Table of Content

Volume 27 Issue 9
27 September 2022

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PI3K/Akt/FOXO3a signaling pathway inducing protective autophagy promotes acquired lung adenocarcinoma resistance remodeling to DDP

ZHOU Huan, XU Ming, LI Bo, LIU Chunying, WANG Chun

2022, 27(9):  961-970.  doi:10.12092/j.issn.1009-2501.2022.09.001

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AIM: To investigate the mechanism of acquired resistance remodeling to DDP (named cisplatin) by comparing the level of autophagy between the parental and DDP-resistant cells.  METHODS: Human lung adenocarcinoma A549 (parental cells) and A549/DDP cells (DDP-resistant cells) were treated with different concentrations of DDP, the drug resistance index (RI) was determined by CCK-8 assay and the autophagy associated proteins, like Beclin 1, LC3Ⅱ and p62 were measured by Western blot. A549 and A549/DDP cells were treated with 10 μmol/L DDP (about IC50 of A549 cells), the cell viability was determined by CCK-8 assay, the autophagy and apoptosis associated proteins (including Beclin 1, LC3Ⅱ, p62, Bcl-2, Bax and cleaved-caspase 3) were measured by Western blot, and the activity of transcription factor FOXO3a and its subcellular localization were detected by Western blot and laser confocal scanning microscopy. Finally, the autophagy inhibitor Baflomycin A1 (Baf A1) and the protein kinase inhibitor of PI3K/Akt signaling pathway were co-treated with DDP respectively to test the mechanism of drug resistance. RESULTS: Compared with the parental A549 cells, the acquired resistant A549/DDP cells showed DDP-resistance and higher level of basal autophagy. More survival count of A549/DDP cells than that of A549 cells in the same environment stress of 10 μmol/L DDP. 10 μmol/L DDP induced A549 cells apoptosis by down-regulated Bcl-2, and increased Bax and cleaved-caspase 3, which followed the inhibition of PI3K/Akt signaling pathway and up-regulated the expression level of transcription factor FOXO3a. While the same concentration of DDP activated A549/DDP cells autophagy by up-regulated Beclin 1 and LC3Ⅱ, down-regulated p62, which followed the inhibition of PI3K/Akt signaling pathway and inhibited the phosphorylation of FOXO3a. CONCLUSION: DDP induces apoptosis by up-regulating the transcription factor FOXO3a via inhibiting the PI3K/Akt/FOXO3a signaling pathway in A549 cells, while activating autophagy by inducing the phosphorylation of FOXO3a via inhibiting the PI3K/Akt/FOXO3a signaling pathway in A549/DDP cells.

Tyrosine phosphorylation of TRPM3 ion channel mediates diabetes-induced heat hyperalgesia

YANG Li, BAI Huhu, HE Shasha, JIN Yue, LIU Chengsong

2022, 27(9):  971-976.  doi:10.12092/j.issn.1009-2501.2022.09.002

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AIM: To investigate the relationship between TRPM3 and diabetes-induced painful peripheral neuropathy.  METHODS: Treptozotocin (STZ) was intraperitoneal injected for establishment of diabetic mice model, behavioral tests of paw withdraw thresholds (PWTs) and paw withdraw latencies (PWLs) were conducted; Protein contents and tyrosine phosphorylation levels of TRPM3 were detected by immunoprecipitation and immunoblotting. RESULTS: The PWTs and PWLs in diabetic mice were significantly reduced; TRPM3 tyrosine phosphorylation in the dorsal root ganglia (DRG) of diabetic mice significantly increased compared with control, while the protein expression shows no statistical significance; Enhanced tyrosine phosphorylation of TRPM3 by BPV can evoke heat hyperalgesia in intact mice; Reduce of the tyrosine phosphorylation levels of TRPM3 through PP2 significantly alleviates diabetes-induced heat hyperalgesia, without affecting mechanical allodynia. CONCLUSION: The upregulation of tyrosine phosphorylation of TRPM3 plays a key role in heat related painful diabetic peripheral neuropathy.

Population pharmacokinetics of teicoplanin in patients with renal insufficiency

XU Tao, ZHU Suyan, QIU Xiangjun, XU Ping

2022, 27(9):  977-983.  doi:10.12092/j.issn.1009-2501.2022.09.003

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AIM: To analyze the effect of influential factors on the estimation of pharmacokinetic parameters of teicoplanin, this study was proposed to develop the population pharmacokinetic (PPK) model of teicoplanin in patients with renal insufficiency.  METHODS: A total of 66 routine blood teicoplanin concentration monitoring data were collected from 46 cases with renal insufficiency, and a nonlinear mixed effect modeling program was used to establish one-compartment model with Monolix 2021R1 software. Furthermore, 20 routine blood teicoplanin concentration monitoring data were also collected from the other 20 cases with renal insufficiency, and the external validation of the model was performed by goodness-of-fit parameter method. RESULTS: The one compartment model was an appropriate model for simulating the pharmacokinetics of teicoplanin in patients with renal insufficiency. The typical values of apparent volume of distribution and clearance rate were 148.9 L and 0.13 L/h, respectively. Glomerular filtration rate and body weight, instead of other factors, were the primary variables that affected the elimination of teicoplanin in vivo. CONCLUSION: The population pharmacokinetic model of teicoplanin established in the present study was effective and stable, which could also predict the dynamic change of teicoplanin concentration. As a result, the population pharmacokinetic model could provide references for the rational use of teicoplanin in special populations.

Meropenem population pharmacokinetic model for the Chinese elderly established by model-based META analysis

YE Hongbo, SONG Yangyang, XUE Ling, RUI Jianzhong

2022, 27(9):  984-990.  doi:10.12092/j.issn.1009-2501.2022.09.004

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AIM: To build a meropenem population pharmacokinetic model for Chinese elderly through model-based meta-analysis. METHODS: Informations including dosing regimen, sampling times, concentrations, sample size, age, gender, body weight (BW) and creatinine clearance were extracted after the literature were retrieved. The model was built by NONMEM. Stepwise covariate modeling strategy was used for covariates analysis.RESULTS: A two-compartment model was applied to describe meropenem pharmacokinetics. After stepwise covariate modeling, covariates that remained significant in the final model were creatinine clearance (CLcr) on CL and the BW on V1. The stability and predictive performance were confirmed by bootstrapping and visual predictive check. CONCLUSION: A more representative population pharmacokinetics model of meropenem in Chinese elderly patients is built through model-base meta-analysis method.

Associations of POR*28 polymorphisms with tacrolimus stable dose in Chinese kidney transplantation patients

WANG Shuang, LIU jia, ZHANG Yueli

2022, 27(9):  991-997.  doi:10.12092/j.issn.1009-2501.2022.09.005

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AIM: To investigate the correlation between POR*28 single nucleotide polymorphism (SNP) and tacrolimus stable dose in Chinese kidney transplant patients, and to provide reference for the development of individualized dose adjustment programs in this population.  METHODS: A total of 350 Chinese kidney transplant patients were enrolled. CYP3A5*3 and POR*28 genes were detected by Mass ARRAY Analyzer Compac Mass spectrometry in Shenggong Bioengineering (Shanghai) Co., LTD. Serum trough concentration of tacrolimus was determined by ENZYME amplification immunoassay (EMIT). The correlation between the above genotypes and tacrolimus stable dose was analyzed. RESULTS: The frequencies of CYP3A5*3 and POR*28 alleles were consistent with hardy-Weinberg genetic balance. The stable dose in patients with CYP3A5*3 GG genotype was significantly lower than that in patients with AG and AA genotype. Based on stratified analysis of CYP3A5, different POR genotypes were significantly correlated with the stable dose of tacrolimus in CYP3A5 expression and non-expression groups. The mean stable dose of tacrolimus was statistically significant between POR*28 patients with at least one T allele and CC wild-type patients (P=0.003 7 and P=0.003 1). Multiple Regression Analysis showed that CYP3A5*3 and POR*28 explained 36.6%and 1.7%of the individual differences in stable doses of Tacrolimus, respectively. CONCLUSION: CYP3A5*3 and POR*28 genotypes are significantly correlated with tacrolimus stable dose in Chinese kidney transplant recipients, and detection before transplantation will contribute to clinical individualized tacrolimus medication.

Postoperative analgesic effect of low-dose esketamine in patients with thoracoscopic lobectomy

WANG Xin, SUN Heliang, ZHANG Qingwei, LIU Cunming, WANG Zhongyun, YANG Chun

2022, 27(9):  998-1003.  doi:10.12092/j.issn.1009-2501.2022.09.006

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AIM: To observe the analgesic effect of esketamine in patients with thoracoscopic lobectomy. METHODS: Sixty patients scheduled with thoracoscopic lobectomy were randomly divided into group esketamine (ESK, n=30) and group saline (SAL, n=30). Esketamine in ESK group was given 0.2 mg/kg at induction and 0.12 mg·kg-1·h-1 during surgery. SAL group was given the same volume of saline. VAS scores, expression of inflammatory factors, anxiety and depression scores and related adverse reactions of patients were recorded at departure from PACU (T1), 6 h (T2), 24 h (T3), and 48 h (T4) after surgery. RESULTS: No significant difference was found in demographic data between the two groups. Compared with SAL group, the VAS scores of patients in ESK group at T1, T2 and T4 in resting state and T1 in cough state were significant decreased (P<0.05), and the amount of dezocine use was smaller. The patients in ESK group had significantly lower WBC level, but not IL-6, than SAL group. Difference in the postoperative SpO2 alteration and the incidence of adverse reaction including postoperative nausea, vomiting, dizziness and dissociative symptom had no significance between two groups (P>0.05). CONCLUSION: The administration of esketamine can alleviate the acute postoperative pain in patients that received thoracoscopic lobectomy without increasing side effects, and the underlying mechanism may be related to the alleviation of postoperative leukocytosis. 

Efficacy of antiplatelet therapy with ticagrelor monotherapy after short-term double antibody therapy in patients with acute coronary syndrome after PCI

PANG Shengfeng, ZHANG Jing, WU Ningning, LI Ru, CAO Jun, HE Shenghu

2022, 27(9):  1004-1009.  doi:10.12092/j.issn.1009-2501.2022.09.007

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AIM: To observe the clinical efficacy of antiplatelet therapy with ticagrelor monotherapy after short-term double antibody therapy in patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI).  METHODS: A total of 172 patients with ACS who had undergone PCI from October 2018 to April 2022 in our hospital and Subei People's Hospital of Jiangsu Province were selected and divided into three groups according to the patients' medication status: 50 patients in group A (tegretol alone group); 62 patients in group B (aspirin enteric coated tablets + tegretol group); and 60 patients in group C (aspirin enteric coated tablets + clopidogrel hydrogen sulfate group). The patients were observed for postoperative recurrent angina pectoris, in-stent restenosis, revascularization, heart failure, and bleeding. RESULTS: There were no significant differences in postoperative recurrent angina, in-stent restenosis, re-hematologic reconstruction, heart failure, and bleeding between the 3 groups. CONCLUSION: There is no increase in ischemic events, heart failure in patients treated with tegretol antiplatelet therapy alone after a short course of dual antibiotics after PCI and it reduces risk of bleeding.

Effects of sakubatril valsartan combined with dagliflozin in the treatment of patients with HFrEF and the effect on serum cTnⅠ and BNP levels

YANG Sheng, WANG Deguo

2022, 27(9):  1010-1015.  doi:10.12092/j.issn.1009-2501.2022.09.008

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AIM: To investigate the effect of sakubatril valsartan combined with dagliflozin in the treatment of patients with HFrEF and the effect on serum cardiac troponin I (CTnI) and B-type brain natriuretic peptide (BNP) levels.  METHODS: Seventy patients with HFrEF admitted to our hospital from January 2020 to October 2021 were selected and divided, using random number table method, into control group (35 cases, conventional treatment + sakubatril valsartan) and observation group (35 cases, conventional treatment + sakubatril valsartan + dagliflozin). The treatment effect, myocardial markers (serum cTnI, BNP), exercise capacity ( 6 min walking experiment), myocardial remodeling-related indexes ［(left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic internal diameter (LVESD), left ventricular ejection fraction (LVEF)］ and adverse effects were compared between the two groups. RESULTS: The total effective rate of treatment in the observation group was lower than that in the control group (P<0.05), and the difference was not statistically significant (P>0.05); the changing trends of serum BNP and cTnI expressions were the same in the two groups at 3 months and 6 months of treatment, and the serum BNP and cTnI expressions of patients in the observation group were lower than those in the control group (P<0.05); at the end of treatment, the 6 min walk test results of patients in the observation group were better than those in the control group (P<0.05); At the end of treatment, the LVEDd and LVESD values in the observation group were lower than those in the control group, and the LVEF values were higher than those in the control group (P<0.05); the differences were not statistically significant when comparing the total incidence of adverse reactions between the two groups (P>0.05). CONCLUSION: The combination of sakubatril valsartan and dagliflozin is effective for patients with HFrEF, and can effectively regulate serum cTnI and BNP levels with low adverse reactions.

Advances in the research and clinical application of the third generation EGFR TKIs in the treatment of non-small cell lung cancer

ZHANG Kexin, JIA Wenjing, CUI Jiawen, AO Luyao, ZHOU Fang, WANG Guangji, LIU Jiali

2022, 27(9):  1016-1030.  doi:10.12092/j.issn.1009-2501.2022.09.009

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Epidermal growth factor receptor (EGFR) is one of the most common targeted oncogenes in non-small cell lung cancer (NSCLC). The third-generation EGFR tyrosine kinase inhibitors (TKIs) have become the standard treatment for metastatic or recurrent NSCLC patients harboring EGFR positive or concomitant T790M mutations. However, the inevitable emergence of acquired resistance markedly limits their prolonged clinical benefits, although the third-generation EGFR TKIs have shown potent clinical outcomes in initial several months. This paper firstly reviews the characteristics and clinical efficacy of the third-generation EGFR TKIs in the market or in the clinical development. Then this article summarizes the detailed mechanisms behind the acquired drug resistance of third-generation EGFR TKIs，and further expounds the current treatment strategies to overcome the resistance. Collectively, this review could provide more information for the development and clinical application of drugs targeting EGFR.

Human body networks mechanisms of melatonin and its clinical applications

SHAO Mingkun, LIU Rong, SUN Pin, GUAN Shui, LIAO Bingcan, LI Sha, CONG Tao, LIANG Kai, MA Hui, SUN Changkai

2022, 27(9):  1031-1040.  doi:10.12092/j.issn.1009-2501.2022.09.010

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Melatonin is mainly an endogenous indoleamine hormone with many physiological functions. Melatonin not only plays an important role in the treatment of sleep disorders, but also plays an important role in the treatment of nervous system diseases, cancer, cardiovascular diseases, and bone diseases. In this paper, the human body networks mechanisms and the clinical applications of melatonin were summarized to provide reference for exploring the focus and direction of further clinical application research.

New Advances in Lipoprotein Lipase

LV Yuan, WANG Shuzhi, DAI Bin, LIANG Zhonghou

2022, 27(9):  1041-1048.  doi:10.12092/j.issn.1009-2501.2022.09.011

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Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. LPL mainly hydrolyzes triglyceride-rich lipoproteins and provides free fatty acid (FFAs) for metabolic tissues. LPL acts as a molecular bridge between lipoproteins and cell surface lipoprotein receptors, facilitating lipoprotein uptake. Recent studies have shown that LPL is widely expressed in tissues. LPL has a variety of physiological functions, which regulates lipid metabolism and energy balance in the brain. Besides, it is closely related to Alzheimer's disease. This paper mainly reviews the latest research progress of LPL in the nervous system and provides new targets for the treatment and prevention.

Metformin regulates AMPK/SREBP-1 pathway and its clinical application

WANG Xin, LIU Weiying, WU Chen, KAI Jinjun, LIANG Xuejie, CHANG Yingxuan

2022, 27(9):  1049-1054.  doi:10.12092/j.issn.1009-2501.2022.09.012

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Metformin is one of the commonly used hypoglycemic drugs in clinical practice. In addition to hypoglycemia, there are a variety of medical biological values that have been constantly discovered and attracted much attention. In recent years, studies have shown that metformin through activation of AMPK inhibition of sterols regulating element binding protein 1 (SREBP-1) reduce lipid synthesis, in the treatment of liver steatosis, improve insulin sensitivity, prevention of atherosclerosis and cardiovascular dysfunction, tumor, polycystic ovary syndrome and adjuvant therapy of COVID-19 aspects play a role. Therefore, this article reviews the possible mechanism and clinical application of metformin in regulating glucose and lipid metabolism by inhibiting SREBP-1 through activating AMPK.

General considerations for clinical data management of antineoplastic drugs

MIAO Yadong, LI Xi, WANG Yan, GAO Po, ZHOU Min, YU Hao

2022, 27(9):  1055-1060.  doi:10.12092/j.issn.1009-2501.2022.09.013

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With the enormous resources having been invested in oncology drugs development in China in recent years, the Center for Drug Evaluation (CDE) of National Medical Products Administration has been issuing a number of technical guidelines to further standardize the requirements on implementation and registration of domestic oncology clinical trials. As data is the cornerstone of clinical trials, data integrity and quality will directly decide the outcome of clinical studies. Given the specific characteristics of oncology therapeutic clinical trials, and combined with the clinical data standards established by the Clinical Data Interchange Standards Consortium (CDISC) and the issued industrial guidelines, this article introduces the general considerations of clinical data management for oncology clinical trials, with the aim of emphasizing normative data collection and timely data monitoring to ensure the data quality and reliability of results of the study. This article discusses the impact of complex study design on CRF, design CRF according to CDASH, develop DVP scientifically, rolling submissions and data cut-off.

Research progress of autophagy in intestinal ischemia-reperfusion injury

ZHANG Wei, WANG Yingbin, CAO Lu, LIU Yan, ZHANG Li, LIU Jieting

2022, 27(9):  1061-1066.  doi:10.12092/j.issn.1009-2501.2022.09.014

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Intestinal ischemia/reperfusion injury (II/RI) is a common pathological process in clinical practice. Ischemia/reperfusion causes damage to intestinal mucosa and distant organs, and induces systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Autophagy is a defense regulation mechanism under stress conditions, which can maintain the homeostasis of cytoplasm, proteins and organelles. The mechanism of autophagy is complex, which is co-regulated by protein complexes encoded by evolutionarily conserved autophagy-related gene (ATG) and a variety of signaling molecules and pathways. Studies have found that autophagy is involved in the process of intestinal ischemia-reperfusion injury. Therefore, revealing the mechanism of autophagy in II/RI can provide evidence for the prevention and treatment of II/RI.

Research progress of finerenone in the treatment of type 2 diabetes mellitus complicated with chronic kidney disease

ZHAI Weiwei, YU Qiaoling, LIU Ping, QIU Bo, WU Huizhen

2022, 27(9):  1067-1074.  doi:10.12092/j.issn.1009-2501.2022.09.015

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Finerenone is a new non-steroidal mineralocorticoid receptor antagonists, which can prevent and treat type 2 diabetes mellitus complicated with chronic kidney disease through antioxidant, anti-inflammatory and anti-fibrosis effects, and has a significant cardiovascular protection effect. Compared with traditional mineralocorticoid receptor antagonists, finerenone has a higher selectivity. In this review, the basic introduction, basic research, clinical research and limitations of finerenone were reviewed in order to provide more ideas and options for the treatment of type 2 diabetes mellitus complicated with chronic kidney disease.

Research progress on the mechanism of iron overload in the occurrence and development of osteoarthritis

WANG Liang, ZHANG Hulin, WANG Xiaomin, YANG Chaoqiang, WANG Yican, LAI Xueqian

2022, 27(9):  1075-1080.  doi:10.12092/j.issn.1009-2501.2022.09.016

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Osteoarthritis (OA) is a common chronic degenerative disease, and its condition tends to worsen with age. The pathogenesis of OA is complex, and many risk factors can lead to the occurrence of OA. Iron is one of the essential trace elements in the body, and its metabolic balance is extremely important to human health. Iron overload is closely related to the occurrence and development of OA. Excessive iron deposition in joint tissue can easily lead to lesions of articular cartilage and synovium, as well as affect subchondral bone reconstruction and lead to the occurrence of OA. The author reviewed the relevant research literature in recent years, and reviewed the mechanism of iron overload in the occurrence and development of OA, in order to provide new ideas and directions for the research and diagnosis and treatment of OA.