Background::Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms. Methods::Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-cateninΔ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-cateninΔ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV); β-cateninlox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer. Results::MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-cateninlox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer. Conclusion::MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.

The absorption is the key to the resulted efficacy of orally administered drugs and the small intestine is the main site to absorb the orally administered drug. In this paper, internationally recognized human colon adenocarcinoma cell line(Caco-2) monola-yer model which can simulate small intestinal epithelial cell was used to comparatively study the absorption and transportation diffe-rences of total coumarins and main individual coumarin in Angelica dahurica 'Yubaizhi' by separately using 6-and 12-well plates. It was found that apparent permeability coefficient(P_(app)) values of oxypeucedanin hydrate, byakangelicin and phellopterin were at the quantitative degree of 1 × 10~(-5) cm·s~(-1) when the individual administration was conducted independently, indicating that they were well-absorbed compounds. P_(app) ratio of their bi-directional transportation was close to 1, indicating that they can be absorbed across Caco-2 monolayer by passive diffusion mechanism without carrier mediation during the transportation. The similar trend of transportation was also observed for imperatorin, isoimperatorin and bergapten. The P_(app) values of oxypeucedanin hydrate, byakangelicin and bergapten were at quantitative degree of 1 × 10~(-5) cm·s~(-1) when the administration of total coumarins in Angelica dahurica 'Yubaizhi' was conducted, indicating that they were well-absorbed compounds. The results were consistent with those of independent administration of individual coumarins. Whereas, the P_(app) values of imperatorin, phellopterin and isoimperatorin in the total coumarins decreased, indicating that the interaction between compounds may exist although the P_(app) value ratio of bi-directional transportation was between 0.5 and 1.5. The results laid the foundation for intestinal absorption study of Angelica dahurica 'Yubaizhi' coumarins in compound Chinese medicine.
Angelica ; Caco-2 Cells ; Coumarins ; Drugs, Chinese Herbal ; Humans ; Intestinal Absorption ; Plant Roots

Objective:To explore the therapeutic effects of biofeedback therapy of perineal surface on stress urinary incontinence(SUI) in elderly women.Methods:A total of 87 elderly women with SUI treated at the outpatient clinics of Beijing Hospital and Yunnan First People's Hospital between January 2018 and December 2019 were recruited in this prospective cohort study.All participants were therapeutically divided into the perineal BF group(n=53)and the intravaginal BF group(n=34), based on the voluntary selection.In the intravaginal BF group, 3/34 cases dropped out of the study, and finally in 31 cases the treatment was completed.All patients were treated with biofeedback for 8 weeks with twice treatment per week.The quality of life was assessed by the incontinence impact questionnaire scores.Patients underwent the 1-hour pad-weighing test, pelvic floor muscle assessment and quality of life assessment by incontinence impact questionnaire(ⅡQ-7)scores before and after treatment.The effective rate of treatment, adverse reactions and treatment satisfaction scores were compared between the two groups.Results:The urine leakage and scores of ⅡQ-7 questionnaire were significantly improved after versus before 8 weeks of treatment in the perineal BF group[(4.65±2.33) g vs.(11.02±4.85) g, (7.96±5.11) scores vs.(4.34±2.66) scores, t=8.62 and 4.58, P<0.001], and in the intravaginal BF group[(3.85±1.89) g vs.(12.43±3.96) g, (3.81±1.23) scores vs.(8.29±5.01) scores, t=10.89 and 4.84, P<0.001]. Compared with before treatment, the grading of pelvic floor muscle strength was improved after treatment, but had no significant difference in the perineal BF group(3.93±2.77 vs.2.98±2.10, t=1.99, P=0.056)and in the intravaginal BF group(4.51±3.38 vs.3.07±2.02, t=2.04, P=0.051). There was no significant difference in the urine leakage, grading of pelvic floor muscle strength and scores of ⅡQ-7 questionnaire between two groups( P>0.05). The effective rate of treatment had no significant difference between the perineal and intravaginal BF groups(81.13% or 43/53 vs.83.87% or 26/31, χ2=0.10, P=0.750). The incidences of adverse effects were higher(20.59% or 7/34 vs.1.89% or 1/53, χ2=8.68, P=0.003)and the comfort levels during treatment assessed by visual analog scale(VAS)scores were lower in the intravaginal BF group than in the perineal BF group[(8.11±2.93) scores vs.(9.88±3.84) scores, t=2.95, P=0.004]. The main adverse effects included pain or discomfort, vaginal bleeding and increased vaginal discharge in the intrasvaginal BF treatment group. Conclusions:The perineal BF method is as effective as intravaginal BF in female stress urinary incontinencetreatmentin elderly women, and has fewer adverse effects.

The chemical constituents from lipophilic parts in the roots of Angelica dahurica cv. Yubaizhi were studied in this paper. The compounds were separated and purified by repeated column chromatographic methods on silica gel and HPLC, and the chemical structures of compounds were determined by spectral data analyses. Thirty-three compounds were obtained and identified as isoimperatorin (1), imperatorin (2), stigmasterol (3), isooxypeucedanin (4), pabulenol (5), psoralen (6), bergapten (7), isodemethylfuropinarine (8), phellopterin (9), osthenol (10), alloimperatorin (11), xanthotoxin (12), xanthotoxol (13), isopimpinellin (14), alloisoimperatorin (15), β-sitosterol (16), oxyalloimperatorin (17), pabularinone (18), 5-hydroxy-8-methoxypsoralen (19), columbianetin (20), heracol (21), isogosferol (22), 2″R-neobyakangelicol (23), byakangelicin ethoxide (24), byakangelicin (25), oxypeucedanin hydrate (26), uracil (27), umbelliferone (28), bergaptol (29), demethylfuropinarine (30), isobyakangelicol (31), oxypeucedanin ethanolate (32), heraclenol (33). Among them, compounds 8, 10, 17, 21, and 30 were obtained from the roots of title plant for the first time.

Objective To determine whether the integration of immature neurons born before status epilepticus (SE)can be disrupted by an epileptogenic insult.Methods Pilocarpine was used to induce SE in mice. At week 1 before induction,BrdU or retroviral vector expressing green fluorescent protein (RV-GFP)was used to label the newly born cells in the dentate gyrus (DG).At week 8 after SE,BrdU+Map2 or BrdU+NeuN double-labeling staining was carried out to visualize hilar basal dendrite or hilar ectopic migration.Virus-transduced GFP signals were used to identify the mossy fiber sprouting from the newly generated neurons.The number of cells with aberrant integrations was compared using unpaired Student's t-test.Results The percentage of newborn neurons with aberrant dendritic morphology was (20.8±8.4)% at week 8 after SE.The percentage of BrdU+NeuN double labeled cells ectopically migrated into the hilus was (15.9 ± 7.4)%.At week 8 after SE,the chronically epileptic mice showed many GFP+ processes in the IML with the same axonal appearance and small mossy fiber bouton-like structures as those seen in the hilus.The number of newborn neurons with aberrant integrations in SE mice wassignificantly increased when compared with the control mice (P <0.05).Conclusion These data demonstrate the existence of aberrant integrations-hilar basal dendrites,hilar ectopic migration and mossy fiber sprouting in the DG-generated cells born 1 week before an SE insult.

BACKGROUNDAntiplatelet therapy (APT) was prevalently being used in the prevention of vascular disease, but the influence of prior APT on the prognosis of patients with intracerebral hemorrhage (ICH) remains controversial. This meta-analysis was to explore the effects of prior APT on the prognosis of patients with primary ICH.

METHODSPubMed and Embase were searched to identify the eligible studies. The studies comparing the mortality of ICH patients with or without prior APT were included. The quality of these studies was evaluated by the Newcastle-Ottawa quality assessment scale. The adjusted or unadjusted odds ratio (OR) for mortality between ICH patients with and without prior APT were pooled with 95% confidence interval (95% CI) as the effect of this meta-analysis.

RESULTSTwenty-two studies fulfilled the inclusion criteria and exhibited high qualities. The pooled OR was 1.37 (95% CI: 1.13-1.66, P = 0.001) for univariate analysis and 1.41 (95% CI: 1.05-1.90, P = 0.024) for multivariate analysis. The meta-regression indicated that for each 1-day increase in the time of assessment, the adjusted OR for the mortality of APT patients decreased by 0.0049 (95% CI: 0.0006-0.0091, P = 0.026) as compared to non-APT patients.

CONCLUSIONPrior APT was associated with high mortality in patients with ICH that might be attributed primarily to its strong effect on early time.

Objective: The aim of the study is to validate whether the Recognition Of Stroke In the Emergency Room (ROSIER) scale can be used by general practitioners (GPs) in an emergency medical service (EMS) protocol to transfer stroke patients from primary care center to advanced hospital with acute stroke center. Methods: GPs prospectively performed the ROSIER scale and the Cincinnati Prehospital Stroke Scale (CPSS) on suspected stroke patients as a transfer protocol. All patients were immediately transferred to the Level-II hospital for further treatment. Results: 468 of the 512 suspected stroke patients met the inclusion criteria in this study. The ROSIER scale showed a diagnostic sensitivity of 83.13% (95% confidence intervals [CI] 79.74-86.52%) and specificity of 80.88% (95% CI 77.32- 84.44%). The CPSS showed a diagnostic sensitivity of 78.01% (95% CI 74.26-81.76%) and specificity of 70.59% (95% CI 66.46-74.72%). The Kappa statistic value of the ROSIER scale and the CPSS were 0.601 and 0.454, respectively. The area under the curve (AUC) of ROSIER scale was large than the CPSS (AUC 0.855 vs. 0.791). However, the difference was not significantly different. Conclusions: This study suggest that ROSIER and CPSS could be used in an EMS protocol to transfer stroke patients from a primary care center to an advanced hospital offering thrombolysis service
Stroke

The chemical constituents from lipophilic parts in the roots of Angelica dahurica var. formosana cv. Chuanbaizhi were studied in this paper. The compounds were separated and purified by repeated column chromatographic methods on silica gel and HPLC, and the chemical structures of compounds were determined by spectral data analyses. Twenty-nine compounds were obtained and identified as isoimperatorin (1), β-sitosterol (2), imperatorin (3), bergapten (4), osthenol (5), xanthotoxin (6), isoimpinellin (7), dehydrogeijerin (8), phellopterin (9), isodemethylfuropinarine (10), 7-demethylsuberosin (11), alloimperatorin (12), xanthotoxol (13), isooxypeucedanin (14), alloisoimperatorin (15), demethylfuropinarine (16), 5-hydroxy-8-methoxypsoralen (17), oxypeucedanin methanolate (18), pabulenol (19), byakangelicin (20), marmesin (21), (+) -decursinol (22), heraclenol (23), oxypeucedanin hydrate (24), marmesinin (25), ulopterol (26), erythro-guaiacylglycerol-β-ferulic acid ether (27), threo-guaiacylglycerol-β-ferulic acid ether (28), and uracil (29). Compounds 5, 8, 11, 18, 21-23, and 26-28 were obtained from the roots of title plant for the first time.
Angelica ; chemistry ; Coumarins ; chemistry ; isolation & purification ; Furocoumarins ; chemistry ; isolation & purification ; Methoxsalen ; chemistry ; isolation & purification ; Phytochemicals ; analysis ; chemistry ; Plant Roots ; chemistry

The chemical constituents from polarity part in the roots of Angelica dahurica var. formosana cv. Chuanbaizhi were studied in this paper. The compounds were separated and purified by repeated column chromatographic methods on silica gel and HPLC, and the chemical structures of compounds were determined by spectral data analyses. Fourteen compounds were obtained and identified as tert-O-β-D-glucopyranosyl-(R)-byakangelicin (1), (2"S) -3"-O-β-D-glucopyranosyl-oxypeucedanin hydrate (2), marmesinin (3), sec-O-β-D-glucopyranosyl-byakangelicin (4), isofraxidin-7-O-β-D-glucopyranoside (5), benzyl-O-β-D-glucopyranoside (6), 8-O-β-D-glycopyranosylxanthotoxol (7), prenyl-O-β-D-glucopyranoside (8), scopolin (9), (2' R) -5'-hydroxymarmesin-5'-O-β-D-glucopyranoside (10), (2'S,3'R) -3'-hydroxymarmesinin (11), skimmin (12), benzyl-O-β-D-apiofuranosyl-(1"--> 6')-β-D-glucopyranoside (13), and decuroside IV (14). Among them, compounds 2, 5, 6, 8, and 10-13 were obtained from the roots of title plant for the first time.
Angelica ; chemistry ; Drugs, Chinese Herbal ; chemistry ; isolation & purification ; Mass Spectrometry ; Molecular Structure ; Plant Roots ; chemistry

Objective To discusse the mechanism and clinical significance of bradycardia -hypotension phenomenon which is caused by vagal reflex during and after the RFCA and present the experience of using appropriate measures to decrease the incidence of this situation. Methods The patients who were suffering from tachyarrhythmias and treated by RFCA were divided into two groups. The groups were as follows:148 patients who were not taken special measures in the early stage were selected in control group;1 540 patients who were taken measures to prevent vasovagal reflex were selected in observation group. Result During the RFCA, the incidence of bradycardia -hypotension phenomenon in control group was 13.5% (20/148), the incidence of bradycardia-hypotension phenomenon in observation group was 5.0%(77/1540) (<0.01) .Conclusions The incidence of bradycardia-hypotension phenomenon caused by vagal reflex during the RFCA is related to catheter irritation to the heart,pressure on the vessels and hypovolemia. The incidence of this phenomenon can be decreased obviously by some measures,such as non-restricted diet before RFCA,discretion rehydration during and after the RFCA and hemostasis with appropriate force after extubation. The key to rescue patients successfully are early detection and timely processing.