OBJECTIVES: To investigate the role and mechanism of fibroblast growth factor (FGF) 19 in inflammation-induced injury of vascular endothelial cells caused by high glucose (HG). METHODS: Human umbilical vein endothelial cells (HUVECs) were randomly divided into four groups: control, HG, FGF19, and HG+FGF19 (n=3 each). The effect of different concentrations of glucose and/or FGF19 on HUVEC viability was assessed using the CCK8 assay. Flow cytometry was utilized to examine the impact of FGF19 on HUVEC apoptosis. Levels of interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were measured by ELISA. Real-time quantitative PCR and Western blotting were used to determine the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), nuclear factor erythroid 2 related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Cells were further divided into control, siRNA-Nrf2 (siNrf2), HG, HG+FGF19, HG+FGF19+negative control, and HG+FGF19+siNrf2 groups (n=3 each) to observe the effect of FGF19 on oxidative stress injury in HUVECs induced by high glucose after silencing the Nrf2 gene. RESULTS: Compared to the control group, the HG group exhibited increased apoptosis rate, increased IL-6, iNOS and MDA levels, and increased VEGF mRNA and protein expression, along with decreased T-SOD activity and decreased mRNA and protein expression of Nrf2 and HO-1 (P<0.05). Compared to the HG group, the HG+FGF19 group showed reduced apoptosis rate, decreased IL-6, iNOS and MDA levels, and decreased VEGF mRNA and protein expression, with increased T-SOD activity and increased Nrf2 and HO-1 mRNA and protein expression (P<0.05). Compared to the HG+FGF19+negative control group, the HG+FGF19+siNrf2 group had decreased T-SOD activity and increased MDA levels (P<0.05). CONCLUSIONS FGF19 can alleviate inflammation-induced injury in vascular endothelial cells caused by HG, potentially through the Nrf2/HO-1 signaling pathway.
Humans ; NF-E2-Related Factor 2/genetics* ; Signal Transduction ; Human Umbilical Vein Endothelial Cells/drug effects* ; Fibroblast Growth Factors/pharmacology* ; Heme Oxygenase-1/physiology* ; Apoptosis/drug effects* ; Glucose ; Inflammation ; Interleukin-6/analysis* ; Vascular Endothelial Growth Factor A/genetics* ; Nitric Oxide Synthase Type II/analysis* ; Cells, Cultured

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.

Objective To explore the clinical efficacy of low molecular weight heparin combined with insulin in the treatment of hyper-triglyceridemic-acute pancreatitis(HTG-AP).Methods A total of 106 patients diagnosed with HTG-AP who were admitted to the department of gastroenterology of Huaibei People's Hospital from May 2022 to July 2023 were selected as the research objects.According to the random number table method,the low-molecular heparin group(35 cases,received a 5 000 U subcutaneous injection low-molecular heparin once every 12 hours for 6 days),the insulin group(35 cases,received intravenous insulin pumping at a rate of 2 U/h,with careful monitoring of the patient's random blood glucose levels to prevent hypoglycemia),and the combination therapy group(36 cases,received both low-molecular heparin and insulin).Before treatment and at 1,2,and 6 days after treatment,the difference of serum triacylglycerol(TG),total cholesterol(TC),blood amylase,inflammatory factors[C-reactive protein(CRP),interleukin-6(IL-6)],calcium ions,and creatinine levels among the three groups were compared.The modified computed tomography severity index(MCTSI)scores,acute physiology and chronic health evaluationⅡ(APACHEⅡ),hospital length of stay,and hospital costs before and after 6 days of treatment were observed.Results After treatment,the TC of all three groups significantly decreased compared to before treatment(P<0.05),but there was no significant difference among the three groups.The calcium ion levels of the three groups did not show a statistically significant difference before and after treatment.After 6 days of treatment,the creatinine levels of the three groups significantly decreased compared to before treatment,but there was no significant difference among the three groups.After 2 days of treatment,serum TG levels were significantly lower in the combination therapy group and insulin group compared to the low-molecular heparin group(mmol/L:4.6±1.7,4.4±1.8 vs.5.6±2.0,both P<0.05).However,there was no statistically significant difference between the combination therapy group and the insulin group.After 6 days of treatment,the combination therapy group showed significantly lower levels of serum TG,blood amylase,CRP,and IL-6 compared to the insulin group and the low-molecular heparin group[TG(mmol/L):2.8±1.9 vs.4.3±1.9,5.0±2.2,blood amylase(U/L):36.0(32.0,45.0)vs.59.0(43.0,71.0),52.0(45.0,64.0),CRP(mg/L):12.9(8.8,29.7)vs.35.3(21.7,50.3),31.4(23.0,45.1),IL-6(ng/L):15.4(9.8,23.5)vs.25.6(16.4,51.5),32.9(14.7,41.4),all P<0.05].After 6 days of treatment,the APACHEⅡscores of all three groups decreased significantly(all P<0.05).The MCTSI scores of the insulin group and the combined treatment group also decreased significantly compared to before treatment.Furthermore,the MCTSI and APACHEⅡscores of the combination therapy group were significantly lower than those of the low-molecular heparin group and the insulin group(MCTSI score:2.3±0.7 vs.3.3±1.7,2.9±1.3,APACHEⅡscore:1.3±1.2 vs.2.5±2.4,2.6±2.5,all P<0.05).The combination therapy group had significantly lower length of hospital stay and treatment cost compared to the low molecular heparin and insulin groups[length of hospital stay(days):6.9±1.6 vs.8.8±3.4,8.5±2.8,and cost of treatment(yuan):6 040.5(5 239.4,7 105.9)vs.6 696.4(5 791.5,11 026.2),6 918.5(6 087.9,10 080.8),all P<0.05].Conclusions The combination of low-molecular heparin and insulin treatment can significantly reduce serum TG and inflammatory factor levels,as well as the severity and duration of the disease.This approach can also reduce the cost of treatment.Therefore,it is worth promoting and applying in clinical settings.

Objective:To investigate the effect of construction and practice of problem-based learning(PBL)case database based on post competency for postgraduates majoring in Clinical Pharmacy.Methods:Through collective discussion,the case theme selection,case design and teaching process were clarified,and the case database was constructed.Students in grade 2021 received the traditional teaching method and students in grade 2022 received case-based teaching method.The teaching effect was evaluated according to the training objectives.Results:Compared with students in grade 2021,the students in grade 2022 showed an improvement trend in various evaluation indicators such as stimulating learning interest,literature review ability,problem analysis ability,problem-solving ability,team collaboration ability,and final exam score(P＜0.05).Conclusion:The PBL teaching method based on post competency case is conducive to improving the practical ability to find,analyze and solve practical problems in practical work of postgraduates majoring in Clinical Pharmacy.

AIM:To explore the expression of calcium binding and coiled-coil domain 2(CALCOCO2)in ani-mal models of atrial fibrillation(AF)and its role and mechanism in reversing atrial remodeling in AF mice.METHODS:Twelve rats and 12 mice were randomly divided into the following 2 groups(n=6 each):saline control group(saline group)and angiotensin Ⅱ(Ang Ⅱ)-induced AF group(Ang Ⅱ group).Western blot and immunohistochemistry(IHC)were used to detect CALCOCO2 expression in rat and mouse atrial muscle tissues.Another 24 mice were randomly divided into 4 groups(n=6 each):saline-oeNC,Ang Ⅱ-oeNC,saline-oeCALCOCO2,and Ang Ⅱ-oeCALCOCO2.An adeno-asso-ciated virus was used to induce CALCOCO2 overexpression in mouse atrial myocardium.Subsequently,transthoracic echocardiography and intracardiac electrophysiological testing were used to compare mouse cardiac function among the 4 groups.Western blot and TUNEL staining were also used to evaluate the effect of CALCOCO2 on apoptosis of cardiomyo-cytes in AF models.Additionally,IHC was used to assess the effect of CALCOCO2 on the levels of oxidative stress-related proteins[NADPH oxidase 2(NOX2)and NOX4]and fibrosis-related proteins[collagen type Ⅰ(Col Ⅰ),connexin 40(Cx40)and α-smooth muscle actin(α-SMA)]in AF atrial myocardium.RESULTS:The CALCOCO2 protein level in the atrial myocardium of rats and mice was significantly decreased in Ang Ⅱ group compared with saline group,as detected by Western blot and IHC(0.19±0.01 vs 0.32±0.03 for rats,0.37±0.10 vs 1.00±0.10 for mice,P<0.01).Compared with Ang Ⅱ-oeNC group,the mice in Ang Ⅱ-oeCALCOCO2 group exhibited decreased left atrial inner diameter,shorter AF duration,and increased ejection fraction(P<0.05).Semi-quantitative analysis of TUNEL staining revealed a signifi-cantly decreased apoptosis rate of mouse atrial myocytes in Ang Ⅱ-oeCALCOCO2 group compared with Ang Ⅱ-oeNC group(0.30±0.06 vs 0.61±0.03,P<0.01),which was consistent with the Western blot trend of apoptosis-related proteins such as BAX(1.94±0.34 vs 3.14±0.34,P<0.05)and cleaved caspase-3(2.19±0.41 vs 3.52±0.55,P<0.05).The semi-quantitative results of IHC and immunofluorescence revealed significantly increased levels of oxidative stress-related pro-teins(NOX2 and NOX4)and fibrosis-related proteins(Col Ⅰ and α-SMA),as well as decreased Cx40 levels,in Ang Ⅱ-oeNC group compared with saline-oeNC group.However,the expression levels of these proteins were significantly re-versed after CALCOCO2 overexpression(all P<0.05).CONCLUSION:Overexpression of CALCOCO2 reverses AF-in-duced electrical and structural remodeling by inhibiting the oxidative stress,apoptosis and fibrosis in mouse atrial tissues.

Objective To explore high density lipoprotein(HDL)/low density lipoprotein(LDL)and total type Ⅰ collagen amino terminal extender peptide(t-PINP)/C-terminal peptide of type Ⅰ collagen β special sequence(β-CTX)and risk of os-teoporosis vertebral fractures(OPVFs)in elderly women.Methods The clinical data of 446 female OPVFs patients aged above 60 years old from January 2019 to December 2020 were retrospectively analyzed.According to whether or not fracture,patients were divided into non-fracture group(186 patients)and fracture group(260 patients).Univariate analysis was performed to analysis age,body mass index(BMI),N-terminal mioldle molecular fragment of osteocalcin,N-MID OC),t-PINP,β-CTX,25-hydroxyvitamin D[25-(OH)VitD],blood sugar(Glu),total cholesterol(TC),high-density lipoprotein(HDL),low-density lipoprotein(LDL),Ca,P,Mg,urea(UREA),creatinine(Cr)and Cystatin C(CysC),and correlation between OPVFs and the above indexes and lipid,bone metabolism indexes between two groups;Logistic regression was performed to analyze risk factors and stratification relationship between vertebral fracture and HDL/LDL,t-PINP/β-CTX.Logistic regression was used to ana-lyze risk factors and stratification relationship between OPVFs and HDL/LDL,t-PINP/β-CTX.Results There were no signif-icant difference in age and BMI between non-fracture group and fracture group(P＞0.05).Compared with non-fracture group,contents of HDL,t-PINP/β-CTX and HDL/LDL in fracture group were decreased,and contents of β-CTX were increased(P＜0.05).OPVFs was positively correlated with β-CTX(r=0.110,P＜0.05),and negatively correlated with HDL,HDL/LDL and t-PINP/β-CTX(r=-0.157,-0.175,-0.181,P＜0.05).HDL and HDL/LDL were negatively correlated with β-CTX(r=-0.22,-0.12,P＜0.05)and t-PINP(r=-0.13,-0.10,P＜0.05).25-(OH)VitD was positively correlated with TC and HDL(r=0.11,0.18,P＜0.05).HDL/LDL was positively correlated with t-PINP/β-CTX(r=0.11,P=0.02).t-PINP/β-CTX[OR=0.998,95％CI(0.997,1.000),P＜0.05],HDL/LDL[OR=0.228,95％CI(0.104,0.499),P＜0.01]were risk factors for vertebral fracture.The lower levels between two tristratified indicators,the higher the vertebral fracture rate.The risk of fracture was 2.5 and 2 times higher in the lowest stratum than in the highest stratum,with an adjusted OR was[2.112,95％CI(1.310,3.404)]and[2.331,95％CI(1.453,3.739)],respectively.Conclusion Serum low HDL/LDL and t-PINP/β-CTX are independent risk factors for OPVF in elderly women,and have good predictive value for OPVF risk.

Objective To summarize the endoscopic and clinical diagnosis and treatment of 4 cases of gastric fundus adenocarcinoma.Method A retrospective analysis was conducted on the clinical data of four cases of gastric fundus adenocarcinoma from July 2021 to December 2023.Result All the 4 cases of gastric fundus adenocarcinoma were completely removed by endoscopic submucosal dissection(ESD),with good postoperative recovery,no surgical complications,and no recurrence or metastasis during follow-up.Conclusion ESD treatment for gastric fundus adenocarcinoma is safe,reliable,and can completely remove the lesion.

Background/Aims: The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD). Methods: This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert panel criteria including ethnicity-specific BMI cut-offs. A comparison of clinical and tumour characteristics was performed between single-MAFLD, mixed-MAFLD, and non-MAFLD HCC. Results: 22 studies (56,565 individuals with HCC) were included. Total and single-MAFLD HCC prevalence was 48.7% (95% confidence interval [CI] 34.5–63.0%) and 12.4% (95% CI 8.3–17.3%), respectively. In HCC due to chronic hepatitis B, C, and alcohol-related liver disease, mixed-MAFLD prevalence was 40.0% (95% CI 30.2–50.3%), 54.1% (95% CI 40.4–67.6%) and 64.3% (95% CI 52.7–75.0%), respectively. Mixed-MAFLD HCC had significantly higher likelihood of cirrhosis and lower likelihood of metastatic spread compared to single-MAFLD HCC, and a higher platelet count and lower likelihood of macrovascular invasion compared to non-MAFLD HCC. Conclusions MAFLD is common as a sole aetiology, but more so as a co-factor in mixed-aetiology HCC, supporting the use of positive diagnostic criteria.

Purpose: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal malignancy that occurs primarily in children and adolescents. The clinical and pathological features of IMT in adult patients are not well understood. Materials and Methods: We retrospectively searched for records of adult patients with IMT at Fudan University Shanghai Cancer Center from 2006 to 2021. Clinicopathological data, treatments, and outcomes were collected and analyzed. Results: Thirty adult patients with IMT, mostly women (60.0%), were included. The median age of the patients was 38 (21-77). The most common primary site was abdominopelvic region (53.3%), followed by lungs (20.0%). Seven patients had an abdominal epithelioid inflammatory myofibroblast sarcoma (EIMS). The positivity rate of anaplastic lymphoma kinase (ALK) was 81.5% (22/27). Sixteen patients with advanced ALK-positive disease received crizotinib, with an objective response rate (ORR) of 81.3% and a disease control rate of 87.5%. The median progression-free survival was 20.8 months. EIMS was associated with more aggressive behavior; however, the prognosis was similar to that of non-EIMS patients after treatment with an ALK inhibitor. At a median follow-up time of 30 months (95% confidence interval [CI], 13.6 to 46.4), the 5-year overall survival was 77% (95% CI, 66 to 88) in all patients. Conclusion Adult IMTs appeared more aggressive, with a higher incidence of recurrence and metastases, and patients with EIMS had more aggressive cases. Treatment with ALK inhibitors resulted in a high ORR and a durable response, which suggested that ALK inhibitors could be used as a first-line treatment option in adult patients with ALK-positive advanced IMT.