Incidence and prognosis of olfactory and gustatory dysfunctions related to infection of SARS-CoV-2 Omicron strain: a national multi-center survey of 35 566 population / 中华耳鼻咽喉头颈外科杂志

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.

Curcumin alleviated oxidation stress injury by mediating osteopontin in nephrolithiasis rats

Purpose: To explore the role and mechanism of curcumin (Cur) in reducing oxidative stress damage in rats with nephrolithiasis induced by ethylene glycol (EG). Methods: Thirty male rats were divided into normal control, model, positive (10% potassium citrate), Cur-10 (10 mg/kg curcumin) and Cur-20 (20 mg/kg curcumin) groups. Results: The results of kidney tissue section stained by hematoxylin-eosin and von Kossa showed that curcumin treatment can inhibit the formation of kidney stones. The biochemical test results showed that the urea (Ur), creatinine (Cr), uric acid (UA), inorganic phosphorus and Ca2+ concentrations in urine decreased after being treated with curcumin. There were significant differences between different doses of curcumin (P < 0.05). Compared with the Cur-10 group, Cur-20 had a more significant inhibitory effect on malondialdehyde (MDA) (P < 0.05). In addition, reverse transcription polymerase chain reaction (PCR) detection and immunohistochemical results indicated that the osteopontin (OPN) in the kidney was significantly reduced after curcumin treatment. Conclusion: Curcumin could reduce the oxidative stress damage caused by EG-induced kidney stones.

Effect and mechanism of MLL5 knock-out on the growth of colon cancer CT26 cell transplanted tumor / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨混合谱系白血病5（MLL5）基因在小鼠结肠癌CT26细胞移植瘤生长中的作用及其分子机制。方法：利用CRISPR/Cas9技术构建MLL5基因缺失、MLL5和DDX58双基因缺失的结肠癌CT26细胞模型，用Sanger测序和WB法验证敲除效果。将基因敲除的CT26细胞接种到野生型BALB/c小鼠和免疫缺陷型NSG小鼠皮下，构建基因缺失结肠癌CT26细胞移植瘤小鼠模型，并观察移植瘤的生长及荷瘤小鼠的总生存期（OS）。结果：在野生型小鼠中，MLL5基因缺失的CT26细胞移植瘤生长速度显著性低于野生型癌细胞移植瘤，并延长荷瘤小鼠的OS（P<0.01）；在NSG小鼠中，MLL5基因缺失对CT26细胞移植瘤的生长速度以及荷瘤小鼠的OS没有明显改变。MLL5基因缺失提高了癌细胞中视黄酸诱导基因1（RIG-1）蛋白水平，DDX58基因缺失可逆转MLL5基因缺失在CT26细胞移植瘤中的作用。结论：MLL5基因缺失可提高结肠癌CT26细胞中RIG-1蛋白水平、促进肿瘤免疫，从而抑制荷瘤小鼠肿瘤生长，提示MLL5可能成为结肠癌治疗的新靶点。

"Massive hemoptysis" and shock after fever and cough / 中国当代儿科杂志

A boy, aged 11 years, was admitted due to intermittent fever for 15 days, cough for 10 days, and "hemoptysis" for 7 days. The boy had fever and cough with left neck pain 15 days ago, and antibiotic treatment was effective. During the course of disease, the boy developed massive "hemoptysis" which caused shock. Fiberoptic bronchoscopy revealed a left pyriform sinus fistula with continuous bleeding. In combination with neck and vascular imaging examination results, the boy was diagnosed with internal jugular vein injury and thrombosis due to congenital pyriform sinus fistula infection and neck abscess. The boy was improved after treatment with temperature-controlled radiofrequency ablation for the closure of pyriform sinus fistula, and no recurrence was observed during the follow-up for one year and six months. No reports of massive hemorrhage and shock due to pyriform sinus fistula infection were found in the searched literature, and this article summarizes the clinical features, diagnosis, and treatment of this boy, so as to provide a reference for the early diagnosis of such disease and the prevention and treatment of its complications.

Predictive value of impedance of leadless pacemaker during implantation on trend changes of pacing threshold / 中华心血管病杂志

Objective: To explore the predictive value of the impedance measured during leadless pacemaker Micra implantation on the trend of changes of pacing threshold post implantation. Methods: This is a retrospective cross-sectional study. Patients who received implantation of leadless pacemaker Micra at the Second Xiangya Hospital of Central South University from December 2019 to August 2020 were enrolled. The clinical data and the intraoperative electrical parameters during leadless pacemaker implantation were collected. The impedance and pacing threshold data were analyzed at three time points: immediate release, 5-10 min after release, and after traction test. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to analyze the value of the impedance at immediate release on predicting the trend of changes of pacing threshold post implantation. Results: A total of 21 patients (mean age: (72.2±12.5) years, 12 males) were included. The impedance of 21 patients was (798.1±35.3) Ω immediately after implantation, (800.9±35.6) Ω after 5-10 minutes of release, and (883.6±31.7) Ω after traction test. Impedance was similar between the three time points (P>0.05). The threshold was (0.97±0.11) V/0.24 ms immediately after implantation, (0.95±0.12) V/0.24 ms at 5-10 min after the release, and (0.59±0.06) V/0.24 ms after the traction test. The threshold was significantly lower after the traction test than that immediately after release (P=0.003) and than that at 5-10 minutes after release (P=0.008), suggesting a decreased tendency of the threshold over time. According to the analysis of the ROC curve, the immediate impedance after the release ≥680 Ω could predict the ideal pacing threshold after the traction test (AUC=0.989, 95%CI 0.702-0.964, P<0.001), the prediction sensitivity was 87%, and the specificity was 100%. The pacing threshold would be not ideal with the immediate impedance ≤ 520 Ω (95%CI 0.893-1.000, P<0.001), the sensitivity was 100%, and the specificity was 80%. Conclusions: The impedance immediately after the release has predictive value for the changing trend of threshold post leadless pacemaker Micra implantation. Impedance ≥680 Ω immediately after release is often related with ideal pacing threshold after the traction test. In contrast, the impedance ≤ 520 Ω pacing is often related with unsatisfactory threshold after the traction test, therefore, it is recommended to find a new pacing site to achieve the impedance ≥680 Ω immediately after release during leadless pacemaker Micra implantation.

Valor Prognóstico da Ultrassonografia Pulmonar para Resultados Clínicos em Pacientes com Insuficiência Cardíaca: Uma Revisão Sistemática e Metanálise / Prognostic Value of Lung Ultrasound for Clinical Outcomes in Heart Failure Patients: A Systematic Review and Meta-Analysis

Resumo Fundamento Existem informações conflitantes sobre se a ultrassonografia pulmonar avaliada por linhas B tem valor prognóstico em pacientes com insuficiência cardíaca (ICa). Objetivos Avaliar o valor prognóstico da ultrassonografia pulmonar avaliada por linhas B em pacientes com ICa. Métodos Quatro bases de dados (PubMed, EMBASE, Cochrane Library e Scopus) foram sistematicamente pesquisadas para identificar artigos relevantes. Reunimos a razão de risco (RR) e o intervalo de confiança de 95% (IC) de estudos elegíveis e realizamos análises de heterogeneidade, avaliação de qualidade e viés de publicação. Os dados foram agrupados usando um modelo de efeitos fixos ou de efeito aleatório. Um valor de p <0,05 foi considerado para indicar significância estatística. Resultados Nove estudos envolvendo 1.212 participantes foram incluídos na revisão sistemática. As linhas B > 15 e > 30 na alta hospitalar foram significativamente associadas ao aumento do risco de desfecho combinado de mortalidade por todas as causas ou hospitalização por ICa (RR, 3,37, IC de 95%, 1,52-7,47; p = 0,003; RR, 4,01, IC de 95%, 2,29-7,01; p <0,001, respectivamente). O ponto de corte da linha B > 30 na alta foi significativamente associado ao aumento do risco de hospitalização por ICa (RR, 9,01, IC de 95%, 2,80-28,93; p <0,001). Além disso, o ponto de corte da linha B > 3 aumentou significativamente o risco de desfecho combinado de mortalidade por todas as causas ou hospitalização por ICa em pacientes ambulatoriais com ICa (RR, 3,21, IC de 95%, 2,09-4,93; I2 = 10%; p <0,00001). Conclusão As linhas B podem predizer mortalidade por todas as causas e hospitalizações por ICa em pacientes com ICa. Outros grandes ensaios clínicos randomizados são necessários para explorar se lidar com as linhas B melhoraria o prognóstico nos ambientes clínicos. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Abstract Background There is conflicting information about whether lung ultrasound assessed by B-lines has prognostic value in patients with heart failure (HF). Objectives To evaluate the prognostic value of lung ultrasound assessed by B-lines in HF patients. Methods Four databases (PubMed, EMBASE, Cochrane Library, and Scopus) were systematically searched to identify relevant articles. We pooled the hazard ratio (HR) and 95% confidence interval (CI) from eligible studies and carried out heterogeneity, quality assessment, and publication bias analyses. Data were pooled using a fixed-effects or random-effect model. A p value < 0.05 was considered to indicate statistical significance. Results Nine studies involving 1,212 participants were included in the systematic review. B-lines > 15 and > 30 at discharge were significantly associated with increased risk of combined outcomes of all-cause mortality or HF hospitalization (HR, 3.37, 95% CI, 1.52-7.47; p = 0.003; HR, 4.01, 95% CI, 2.29-7.01; p < 0.001, respectively). A B-line > 30 cutoff at discharge was significantly associated with increased risk of HF hospitalization (HR, 9.01, 95% CI, 2.80-28.93; p < 0.001). Moreover, a B-line > 3 cutoff significantly increased the risk for combined outcomes of all-cause mortality or HF hospitalization in HF outpatients (HR, 3.21, 95% CI, 2.09-4.93; I2 = 10%; p < 0.00001). Conclusion B-lines could predict all-cause mortality and HF hospitalizations in patients with HF. Further large randomized controlled trials are needed to explore whether dealing with B-lines would improve the prognosis in clinical settings.

Identification of separation phenomenon during brain death determination of potential organ donor and analysis of relative factors

Background: With analyzing the incongruent phenomenon of electrical active and cerebral blood flow in brain death determination and screening the related factors, offer correct explanations and countermeasure to ensure the successful implementation of donation after brain death.Methods: Relevant clinical data of potential brain death organ donors were prospectively collected between June 2018 and May 2019. The related parameters of neurological examination, laboratory examination and neuroimaging examination during the period of brain death determination were dynamically recorded. Separation phenomenon was used as grouping factors to screen the factors related to separation phenomena through univariate and multivariate analysis.Results: According to the inclusion criteria, 127 patients were included in the study. Among 22 patients (17.3%) with incongruent phenomenon, 17 (77.3%) had electrical silence earlier than cerebral blood flow arrest, and 9 (22.7%) had cerebral blood flow arrest earlier than electrical silence. Univariate and multivariate analysis showed that age <14 years (OR=6.25, 95%CI 1.21-32.22, p=0.028),  SBP≥140 mmHg (OR=7.43, 95%CI 1.62-33.99, p=0.010), primary brainstem injury (OR=15.89, 95%CI 3.04-82.93, p=0.006), spontaneous respiratory arrest time ≤72 hours (OR=11.96, 95%CI 1.59-89.78, p=0.009) and decompression craniotomy(unilateral or bilateral) (OR=16.28, 95%CI 2.25-117.73, p=0.001) were associated with separation phenomenon..Conclusions: Separation phenomenon is a common during the confirmation test of brain death determination in China, and should be correctly recognized. To adopt corresponding measures according to risk factors is useful for successful implementation of donation after brain death.

Platelets can reflect the severity of Crohns disease without the effect of anemia

OBJECTIVES: Anemia and changes in platelets (PLT) are common in inflammatory bowel disease (IBD). In our study, we aimed to verify whether PLT count can independently reflect the severity of IBD. METHODS: In our hospital, 137 Crohn's Disease (CD), 69 Ulcerative colitis (UC) patients, and 412 healthy controls were included to compare the differences in PLT count. In addition, the effect of anemia, C-reactive protein (CRP), age, CD activity index (CDAI) or Mayo on PLTs was also analyzed. If PLTs independently affected CD or UC, we used the receiver operating characteristic (ROC) curve to verify the diagnostic value and obtain the cut-off value of PLT. RESULTS: CD and UC patients had higher PLT than controls (p<0.001, p<0.001; respectively). In CD patients, the results showed that patients with anemia (P<0.01), Iron Deficiency Anemia (IDA) (p<0.001), CRP≥8 mg/L (p=0.046), and CDAI≥150 (p<0.001) had higher PLT, while in UC patients, those with anemia (p=0.018), CRP≥8 mg/L (p=0.045), and Mayo≥3 (p=0.029) had higher PLT. Univariate analysis showed that CDAI was positively correlated with PLT count (p<0.001), while hemoglobin (p=0.001) and age (p<0.001) were negatively correlated with PLT in CD. In UC patients, Mayo (p=0.001) and CRP (p<0.001) were positively correlated with PLT, while hemoglobin (p=0.002) was negatively correlated. Finally, by linear stepwise multivariate analysis, we clarified the positive relationship between PLT and CD (p<0.001) by eliminating the interference of hemoglobin, and determined the cut-off value of PLT as 298×109/L. For UC, we did not obtain similar results. CONCLUSIONS: PLT can be an indicator of disease severity in CD, while there is a lack of evidence regarding this finding in UC.

LINC00511 knockdown prevents cervical cancer cell proliferation and reduces resistance to paclitaxel

Cervical cancer (CC) is one of the most common female malignancies in the world. Although paclitaxel (PTX) is a criticalchemotherapy agent for the treatment of CC, its treatment outcome is limited by the development of drug resistance. Thepresent study aims to define the role of long non-coding RNA (lncRNA) LINC00511 in the progression of CC with theinvolvement of cell proliferation, apoptosis and resistance to PTX in Hela/PTX cells. CC and adjacent normal tissuesamples were collected from 84 patients with CC, and used to determine LINC0051 expression. PTX-resistant Hela/PTXcell line was constructed, in which LINC0051 was overexpressed or silenced to further investigate the effect of LINC00511on PTX-resistant Hela/PTX cell viability, proliferation, migration, invasion, cell cycle, apoptosis and resistance of CC cellsto PTX. The expression of Bcl-2, Bax, cleaved-caspase-3, matrix metalloproteinase (MMP)-2, MMP-9, multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-GP) was also assessed. High-expression of LINC00511 was found in CCwith its close association with the tumor stage, tumor size and lymph node metastasis. After silencing LINC00511expression, the expression of MRP1, P-GP, Bcl-2, MMP-2 and MMP-9 was decreased, while Bax and cleaved-caspase-3increased with more CC cells arrested at G1 phase. Furthermore, silencing of LINC00511 could suppress cell resistance toPTX, cell viability, cell proliferation, migration and invasion yet promoted cell apoptosis in PTX-resistant Hela/PTX cells.Collectively, our findings demonstrate that silencing of LINC00511 could inhibit CC cell resistance to PTX, cell proliferation, migration and invasion, and promote cell apoptosis in CC. Silencing of LINC00511 provides a novel therapeutictarget for CC.

Comparative outcomes of subcutaneous and transvenous cardioverter-defibrillators / 中华医学杂志(英文版)

BACKGROUND@#The comparative outcomes of subcutaneous implantable cardioverter-defibrillator (S-ICD) and transvenous ICD (T-ICD) have not been well studied. The aim of this study was to evaluate the safety and efficacy of currently available S-ICD and T-ICD.@*METHODS@#The study included 86 patients who received an S-ICD and 1:1 matched to those who received single-chamber T-ICD by gender, age, diagnosis, left ventricular ejection fraction (LVEF), and implant year. The clinical outcomes and implant complications were compared between the two groups.@*RESULTS@#The mean age of the 172 patients was 45 years, and 129 (75%) were male. The most common cardiac condition was hypertrophic cardiomyopathy (HCM, 37.8%). The mean LVEF was 50%. At a mean follow-up of 23 months, the appropriate and inappropriate ICD therapy rate were 1.2% vs. 4.7% (χ = 1.854, P = 0.368) and 9.3% vs. 3.5% (χ = 2.428, P = 0.211) in S-ICD and T-ICD groups respectively. There were no significant differences in device-related major and minor complications between the two groups (7.0% vs. 3.5%, χ = 1.055, P = 0.496). The S-ICD group had higher T-wave oversensing than T-ICD group (9.3% vs. 0%, χ = 8.390, P = 0.007). Sixty-five patients had HCM (32 in S-ICD and 33 in T-ICD). The incidence of major complications was not significantly different between the two groups.@*CONCLUSIONS@#The efficacy of an S-ICD is comparable to that of T-ICD, especially in a dominantly HCM patient population. The S-ICD is associated with fewer major complications demanding reoperation.

Early diagnostic value of bronchoalveolar lavage for pulmonary aspergillosis in non-immunocompromised patients / 中国内镜杂志

Objective To investigate the early diagnostic value of bronchoalveolar lavage for pulmonary aspergillosis in non-immunocompromised patients. The GM absorbances of recycled bronchoalveolar lavage fluid in different orders were compared, in order to estabilsh a uniform of broncholaveolar lavage in GM test. Methods We mainly focused on the patients (84 cases) confirmed as pulmonary infection by HRCT chest imageological examination from January 2016 to February 2017. They underwent the bronchoalveolar lavage before empirical or pathogenic antifungal therapy. Meanwhile, the lavage was collected in order of the first and the second tube. Then, BALF-GM test was performed. The GM absorbance (A) and I value of bronchoalveolar lavage fluid were detected by ELISA method. The GM test result of the first tube of bronchoalveolar lavage fluid was included into GM1 group and the GM test result of the second tube of bronchoalveolar lavage fluid was included into GM2 group. According to the standards, the patients were divided into case group (proven 2 cases, probable 7 cases, possible 13 cases) and non-IPA group (62 cases). The GM test diagnostic efficiency of bronchoalveolar lavage fluid collected in different orders were statistically analyzed between the case group and control group. Results The GM-I values showed significant difference between GM1 and GM2 groups (Z = -3.98, P = 0.000). the average rank I value of BALF-GM1 (1.78 ± 1.71) was significantly higher than the BALF-GM2. According to the ROC curve, the optimal cut-off of BALF-GM1 was 0.6, the sensitivity was 86.36％, the specificity was 93.55％, the positive predictive value was 82.61％ and the negative predictive value was 95.08％. The area under the curve of BALF- GM1 (0.941) was significantly higher than that of BALF-GM2 (0.798), indicating that the diagnostic efficiency of BALF-GM1 was higher. Conclusion The operation sequence of collecting bronchoalveolar lavage could affect the I value of BALF-GM test. The diagnostic efficiency of BALF-GM test result of the first tube of bronchoalveolar lavage fluid was higher and had the higher application value in the diagnosis of pulmonary aspergillosis.

Multivariate model for predicting semen cryopreservation outcomes in a human sperm bank / 亚洲男科学杂志(英文版)

Semen cryopreservation is widely used in assisted reproductive technologies, but it reduces sperm quality dramatically. The aim of this study was to develop a model using basal semen quality to predict the outcome of postthaw semen parameters and improve the efficiency of cryopreservation in a human sperm bank. Basal semen parameters of 180 samples were evaluated in the first stage, and a multiple logistic regression analysis involving a backward elimination selection procedure was applied to select independent predictors. After a comprehensive analysis of all results, we developed a new model to assess the freezability of sperm. Progressive motility (PR), straight-line velocity (VSL) and average path velocity (VAP) were included in our model. A greater area under the receiver operating characteristic curve was obtained in our model when compared with other indicators. In the second stage of our study, samples that satisfied the new model were selected to undergo freeze-thawing. Compared with the first stage, the rate of good freezability was increased significantly (94% vs 67%, P = 0.003). By determining basal semen quality, we have developed a new model to improve the efficiency of cryopreservation in a human sperm bank.

Treatment of pulmonary sinus cusp-derived ventricular arrhythmia with reversed U-curve catheter ablation / 中国介入心脏病学杂志

Objective To summarize the ablation methods,and to provide experience reference for the treatment of pulmonary since cusp(PSC)-derived ventricular arrhythmia(VA)with ablation. Methods A retrospective analysis of the clinical data of 19 patients undergoing catheter ablation for PSC-derived VA in Cardiac Intervention Therapy Center,The Second Xiangya Hospital of Central South University between January 2013 and March 2016 was conducted. Results Among the 19 patients,PSC-derived VA originated from the lower regions of the pulmonary sinuses,generating from the right,left,and anterior sinuses of the PSC were identified in 5,7,and 7 patients,respectively. Twelve patients with PSC-derived VAs originating from the right and anterior sinuses underwent successful reversed U-curve catheter ablation,while the other 7 patients with arrhythmias originating from the left sinus underwent successful ablation with the conventional method(non-reversed U-curve catheter ablation). All the patients were followed-up for 6 to 31 months,and no recurrence of VA or complications were recorded. Conclusions Reversed U-curve catheter ablation is suitable for VA originating from the right and anterior PSCs,while conventional ablation can be used for those originating from the left PSCs.

Mechanistic study on the pharmacokinetic process of salidroside in hypoxic rats / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of hypoxia on the pharmacokinetic process of salidrosidein rats and to explore its underlying mechanisms. METHODS The Caco-2 cell monolayerwas exposed to 1% oxygen (O2) concentration for 24 h to build the hypoxiccell model. The transportation mode of salidroside was investigated with the aid of this hypoxia model by detecting the apparent permeability coefficient(Papp). Healthy Sprague Dawley (SD) rats were exposed to 9% O2 for 72 h for the construction of hypoxic rat model. Liver sample was subsequently collected from the hypoxic rats with an aim to identify enzymes responsible for salidroside metabolism. The expression levels of sali?droside-transporting and salidroside-metabolizing enzymes, including Sodium-dependent glucose cotrans?porters (SGLT1), β-glucosidase (GBA3)and sulfotransferase (SULT2A1), were thereafter detected by RT-PCR and Western blot. The metabolic activity of GBA3 and SULT2A1 was monitored by rat liver microsome incubation.In addition, the renal function of rats under hypoxia was assessed by detecting concentrations of blood urea nitrogen and creatinine. RESULTS The AUC and t1/2 values of salidroside in hypoxic rats were more than doubled, while the in vivo clearance was significantly reduced. Mechanistic study demonstrated that the PappA- B/PappB- A eualsto 10.3, indicating the potential active transport of salidrosile. The expression of SGLT1 and GBA3 was significantly decreased, which indicated a reduced metabolism of salidroside under hypoxia. Moreover, rat under hypoxia was found to suffer from renal dysfunction, with an abnormal value of blood urea nitrogen. CONCLUSION Due to the reduced metabolism and the abnormal renal function under hypoxia, the systemic exposure of salidroside in rats was signifi?cantly enhanced.

Inhibitory effects of lapachol on rat C6 glioma in vitro and in vivo by targeting DNA topoisomeraseⅠ and topoisomeraseⅡ / 中国药理学与毒理学杂志

OBJECTIVE Lapachol is a natural naphthoquinone compound that possesses extensive biological activities. The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo, as well as the potential mechanisms. METHODS The antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats. The effects of lapachol on C6 cell proliferation, apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/ phenazinemethosulfate (PMS) assay, hoechst 33358 staining, annexinⅤ-FITC/PI staining, and comet assay. Effects of lapachol on topoisomerase I (TOP I) and topoi?somerase Ⅱ (TOP Ⅱ) activities were detected by TOP Ⅰ and TOP Ⅱ mediated supercoiled pBR322 DNA relaxation assays and molecular docking. TOPⅠ and TOPⅡ expression levels in C6 cells were also determined. RESULTS High dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats (P<0.05). It was showed that lapachol could inhibit proliferation, induce apoptosis and DNA damage of C6 cells in dose dependent manners. Lapachol could inhibit the activities of both TOPⅠ and Ⅱ. Lapachol-TOPⅠ showed relatively stronger interaction than that of lapachol-TOPⅡ in molecular docking study. Also, lapachol could inhibit TOPⅡ expression levels, but not TOPⅠ expression levels. CONCLUSION These results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro, which might be related with inhibiting TOPⅠ and TOPⅡ activities, as well as TOPⅡ expression.

Glucuronidation is the dominating in-vivo metabolism pathway of herbacetin:elucidation of herbacetin pharmacokinetics after intravenous and oral administration in rats / 中国药理学与毒理学杂志

OBJECTIVE To map a comprehensive metabolic pathway of herbacetin in rats, specifically, to elucidate the biotransformation of herbacetin in vivo and to simultaneously monitor the pharmacokinetic process of both parent drug and its major metabolites. METHODS liquid chromatography/ion trap mass spectrometry (LC/MSn) and ultra-liquid chromatography coupled with mass spectrometry (UPLC/MS) were combined in the current study for qualitative and quantitative determinations of herbacetin and its metabolites in bile, urine and feces after both oral and intravenous administration of herbacetin to rats. Enzyme kinetic studies on the intestinal and hepatic metabolism of herbacetin were further conducted to elucidate metabolic profiles of herbacetin in rat tissues and organs. Additionally, plasma concentration profiles of herbacetin and its metabolites in rats were obtained to characterize the overall pharmacokinetic behavior of herbacetin. RESULTS It was found that herbacetin was excreted primarily from rat urine in the form of glucuronide-conjugations. Subsequent in vitro enzyme kinetic studies and in vivo pharmacokinetic investigations suggested an extensive hepatic metabolism of herbacetin and the high exposure of herbacetin- glucuronides in systemic circulation. The clearance, half- life and bioavailability of herbacetin in rats were determined as (16.4±1.92)mL·kg-1·min-1, (11.9±2.7)min, and 1.32%, respectively. On basis of these findings, a comprehensive metabolic pathway of herbacetin in rats was composed. In addition, a physiology based pharmacokinetic (PBPK) model was successfully developed with the aid of the GastroPlus to simulate the pharmacokinetic process of herbacetin in rats. Application of the PBPK modeling can provide a useful starting point to understand and extrapolate pharmacokinetic parameters among different species, populations, and disease states. CONCLUSION After oral administration, herbacetin was subjected to colonic degradation and extensive first pass metabolism, with glucuronidation as its dominating in vivo metabolic pathway.

Pharmacokinetics and pharmacodynamics of cisatracurium in children undergoing cleft lip or cleft palate repair surgery / 中国药理学与毒理学杂志

OBJECTIVE The aim of the study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) profile of cisatracurium in 0-2 years and 2-5 years old children patients with cheilopalatognathus, to find if there are some connections between the different muscle relaxation action and different PK procedure . METHODS 14 children patients were divided into two groups, ≤2 years and 2-5 years group, venous samples were taken before injection of a 0.15 mg·kg- 1 dose of cisatracurium and then at 2, 5, 10, 30, 60, 90, and 120 min. Cisatracurium plasma concentrations were determined by ultra- performance liquid chromatography/electrospray ionization/triple quadrupole tandem mass spectrometer system (UPLC/MS/MS). The degree of neuromuscular block was measured by train of four (TOF) testing. An indirect PK-PD link model with a sigmoid Emax model was established using Win Nonlin software. The model were applied to PK and PD data analysis, respectively. RESULTS The TOF monitor parameters showed that cisatracurium works very quickly, the onset time were (2.64± 0.93) min and (2.59 ± 0.90) min for ≤2 years and 2- 5 years group respectively. Young children ≤2 years have longer muscle blocking duration time (62.5 ± 6.01 min vs 53.86 ± 12.18 min) and slower recovery index (32.14±7.10 min and 27.43±10.63 min) than those children in group of 2-5 years. More children ≤2 years have postoperative complication than that in 2-5 children. PK parameters showed that there were no statistical differences in blood concentration and pharmacokinetic parameters. While the concentration of cisatracurium in muscle site calculated by using PK/PD model were higher and longer for ≤2 year children than that of 2-5 year children. This means that cisatracurium could stay at high concentration for a longer time in younger children' muscle tissue. CONCLUSION As a result young children tend to have postoperative complications related to slower muscle recovery action and increased concentration in skeletal muscle. So more careful observation and monitor are needed for younger children, our study could be of use in clinical practice for the administration of cisatracurium to children patients.

Analysis of the key networks, metabolic pathways, and regulation substances of hypoxia based on the omics and zebrafish model / 中国药理学与毒理学杂志

OBJECTIVE Hypoxia is associated with many complicated pathophysiological and biochemical processes that integrated and regulated via the key gene, protein and endogenous metabolite levels. Up to date, the exact molecular mechanism of hypoxia still remains unclear. In this work, we further explore the molecular mechanism of hypoxia and adaption to attenuate the damage in zebrafish model that have potential to resist hypoxic environment. METHODS The hypoxic zebrafish model was established in different concentration of oxygen with 3%,5%,10%,21% in water. The brain tissue was separated and the RNA-seq was used to identify the differentially expressed genes. The related endogenous metabolites profiles were obtained by LC-HDMS, and the multivariate statistics was applied to discover the important metabolites candidates in hypoxic zebrafish. The candidates were searched in HMDB, KEGG and Lipid Maps databases. RESULTS The zebrafish hypoxic model was successfully constructed via the different concentration of oxygen, temperature and hypoxic time. The activities of the related hypoxic metabolic enzymes and factors including HIF-1a, actate dehydrogenase (LDH) and citrate synthase (CS) were evaluated. Significant differences (P<0.05 and fold change >2) in the expression of 422 genes were observed between the normal and 3% hypoxic model. Among them, 201 genes increased depended on the lower concentration of oxygen. 53 metabolites were identified that had significant difference between the hypoxia and control groups (P<0.05, fold change>1.5 and VIP>1.5). The ten key metabolites were increased gradually while six compounds were decreased. The endogenous hypoxic metabolites of phenylalanine, D-glucosamine-6P and several important lipids with the relevant hub genes had similar change in hypoxic model. In addition, the metabolic pathways of phenylalanine, glutamine and glycolipid were influenced in both the levels of genes and metabolites. CONCLUSION The up- regulation of phenylalanine, D- glucosamine- 6P and lipid may have further understanding of protective effect in hypoxia. Our data provided an insight to further reveal the hypoxia and adaptation mechanism.

A validated UPLC–MS/MS method for simultaneous determination of imatinib,dasatinib and nilotinib in human plasma / 药物分析学报

A sensitive, rapid, simple and economical ultra-performance liquid chromatography–tandem mass spectro-metric method (UPLC–MS/MS) was developed and validated for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma using gliquidone as internal standard (IS). Liquid-liquid extraction method with ethyl acetate was used for sample pre-treatment. The separation was performed on an Xtimate Phenyl column using isocratic mobile phase consisting of A (aqueous phase: 0.15% formic acid and 0.05% ammonium acetate)and B(organic phase:acetonitrile)(A:B=40:60,v/v).The flow rate was 0.25 mL/min and the total run time was 6 min. The multiple reaction monitoring (MRM) transitions, m/z 494.5→394.5 for imatinib, 488.7→401.5 for dasatinib, 530.7→289.5 for nilotinib and 528.5→403.4 for IS, were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity and good linearity over the concentration range of 2.6–5250.0 ng/mL for imatinib, 2.0–490.0 ng/mL for dasatinib,and 2.4–4700.0 ng/mL for nilotinib.The method showed acceptable results on sensitivity,specificity, recovery, precision, accuracy and stability tests. This UPLC–MS/MS assay was successfully used for human plasma samples analysis and no significant differences were found in imatinib steady-state trough concentra-tions among the SLC22A5?1889T>C or SLCO1B3 699G>A genotypes(P>0.05).This validated method can provide support for clinical therapeutic drug monitoring and pharmacokinetic investigations of these three tyrosine kinase inhibitors(TKIs).