant cardioprotective effect on heart failure with reduced ejection fraction,heart failure with im-proved ejection fraction,heart failure with mildly reduced ejec-tion fraction,and heart failure with preserved ejection fraction.However,cardiac tissues do not express sodium-glucose cotrans-porter 2,and the underlying mechanisms of clinical cardiovascu-lar benefits of sodium-glucose cotransporter 2 inhibitors remain unclear.This review intends to summarize the cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors in clinical trials and the recommendations suggested by national and inter-national heart failure guidelines and to elucidate further the po-tential mechanisms of sodium-glucose cotransporter 2 inhibitor-mediated cardioprotective effects.

Objective: To investigate the molecular mechanism of how lactate induces high mobility group box 1 (HMGB1) release. Methods: Gastric cancer HGC-27 cells were divided into the control group and the lactate group (The cells were treated with lactate for 6 h). The level of HMGB1 in the cell culture medium was detected by enzyme-linked immunosorbent assay (ELISA), the localization of HMGB1 was detected using laser confocal microscopy, and the nuclear translocation of HMGB1 was detected using the nucleoplasmic separation assay. The phosphorylation and acetylation levels of HMGB1 were determined by co-immunoprecipitation, and Western blot was used to measure the phosphorylation of Akt and protein kinase C (PKC). HGC-27 cells were first treated with lactate and LY294002, the inhibitor of Akt, and then the phosphorylation of HMGB1 and Akt was analyzed by co-immunoprecipitation and Western blot, respectively. The localization of HMGB1 in cells was detected by laser confocal microscopy. EdU and Transwell assays were used to detect the proliferation and migration abilities of HGC-27 cells, respectively. HGC-27 cells were then injected into the BALB/C null mice for subcutaneous tumor implantation. Mice in the lactate group were intraperitoneally injected with lactate (0.2 g/kg/2 d), while those in the control group were intraperitoneally injected with an equal amount of PBS for 20 consecutive days. ELISA was used to detect the HMGB1 levels in the blood samples taken from the medial canthus vein of the mice, while co-immunoprecipitation and Western blot were used to detect the phosphorylation of HMGB1 and Akt in tumor tissue proteins, respectively. Results: The release levels of HMGB1 in the lactate group were (2 995.00±660.91) pg/ml and (696.33±22.03) pg/ml, after lactate treatment for 6 h and 12 h, respectively, both higher than those in the control group (485.00±105.83) pg/ml (P<0.001 and P=0.028, respectively). After lactate treatment for 6 h, the relative expression of HMGB1 protein in the cytoplasm of HGC-27 cells was 1.13±0.09, higher than that of the control group (0.83±0.07, P=0.001), while the relative expression of HMGB1 in the nucleus was 0.79±0.06, lower than that of the control group (1.07±0.06, P=0.007). The phosphorylation level of HMGB1 reached 1.41±0.09, which was higher than that of the control group (0.97±0.10, P=0.031). The phosphorylation level of Akt was 11.16±0.06, higher than that of the control group (0.91±0.022, P=0.002). The phosphorylation level and nuclear translocation of HMGB1 induced by lactate decreased obviously after Akt inhibition; the proliferation and migration abilities induced by lactate were also obviously inhibited after Akt inhibition. In vivo, the HMGB1 level in the peripheral blood was (1 280.70±389.66) pg/ml in the lactate group, which was obviously higher than that in the control group (595.11±44.75) pg/ml (P=0.008), and the phosphorylation levels of HMGB1 and Akt in tumor tissues in the lactate group were obviously enhanced compared with the control group. Conclusion: Lactate induces HMGB1 release through enhancing HMGB1 phosphorylation via the Akt signaling pathway.
Mice ; Animals ; Stomach Neoplasms/pathology* ; Proto-Oncogene Proteins c-akt/metabolism* ; HMGB1 Protein/metabolism* ; Phosphorylation ; Lactic Acid ; Mice, Inbred BALB C ; Signal Transduction

Objective: To investigate the molecular mechanism of how lactate induces high mobility group box 1 (HMGB1) release. Methods: Gastric cancer HGC-27 cells were divided into the control group and the lactate group (The cells were treated with lactate for 6 h). The level of HMGB1 in the cell culture medium was detected by enzyme-linked immunosorbent assay (ELISA), the localization of HMGB1 was detected using laser confocal microscopy, and the nuclear translocation of HMGB1 was detected using the nucleoplasmic separation assay. The phosphorylation and acetylation levels of HMGB1 were determined by co-immunoprecipitation, and Western blot was used to measure the phosphorylation of Akt and protein kinase C (PKC). HGC-27 cells were first treated with lactate and LY294002, the inhibitor of Akt, and then the phosphorylation of HMGB1 and Akt was analyzed by co-immunoprecipitation and Western blot, respectively. The localization of HMGB1 in cells was detected by laser confocal microscopy. EdU and Transwell assays were used to detect the proliferation and migration abilities of HGC-27 cells, respectively. HGC-27 cells were then injected into the BALB/C null mice for subcutaneous tumor implantation. Mice in the lactate group were intraperitoneally injected with lactate (0.2 g/kg/2 d), while those in the control group were intraperitoneally injected with an equal amount of PBS for 20 consecutive days. ELISA was used to detect the HMGB1 levels in the blood samples taken from the medial canthus vein of the mice, while co-immunoprecipitation and Western blot were used to detect the phosphorylation of HMGB1 and Akt in tumor tissue proteins, respectively. Results: The release levels of HMGB1 in the lactate group were (2 995.00±660.91) pg/ml and (696.33±22.03) pg/ml, after lactate treatment for 6 h and 12 h, respectively, both higher than those in the control group (485.00±105.83) pg/ml (P<0.001 and P=0.028, respectively). After lactate treatment for 6 h, the relative expression of HMGB1 protein in the cytoplasm of HGC-27 cells was 1.13±0.09, higher than that of the control group (0.83±0.07, P=0.001), while the relative expression of HMGB1 in the nucleus was 0.79±0.06, lower than that of the control group (1.07±0.06, P=0.007). The phosphorylation level of HMGB1 reached 1.41±0.09, which was higher than that of the control group (0.97±0.10, P=0.031). The phosphorylation level of Akt was 11.16±0.06, higher than that of the control group (0.91±0.022, P=0.002). The phosphorylation level and nuclear translocation of HMGB1 induced by lactate decreased obviously after Akt inhibition; the proliferation and migration abilities induced by lactate were also obviously inhibited after Akt inhibition. In vivo, the HMGB1 level in the peripheral blood was (1 280.70±389.66) pg/ml in the lactate group, which was obviously higher than that in the control group (595.11±44.75) pg/ml (P=0.008), and the phosphorylation levels of HMGB1 and Akt in tumor tissues in the lactate group were obviously enhanced compared with the control group. Conclusion: Lactate induces HMGB1 release through enhancing HMGB1 phosphorylation via the Akt signaling pathway.
Mice ; Animals ; Stomach Neoplasms/pathology* ; Proto-Oncogene Proteins c-akt/metabolism* ; HMGB1 Protein/metabolism* ; Phosphorylation ; Lactic Acid ; Mice, Inbred BALB C ; Signal Transduction

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.
Bronchopulmonary Dysplasia/epidemiology* ; Female ; Gestational Age ; Humans ; Infant ; Infant, Extremely Premature ; Infant, Newborn ; Pregnancy ; Respiratory Distress Syndrome, Newborn/epidemiology* ; Retrospective Studies ; Treatment Outcome

Objective: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. Methods: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. Results: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). Conclusion An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.
Aged ; Asian Continental Ancestry Group ; Blood Glucose/analysis* ; China/epidemiology* ; Cohort Studies ; Diabetes Mellitus/blood* ; Female ; Glucose Tolerance Test ; Glycated Hemoglobin A/analysis* ; Glycemic Index ; Humans ; Male ; Middle Aged ; Uric Acid/blood*

OBJECTIVE: Critical effective constituents were identified from Bufei Yishen formula (BYF), a traditional herbal compound and combined as effective-constituent compatibility (ECC) of BYF I, which may have potential bioactive equivalence to BYF. METHODS: The active constituents of BYF were identified using four cellular models and categorised into Groups 1 (Bufeiqi), 2 (Bushen), 3 (Huatan) and 4 (Huoxue) according to Chinese medicinal theory. An orthogonal design and a combination method were used to determine the optimal ratios of effective constituents in each group and the ratios of "Groups 1 to 4" according to their pharmacological activity. We also comprehensively assessed bioactive equivalence between the BYF and the ECC of BYF I in a rat model of chronic obstructive pulmonary disease (COPD). RESULTS: We identified 12 active constituents in BYF. The numbers of constituents in Groups 1 to 4 were 3, 2, 5 and 2, respectively. We identified the optimal ratios of effective constituents within each group. In Group 1, total ginsenosides:Astragalus polysaccharide:astragaloside IV ratio was 9:5:2. In Group 2, icariin:schisandrin B ratio was 100:12.5. In Group 3, nobiletin:hesperidin:peimine:peiminine:kaempferol ratio was 4:30:6.25:0:0. In Group 4, paeoniflorin:paeonol ratio was 4:1. An orthogonal design was then used to establish the optimal ratios of Group 1, Group 2, Group 3 and Group 4 in ECC of BYF I. The ratio for total ginsenosides:Astragalus polysaccharide:astragaloside IV:icariin:schisandrin B:nobiletin:hesperidin:peimine:paeoniflorin:paeonol was determined to be 22.5:12.5:5:100:12.5:4:30:6.25:25:6.25. A comprehensive evaluation confirmed that ECC of BYF I presented with bioactive equivalence to the original BYF. CONCLUSION Based on the ECC of traditional Chinese medicine formula method, the effective constituents of BYF were identified and combined in a fixed ratio as ECC of BYF I that was as effective as BYF itself in treating rats with COPD.

Background: Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive entity within the World Health Organization classification of lymphoid tumors. The International Prognostic Index is reported to be prognostically meaningful for ENKTL, but lacks discriminatory power for stage I/II ENKTL with extensive local invasion. This study aimed to evaluate the prognostic effects of local invasion by site and tissue type in patients with ENKTL. Methods: We retrospectively analyzed data of 86 patients who were diagnosed with ENKTL by the Department of Pathology of Beijing Tongren Hospital from June 2002 to April 2016, and ascertained tumor infiltration of adjacent structures (AS), bone, and soft tissue for each patient, using physical findings and imaging scans. We used univariate and multivariate analysis to assess the association of each involved tissue or site with patients’ overall survival (OS). Results: Of the 86 patients, 71(82.6%) experienced invasion of AS, 22(25.6%) of soft tissue, and 26(30.2%) had bone involvement. Overall, patients with AS involvement did not show significantly shorter survival than those without AS involvement (Log rank χ² = 1.177, P = 0.278); however, patients who had involved eyeballs or brains showed significantly lower 2-year OS rates than those without eyeball involvement (Log rank χ² = 4.105, P = 0.043) or brain involvement (Log rank χ² = 7.126, P = 0.008). Patients with involved local soft tissue or bones, respectively, showed lower 2-year OS rates than those without involved local soft tissue (Log rank χ² = 10.390, P = 0.001) or bones (Log rank χ² = 8.993, P = 0.003). Multivariate analysis showed that involvement of the cheek or facial muscles (hazard ratio, HR = 5.471, 95% confidence interval [CI]: 1.466–20.416, P = 0.011) and the maxilla bone (HR = 6.120, 95% CI: 1.517–24.694, P = 0.011) were significantly independent predictors of lower 2-year OS rates. Conclusions Imaging can accurately detect ENKTL invasion of AS, soft tissue, and bone. Involvement of local soft tissue or bone was significantly associated with lower 2-year OS rates. Involvements of the cheek or facial muscle, as well as maxilla bone, are independent predictors of lower 2-year OS rates in ENKTL patients.

OBJECTIVE: To investigate the apoptosis of CD34CD38-KG1a leukemia stem cells induced by Qinba selenium-mushroom extract(FA-2-b-β), and its related mechanism. METHODS: CD34CD38--KG1a cells were isolated from KG1a cell line by magnetic activated cell sorting. The proliferation ability of KG1a stem cells treatd by various concentration of FA-2-b-β(1.2-2.4 mg/ml) in vitro for 24 and 48 hours were tested by cell counting Kit-8(CCK8). Flow cytometry was used to detect the apoptosis rate of KG1a stem cells in each group after treated by FA-2-b-β in vitro. Expression of BAX,BCL-2,Casepase-3 and Cyclin D1 protein were detected by Western blot. RESULTS: The proportion of CD34CD38--KG1a stem cells was (95.35±2.63）% after immunomagnetic isolation. The proliferation of KG1a stem cells was inhibited significantly by FA-2-b-β, which shows a time- and dose-dependent manner (24 h,r=0.943; 48 h,r=0.976). Flow cytometry shows that with the increasing of drug concentration, the apoptosis was also increased, when KG1a stem cells was treated by FA-2-b-β for 24 h. Western blot indicated that the expression of apoptosis-related protein BAX and Casepase-3 were up-regulated, the expression of BCL-2 and Cyclin D1 were down-regulated. CONCLUSION FA-2-b-β can regulate proliferation and apoptosis KG1a stem cells, the involved mechanism may be related with the activation of mitochondrial-mediated apoptotic pathway.
ADP-ribosyl Cyclase 1 ; Antigens, CD34 ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Membrane Glycoproteins ; Neoplastic Stem Cells ; Selenium