Table of Content

Volume 26 Issue 6
26 June 2021

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Hyperoside ameliorates the injury of heart and thoracic aorta in mice with myocardial infarction by regulating autophagy pathway

YANG Yongkang, LI Jing, RAO Tingcai, ZHANG Junyan

2021, 26(6):  601-608.  doi:10.12092/j.issn.1009-2501.2021.06.001

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AIM: To explore the protection of Hyperoside (Hyp) on heart and thoracic aorta in mice with myocardial infarction (MI) as well as its potential mechanism.  METHODS: The MI model was generated by a ligation on the left anterior descending coronary artery. The mice were then randomly divided into sham group (saline, 0.1 mg/10 g), model group (saline, 0.1 mg/10 g), Hyp-low, moderate and high concentration groups (Hyp, 9, 18 and 36 mg/kg), Fosinopril group (Fosinopril, 15 mg/kg), and Hyp-high concentration + 3-MA group (Hyp, 36 mg/kg; 3-MA, 30 mg/kg). The mice were treated with Hyp and Fosinopril for two weeks, and then the changes of heart weight versus body weight (HW/BW), electrocardiogram (ECG) remodeling, cardiac function, oxidative stress level in serum, thoracic aorta remodeling and endothelial function were investigated. RESULTS: In the model group, the HW/BW was elevated (P<0.01). The width of QRS in ECG was elevated, as a company with the reduction of height of QRS (P<0.01). The echocardiography assay showed that the cardiac cavity was enlarged (P<0.01). The oxidative stress level in serum was enhanced (P<0.01). The thoracic aorta remodeling and endothelial dysfunction became more serious (P<0.01). After being treated with different concentrations of Hyp and fosinopril for two weeks, the changes above were reserved (P<0.05, P<0.01). Co-treatment with 3-MA, an autophagy inhibitor, suppressed the protective effects of Hyp on impaired hearts and vessels (P<0.05, P<0.01). CONCLUSION: Hyp has protective prospects on injured heart and thoracic aorta remodeling, as well as endothelial dysfunction in MI mice; 3-MA, an autophagy inhibitor, can reverse the cardiovascular protection of Hyp. The mechanism may be explained that Hyp can elevate autophagy level in heart, which further weaken oxidative injury in MI mice.

Anti-FGF-2 nanobody inhibits rat corneal angiogenesis induced by alkali burn 

LU Ruibin, ZHAO Hui, XIE Qiuling, HU Lu, GUO Chaowan, PEI Yunlin, XIONG Sheng

2021, 26(6):  609-615.  doi:10.12092/j.issn.1009-2501.2021.06.002

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AIM: To investigate the possible use of anti-FGF-2 nanobody for the treatment of pathological neovascularization.  METHODS: SD rats were divided into a sham operation group, a control group (3 mm diameter circular filter paper soaked with 1 mol/L NaOH solution was applied to the central part of the cornea of rats for 30 s to prepare the rat model of alkali-burn angiogenesis) and a treatment group (treated with a drop of 3 mg/mL anti-FGF-2 nanobody 7 days after the operation. Repeat application 3x/day for 14 days). Corneal angiogenesis was measured by stereoscopic microscopy and CD31 immunohistochemical staining. The mRNA and protein expression levels of VEGF and FGF-2 were detected by quantitative fluorescence PCR (qPCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry.RESULTS: (1) Blood vessel: The area of the treatment group was significantly reduced compared with the model group, and the vascular lumen was narrower (P<0.05). The difference was the most significant after 14 days of drug intervention; (2) Expression level of FGF-2 mRNA and protein: the model group had similar results to the treatment group (P>0.05); (3) Expression levels of VEGF mRNA and protein: The treatment group was significantly higher than the model group (P<0.05). In addition, the expression of VEGF also increased significantly in the continuous administration of the sham operation group. CONCLUSION: Anti-FGF-2 nanobody can be used for the treatment of angiogenesis. However, the expressions of VEGF will compensatorily increase after blocking FGF-2 in normal or pathological rats. 

Effects of down-regulating lncRNA LINC00176 on cisplatin resistance and autophagy in lung cancer A549/DDP cells

CUI Hua, YAN Hongxia, YIN Mei

2021, 26(6):  616-623.  doi:10.12092/j.issn.1009-2501.2021.06.003

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AIM: To study the effects and mechanism of down-regulating lncRNA LINC00176 on cisplatin resistance and autophagy in lung cancer A549/DDP cells. METHODS: The qRT-PCR method was used to determine the expression changes of LINC00176 in normal bronchial epithelial 16HBE cells and lung cancer A549, A549/DDP, NCI-H1299 and SK-MES-1 cells. A549/DDP cells were divided into Control group, si-NC group, and si-LINC00176 group, si-LINC00176+ Anti-miR-NC group, and si-LINC00176+ Anti-miR-138-5p group. MTT experiment detected the half inhibitory concentration (IC50) of cisplatin on A549/DDP. Flow cytometry was used to measure cell apoptosis. Western blot was used to determine the protein expression of LC3-I, LC3-II, Beclin 1, C-Caspase-3. The luciferase reporter system was used to identify the targeting relationship between LINC00176 and miR-138-5p. RESULTS: The expression level of LINC00176 in A549, A549/DDP, NCI-H1299 and SK-MES-1 cells was higher than that in 16HBE cells (P<0.01). The expression level of LINC00176 in A549/DDP cells was significantly higher than that in A549 cells (P<0.01). Compared with the Control and si-NC groups, the IC50 of A549/DDP cells in the si-LINC00176 group was significantly reduced (P<0.01), the expression of LC3-II/LC3-I, Beclin 1 protein was significantly reduced (P<0.01), the apoptosis rate, and the expression of C-Caspase-3 protein and miR-138-5p were significantly increased (P<0.01). LINC00176 directly bound to miR-138-5p. Compared with the si-LINC00176+Anti-miR-NC group, the IC50 of A549/DDP cells in the si-LINC00176+Anti-miR-138-5p group was significantly increased (P<0.01), and the expression of LC3-II/LC3-I and Beclin 1 protein was significantly increased (P<0.01), the apoptosis rate and C-Caspase-3 protein expression were significantly reduced (P<0.01).CONCLUSION: Down-regulating lncRNA LINC00176 could inhibit cisplatin resistance, inhibit autophagy and induce apoptosis in lung cancer A549/DDP cells by targeting and up-regulating miR-138-5p.

Effects of lycium barbarum polysaccharides on cis-dichlorodiamineplatinum (II)-induced apoptosis in mouse testis sertoli cells TM4#br#

LIU Yunfan, DU Yuemei, LIU Xiaoyi, GAO Liping

2021, 26(6):  624-630.  doi:10.12092/j.issn.1009-2501.2021.06.004

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AIM: To explore the effect of Lycium barbarum polysaccharides (LBP) on cis-dichlorodiamineplatinum (II) (CDDP)-induced apoptosis in mouse testis sertoli cells TM4 and its possible mechanism.  METHODS: TM4 cells were cultured in vitro, the effect of LBP on the survival rate of TM4 cells induced by CDDP was detected by MTT assay, the effect of LBP on the expression of apoptosis related genes Bcl-2, Bax and Caspase-3 in TM4 cells induced by CDDP was detected by Western blot, and the change of cell apoptosis rate was detected by flow cytometry. RESULTS: Compared with control group, TM4 cell apoptosis was significantly increased in CDDP group, the expression of anti-apoptotic gene Bcl-2 and pro-caspase-3 in proenzyme state were significantly decreased, the expression of pro-apoptotic gene Bax and caspase-3 were significantly increased. Compared with CDDP group, the apoptosis of TM4 cells in CDDP+LBP group was significantly decreased, the expression levels of anti-apoptotic genes Bcl-2 and Pro-Caspase3 were significantly increased, the expression levels of pro-apoptotic gene Bax and Caspase-3 were significantly decreased. CONCLUSION: LBP, by acting on CDDP induced TM4 cells, can inhibit CDDP induced TM4 cell apoptosis by enhancing the expression of Bcl-2 and inhibiting the expression of Bax and Caspase-3, thus alleviating the damage caused by CDDP to TM4 cells.

Influence of donor and recipient CYP3A5 genotype on tacrolimus trough concentrations in the early stage after liver transplantation and its clinical significance

WU Yi, FANG Fang, CHEN Ying, Fan Junwei

2021, 26(6):  631-639.  doi:10.12092/j.issn.1009-2501.2021.06.005

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AIM: To analyze the influence of donor and recipient CYP3A5 genotype on tacrolimus trough concentrations in the early stage after liver transplantation and its clinical significance under therapeutic drug monitoring (TDM) strategy retrospectively.  METHODS: A total of 125 patients undergoing liver transplantation in Shanghai General Hospital from January 2015 to March 2019 were involved in this study. Clinical pharmacology parameters and liver function indexes from 1 to 28 days after operation, the occurrence of new onset diabetes mellitus (NODM) was collected. Donor and recipient cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) gene rs776746 locus were genotyped by RT-PCR technology.RESULTS: Median trough concentration (Ctmed) and maximum trough concentration (Ctmax)of tacrolimus in the first week after liver transplantation were (8.3±7.0) ng/mL, (11.2±12.9) ng/mL, respectively. Patients were divided 4 subgroups according to CYPA35 rs776746 genotype: recipients with AA/AG genotype carrying AA/AG genotype donor, recipients with AA/AG genotype carrying GG genotype donor, recipients with GG genotype carrying AA/AG genotype donor and recipients with GG genotype carrying GG genotype donor. There was significant difference of Ctmed and Ctmax in each subgroup (P<0.01). ROC curve analysis showed that the AUC of tacrolimus Ctmax in predicting NODM was 0.716 8 (P=0.000 5) and optimal diagnostic threshold concentration was 14.4 ng/mL. Ct med couldn't predict NODM (P=0.193 6). Preoperative blood glucose level (OR: 5.076, P=0.043), preoperative total cholesterol level (OR: 3.752, P=0.022), glucocorticoid therapy after operation (OR: 12.846, P=0.015) and tacrolimus Ctmax (OR: 17.796, P=0.014) were independent risk factors of NODM. Donor and recipient CYP3A5 genotype had a marked impact on Ctmax. The proportion of patients with Ctmax greater than or equal to 14.4 ng/mL in each subgroup were 14.70%(5/34), 33.33%(12/36), 61.11%(11/18) and 78.57 (22/28), there were significant differences among the four groups (P<0.000 1). CONCLUSION: To combine TDM strategy and donor and recipient CYP3A5 genotype will be helpful to guide tacrolimus administration and reduce the incidence of NODM in liver transplantation.

Analysis of influence factors of voriconazole trough concentration in patients with hematopoietic stem cell transplantation

PENG Min, HUANG Panhao, DENG Yinhua, LIU Wen, LI Wei, YU Zhen, XIA Qing, XIE Yueliang

2021, 26(6):  640-646.  doi:10.12092/j.issn.1009-2501.2021.06.006

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AIM: To study the distribution characteristics of steady-state trough concentration (Cmin) of voriconazole in Chinese patients with hematopoietic stem cell transplantation, and to explore the factors that affect its steady-state Cmin. METHODS: A retrospective analysis of 72 patients using voriconazole, the steady-state Cmin of voriconazole in 226 serum samples were determined, and clinical data of the patients were collected. SPSS 22.0 software was used to analyze the correlation between voriconazole steady-state Cmin and covariates (gender, age, weight, white blood cell count, neutrophil count, C-reactive protein, albumin, liver and kidney function, drug interactions, etc.). RESULTS: The average Cmin of voriconazole was (1.84±0.09) μg/mL, which accounted for 84.5% of the effective blood concentration range. Age, albumin, total bilirubin, and CRP had a significant effect on the blood concentration of voriconazole. Combined use of hormones did not reduce the patient's voriconazole Cmin. It was found that there were significant differences in aminotransferase, alanine aminotransferase and direct bilirubin before and after voriconazole administration. CONCLUSION: There are many factors that affect the blood concentration of voriconazole. Blood concentration monitoring should be enhanced to improve the effectiveness of voriconazole treatment and reduce side effects of drugs.

Analysis of the efficacy of torasemide combined with levocarnitine in the treatment of chronic heart failure

XU Yonghua, SHI Xianghong

2021, 26(6):  647-652.  doi:10.12092/j.issn.1009-2501.2021.06.007

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AIM: To explore the efficacy of torasemide combined with levocarnitine in the treatment of chronic heart failure (CHF).  METHODS: From July 2018 to July 2020, 75 patients with CHF were recruited and randomly assigned into the control group (37 cases) and the study group (38 cases) according to the random number table method. The control and study groups were treated with levocarnitine and the combination of levocarnitine and torasemide, respectively.  The clinical efficacy of the two groups was evaluated. The ventricular remodeling indexes and 6-minute walk test (6MWT) distance were compared between the two groups before and after treatment. The serum levels of serum galectin-3 (Gal-3), interleukin-33 (IL-33), hypersensitive C-reactive protein (hs-CRP), and the plasma concentrations of N terminal pro B type natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) were determined. RESULTS: (1) After treatment, the total clinical effective rate of the study group (92.11%) was  higher than that of the control group (72.97%) (P<0.05). (2) The diastolic interventricular septal thickness (IVST) and diastolic left ventricular posterior wall thickness (LVPWT) were decreased following the treatment in both groups (P<0.05), whereas the treatment led to the increases of the left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF) in both groups (P<0.05). Compared with those in the control group, IVST and LVPWT in the study group were lower (P<0.05), and LVMI and LVEF were higher (P<0.05). (3) The levels of serum Gal-3, IL-33 and hs-CRP in the two groups were decreased after treatment (P<0.05); compared with those in the control group, the levels of serum Gal-3, IL-33 and hs-CRP were reduced to a greater extent in the study group (P<0.05). (4) Compared with that before treatment, 6MWT distance in both groups increased after treatment (P<0.05); the improvement in the study group was more significant relative to those in the control group (P<0.05). (5) Compared with before treatment, the expression levels of plasma NT-proBNP and BNP in the two groups were decreased after treatment (P<0.05); the reduction of plasma NT-proBNP and BNP levels in the study group was greater than the control group (P<0.05). CONCLUSION: Torasemide combined with levocarnitine is more effective than levocarnitine monotherapy in the treatment of CHF and can significantly improve ventricular remodeling index and motor function, reduce serum inflammation, and enhance cardiac function with definite curative effect.

Establishment and application of DUE criteria for human albumin in pediatric patients

WANG Yuanyuan, HONG Yu, ZHANG Lei, YIN Fangxiong, LEI Ting, ZHU Xi

2021, 26(6):  653-661.  doi:10.12092/j.issn.1009-2501.2021.06.008

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AIM: To provide reference for rational application of human albumin in pediatrics.  METHODS: On the basis of the human albumin instructions, refer to the relevant guidelines and literature on the use of human albumin in pediatrics, draft the first draft of the Drug Use Evaluation standard and list it into an expert consultation questionnaire, which is finalized through two rounds of expert discussions. This standard was used to retrospectively evaluate the medical records of hospitalized children who used human albumin in the Pediatric Department of our hospital from June 2019 to January 2020. RESULTS: The standards established in this study included three primary indicators of medication indications, medication process, medication results and 6 secondary indicators of indications, contraindications, treatment process monitoring, drug application, efficacy, and adverse reactions. A total of 269 medical records of hospitalized children were included in this evaluation, of which newborns accounted for the highest proportion (56.88%). 229 cases met the indications, accounting for 85.13%; 251 cases were tested for serum albumin concentration before medication, accounting for 93.31%; after medication, the relevant indicators reached the standard, and the symptoms improved significantly in 226 cases, accounting for 84.01%. CONCLUSION: The Drug Use Evaluation criteria for pediatric human albumin established by our hospital has strong practicability, which is conducive to discovering problems or deficiencies in clinical medication and promoting rational clinical use of medication.

Effects of gut microbiota on pharmacokinetics and its consideration in the evaluation of the consistency of quality and efficacy of generic drugs

ZHENG Binjie, LIU Na, ZENG Xiangchang, HUANG Xinyi, CHEN Lulu, OU-YANG Dongsheng

2021, 26(6):  662-671.  doi:10.12092/j.issn.1009-2501.2021.06.009

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Generic drugs account for more than 95% of the chemicals market in China, and their quality is directly related to the efficacy and safety of the people. The bioequivalence evaluation with pharmacokinetic parameters as the end point is the main content of the consistency evaluation of the quality and efficacy of generic drugs. Gut microbiota is considered to have an important influence on pharmacokinetics. This article reviewed the influence of gut microbiota on pharmacokinetics and analyzed its potential significance in the evaluation of the consistency of quality and efficacy of generic drugs. 

Research progress of relevance between cholecystokinin and depression 

WANG Yeqing, WANG Yuhong, LIU Jian, ZHAO Hongqing, ZOU Manshu

2021, 26(6):  672-679.  doi:10.12092/j.issn.1009-2501.2021.06.010

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Depression is a mental illness characterized by significant and lasting depression. Recent studies have found that cholecystokinin, as a small brain-gut peptide molecule, is widely distributed in the central nervous system and enteric nervous system. In order to further clarify the relationship between CCK and the pathogenesis of depression, this article reviews the effect of CCK in depression, including HPA axis, synaptic function and circuit mechanism, etc.

Bruton tyrosine kinase inhibitors and refractory mantle cell lymphoma

LOU Anqi, YU Junxian, CHENG Zizhao, SU Qiang

2021, 26(6):  680-686.  doi:10.12092/j.issn.1009-2501.2021.06.011

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Bruton tyrosine kinase (BTK) is a key mediator of B-cell receptor signalling cascade and an effective target for treating mantle cell lymphoma (MCL). BTK inhibitors play a critical role in the treatment of MCL. Here we introduced the mechanism of action of BTKI in the treatment of MCL. Though generally well prescribed, Ibrutinib, as the first BTKI, still has limitations of toxicity and resistance. New BTK inhibitors, such as zanubrutinib, acalabrutinib and orelabrutinib, are designed to improve on the safety and efficacy as first-generation BTK inhibitors. Comparing the similarities and differences of the two generations of BTKI in structure and function provides a basis for better clinical application of BTKI. On November 15, 2019, FDA approved zanubrutinib for marketing for patients with adult mantle cell lymphoma. Compared with Ibrutinib, zanubrutinib was found with higher target selectivity, longer-lasting inhibition, fewer adverse reactions, and better patient benefit. Zanubrutinib provides a viable treatment option for patients with r/r MCL. At the same time, it is also actively carrying out clinical researches on the treatment of other B-cell lymphomas. It is a very promising targeted drug.

Disease progression model for Alzheimer's disease and its research progress

ZHANG Ningyuan, ZHENG Xijun, XU Ling, LIU Hongxia, ZHENG Qingshan

2021, 26(6):  687-694.  doi:10.12092/j.issn.1009-2501.2021.06.012

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Alzheimer's disease (AD) is a degenerative neurological disease with unclear pathogenesis. The disease progress/trajectory of AD patients can be adequately described by establishing quantitative pharmacological disease progression model. Integrating biomarker information into the model can provide more insight to understand the potential pathological mechanisms and facilitate the optimization of future trial design. Several empirical and semi-mechanism disease progression models have been published. This mini-review is expected to offer some references for the further AD clinical research and new drug development.

Analysis of ethical issue in the application of artificial intelligence medical devices

LIU Xing, WU Ying, LI Yang, WANG Xiaomin

2021, 26(6):  695-699.  doi:10.12092/j.issn.1009-2501.2021.06.013

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With the rapid development of artificial intelligence in the medical field, artificial intelligence medical devices not only improve the efficiency of diagnosis and treatment which bring great convenience to patients, but also initiate ethical issues of medical safety, data security, algorithm bias and individual autonomy, etc. By proposing enhanced regulation and quality control, soften bias, increased transparency and improved technology as the breakthrough point, plus more respect for the autonomy of patients and doctors, this paper explored in depth the ethical issues of artificial intelligence theory and practice in hope of providing referential ideas for the regulation and supervision of artificial intelligence medical device.

Research progress and mechanism of mesenchymal stem cells in the treatment of autoimmune diseases

LU Ming, YIN Xiaoyu, ZHANG Zhiqing

2021, 26(6):  700-706.  doi:10.12092/j.issn.1009-2501.2021.06.014

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Mesenchymal stromal/stem cells (MSCs) are a type of pluripotent stem cells capable of differentiating into osteoblasts, chondrocytes, adipocytes, and cardiomyocytes. MSCs can be obtained from a variety of sources, including bone marrow, adipose tissue, dental pulp, The umbilical cord and the placenta, peripheral blood, skin, and synovial fluid. Studies at home and abroad have shown that MSCs have important research value and great application potential in the treatment of a variety of autoimmune diseases. MSCs have opened a new door for the medical community, and triggered an upsurge of research on MSCs transplantation for autoimmune disease trials. However, in view of the limitations of current MSCs, the safe application of MSCs in the treatment of autoimmune diseases still requires larger and more in-depth trial and clinical data support. In this paper, we will review the therapeutic effect of MSCs in autoimmune diseases and the possible mechanism of its effect.

Therapeutic drug monitoring in the individualized administration of cyclosporin A: Application and research progress

WANG Hui, XU Xiaofang, LI Rong

2021, 26(6):  707-713.  doi:10.12092/j.issn.1009-2501.2021.06.015

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Cyclosporine A (CsA) is a kind of cellular immunosuppressant, which is widely used in organ transplantation, blood diseases and autoimmune diseases. Because of its poor oral bioavailability, individual differences and prone to adverse reactions, so clinical therapeutic drug monitoring (TDM) and individual administration of CsA can ensure its safety and effectiveness. However, the treatment window of CsA is narrow, and its blood concentration is affected by age, sex, diet, drug factors, genetic factors and so on. Therefore, combined with the literature reports at home and abroad, this paper reviews the research on the application of TDM and individual drug administration of CsA, in order to provide more valuable reference for clinical safe and rational drug use.

Exploration of screening criteria for healthy volunteers in human bioequivalence clinical trials

SUN Yuchen, LIU Yinhui, ZHANG Xian, YUAN Tong, JING Mengyao, ZAHNG Xinyu, YANG Jin

2021, 26(6):  714-720.  doi:10.12092/j.issn.1009-2501.2021.06.016

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Human bioequivalence testing is an important part of evaluating the quality of a formulation. Although these drugs have a large amount of safety data and clinical application data, they may still have ethical risks in healthy subjects. The definition of healthy volunteers, the general inclusion and exclusion criteria, auxiliary inclusion and exclusion criteria, and inclusion and exclusion criteria considering drug specificity are summarized. The basis for determining whether abnormal test values are clinically significant when screening healthy subjects and the considerations for improving the screening pass rate are discussed. It is expected to provide useful reference for the smooth implementation of human bioequivalence testing.