Table of Content

Volume 29 Issue 1
26 January 2024

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Involvement of intracellular organelle stress, autophagy and ferroptosis in cobalt chloride-induced vascular smooth muscle cell injury

LEI Yan, PENG Xiaoyong, DENG Mengsheng, ZHANG Dongdong, ZHU Yingguo, WANG Jianmin, DUAN Zhaoxia, LI Tao, LIU Liangming, YANG Guangming

2024, 29(1):  1-10.  doi:10.12092/j.issn.1009-2501.2024.01.001

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AIM: To investigate the relationship between vascular smooth muscle cell (VSMC) injury, organelle stress response and autophagic cell death (autophagy) and ferroptosis induced by the chemical hypoxia inducer cobalt chloride (CoCl2) through the bioinformatics analysis and in vitro cell experimentation. METHODS: The dataset GSE119226 of VSMC treated with cobalt chloride was acquired from the gene expression database (GEO). The R language was used to investigate the relationship between CoCl2 treatment and organelle stress response (Golgi stress, endoplasmic reticulum stress) and two forms of cell death (ferroptosis and autophagic cell death). With primary cultured rat VSMC (rVSMC) and CoCl2-induced anoxia model, the changes in cell viability were detected by CCK-8 method, and reactive oxygen species (ROS) levels were measured using DCFH-DA method. The expression levels of HIF-1α (a key molecule in hypoxia), Golgi stress markers GM130 and p115, endoplasmic reticulum stress markers GRP78 and CHOP, autophagy markers LC3-II/LC3-I and Beclin1, and ferroptosis markers GPx4 and xCT were detected by Western blot. The effect of inducing or inhibiting organelle stress and cell death on the CoCl2-induced cell damage was also observed. RESULTS: Differentially expressed genes analysis of GSE119226 dataset showed that CoCl2 treatment of VSMCs had significant effects on organelle function and stress response, autophagy and ferroptosis-related genes, in which endoplasmic reticulum stress, protein processing in endoplasmic reticulum, regulation of Golgi to plasma membrane protein transport, autophagy/autophagic cell death, and ferroptosis pathways were remarkably enriched. The results of in vitro experiment showed that compared with normal rVSMC, cell viability was significantly decreased after CoCl2 treatment, as well as HIF-1α protein expression and ROS levels in rVSMCs were increased. In rVSMC treated with CoCl2, the expression levels of Golgi structural proteins GM130 and p115 (reflecting the occurrence of Golgi stress) were decreased, while the markers GRP78 and CHOP (reflecting the occurrence of endoplasmic reticulum stress) were increased. At the same time, CoCl2 treatment also reduced the expression of autophagy markers LC3-II/LC3-I and Beclin1 (indicating the decrease levels of autophagy), while the expression of ferroptosis markers GPx4 and xCT were decreased (indicating the occurrence of ferroptosis). Compared with CoCl2 treatment group, induced Golgi stress, endoplasmic reticulum stress, or ferroptosis could further reduce cell viability, while inhibition of these processes could improve cell viability. On the other hand, increasing the level of autophagy can improve the cell viability. CONCLUSION: Hypoxia induced by cobalt chloride can lead to VSMC injury. Golgi stress, endoplasmic reticulum stress, ferroptosis, and the reduction of autophagy level play an important role in it. Inhibition of organelle stress response and ferroptosis, or increase of autophagy level can improve VSMC injury caused by cobalt chloride.

Mechanism of Yi-xin-yin oral liquid according to homotherapy for heteropathy theory based on UHPLC-Q-TOF/MS combined with network pharmacology and molecular docking techniques

WANG Yejian, JIAO Guangyang, PANG Tao, WENG Nan, GAO Jie, LI Juan, CHEN Wansheng, CHEN Weidong, ZHANG Feng

2024, 29(1):  11-25.  doi:10.12092/j.issn.1009-2501.2024.01.002

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AIM: To predict the core targets and related signaling pathways of Yi-xin-yin oral liquid for the treatment of arrhythmia, heart failure and myocarditis based on UHPLC-Q-TOF/MS, network pharmacology, molecular docking methods, cell experiments, according to the “homotherapy for heteropathy” theory in traditional Chinese medicine. METHODS: UHPLC-Q-TOF/MS was used to analyze and identify the chemical composition of Yi-xin-yin oral liquid Extract and the blood-absorbing components of rats oral administrated with Yi-xin-yin oral liquid extract, which compounds were applied in the databases searching for the potential targets (TCMSP, SwissTargetPrediction) and disease targets (OMIM, Genecard). Venn diagram was used for target intersection, and the subsequent protein-protein interaction network obtained core targets by STRING11.5 database, and then construct a "disease-component-target" network by cytoscape3.9.0. Finally, DAVID database was used to analysis GO function and KEGG enrichment analysis of core targets, and molecular docking validation was performed using Autodock vina software.And, validated with H9c2 cells for potential active ingredients and targets. RESULTS: A total of 156 compounds were identified from Yi-xin-yin Oral Liquid extract; 34 compounds were identified from rat serum, including 6-gingerol, isoliquiritigenin, glycyrrhizic acid and other compounds, and 139 intersecting targets were obtained. The KEGG pathway enrichment analysis mainly involved the TNF signaling pathway, IL-17 signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway and so on. The TNF and IL-6 targets were selected for molecular docking with the main compounds, and the docking results were good (less than -5 kcal/mol). In vitro cellular experiments have shown that Yi-xin-yin oral liquid can exert therapeutic effects by regulating TNF and IL-6. CONCLUSION: The main potential active ingredients of Yi-xin-yin oral liquid may be isoliquiritigenin, glycyrrhetinic acid, calycosin-7-glucoside, salvianolic acid B, and 6-gingerol, which mainly act on TNF, IL-6 and other targets to regulate specific signaling pathways and exert therapeutic effects.

Analysis and verification of the effect of Yi Qi Yang Yin decoction on rheumatoid arthritis

GUAN Rui, YAO Jiashu, ZHAO Yeyu, ZHENG Jiannan, QI Qing, YU Jing, GAO Mingli

2024, 29(1):  26-36.  doi:10.12092/j.issn.1009-2501.2024.01.003

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AIM: Yi Qi Yang Yin Decoction (YQYY) has been used to treat patients with rheumatoid arthritis (RA) and achieved good results in clinical applications, but the mechanism still needs to be explored. The purpose was to investigate the mechanism of YQYY in rats with collagen-induced arthritis. METHODS: The possible treatment target and signaling pathway were predicted by bioinformatics and network pharmacology analysis. Elisa,quantitative real-time polymerase chain reaction, and Western Blot were used to verify the mechanism of YQYY in treating RA. RESULTS: FABP4, MMP9 and PTGS2 were the most common predicational therapeutic targets. The results of pathology and CT showed that YQYY could improve ankle swelling, synovitis and bone erosion in CIA rats. Compared with the model group, YQYY or YQYY+MTX can significantly reduce the secretion of CRP, TNF-α, IL-1β and FABP4 in serum of CIA rats (P<0.05 or P<0.01), meanwhile, reduce the mRNA of FABP4, IKKα and p65 in synovial tissue (P<0.01), PPARγ was increased (P<0.01). YQYY could significantly reduce the expression of FABP4, IKKα and pp65 proteins in synovium, and suppress the activate of NF-κB signaling pathway. CONCLUSION: FABP4, MMP9 and PTGS2 may be the targets of YQYY decoction for RA treatment. YQYY can relieve joint symptoms in CIA rats, and regulate inflammation by inhibiting FABP4/PPARγ/NF-κB signaling pathway, playing a role in the treatment of RA. The effect of YQYY combined with MTX was more prominent. This provided experimental evidence for the efficacy of YQYY decoction in clinical practice.

Pharmacokinetics and tissue distribution of tetrahydropalmatine, nobiletin, and costunolide in rats after oral administration of Dalitong extract

ZHANG Yuanmao, ZHANG Ran, LIAO Ruiwei, TAO Lin, MENG Xiuxiu, XU Chen, GAO Fangfang, A Jiye, WANG Guangji

2024, 29(1):  37-51.  doi:10.12092/j.issn.1009-2501.2024.01.004

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AIM: To investigate the pharmacokinetic properties of the main active components of Dalitong extract in SD rats after oral administration using UPLC-MS/MS. METHODS: An UPLC-MS/MS method was established to simultaneously detect tetrahydropalmatine, nobiletin and costunolide in the plasma and tissues of SD rats. The method was applied to investigate the pharmacokinetic characteristics and tissue distribution. RESULTS: After a single oral administration, the three active components were rapidly absorbed into the body, with a peak concentration (Cmax) of (13.73±7.50), (27.01±17.69) and (6.73±29.94) ng/mL for tetrahydropalmatine, nobiletin, and costunolide, respectively. The time to reach the peak concentration (Tmax) was (1.40 ± 0.93), (0.63 ± 0.28) and (2.38 ± 8.81) h, respectively. The area under the curve (AUC) was (80.43±40.03), (41.30±28.69) and (303.90 ± 136.69) ng·h·mL-1, respectively, and the elimination half-life (t 1/2) was (5.82 ± 2.22), (1.08 ± 0.01) and (4.95 ± 2.53) h, respectively. Multiple dosing significantly increased the exposure of the three components. There were significant differences in exposure between male and female rats, with higher exposure observed in female rats (P<0.05). The three active components were widely distributed in various tissues/organs, with the highest exposure observed in the gastrointestinal tract, followed by the liver and kidney. CONCLUSION: The UPLC-MS/MS method is accurate, sensitive, and reliable for the quantitative analysis of tetrahydropalmatine, nobiletin, and costunolide. These three active components in Dalitong extract can be absorbed, widely distributed in various tissues or organs, and rapidly metabolized/eliminated after oral administration. They are potential pharmacokinetic markers of Dalitong extract.

Development and validation of a method for quantitation of cefepime/avibactam in M-H broth: application to antibacterial activity using in vitro PK/PD Model

YAN Bingqian, GUO Siwei, LI You, TIAN Miaomei, XU Bing, JIANG Rong, LI Xin

2024, 29(1):  52-60.  doi:10.12092/j.issn.1009-2501.2024.01.005

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AIM: To establish a method for quantitation of cefepime and avibactam in M-H broth, and applicated in the in vitro dynamic PK/PD model. METHODS: The cefepime was also determined using the high-performance liquid chromatography method (HPLC), the avibactam was also determined using the liquid chromatography-mass spectrometry (LC-MS/MS), an in vitro dynamic?PK/PD?model was established to study the?PK/PD?relationship of cefepime/avibactam against carbapenem resistant Klebsiella pneumoniae (CRKP). RESULTS: The linear ranges of cefepime and avibactam were good at (0.5-20) and (0.1-25) μg/mL (r=0.999), and the lower limit concentrations were 0.5 and 0.1 μg/mL. The extraction recoveries of cefepime and avibactam in M-H broth were 88.0%-101.7% and 90.9%-95.2%, the relative standard deviation of intra-day precision and inter-day precision were less than 5.2%. The concentration-time curves were well simulated by the PK/PD model. All observed concentrations in each experiment were in the range of 20% of the targeted values. For the CRKP of MIC=8 μg/mL and MIC=16 μg/mL, the colony decreased to 2.783Log10 CFU/mL and 1.325Log10 CFU/mL at the cefepime/avibactam 2.5 g q8 h administration after 24 h. CONCLUSION: The determination method of cefepime and avibactam in broth established in this study has high sensitivity and good stability. For the CRKP with MIC≤8 μg/mL，cefepime/avibactam showed that good anti-CRKP activity under routine administration in vitro dynamic PK/PD model.

Experimental study on pharmacodynamics of Su Bei Zhi Ke granules (SBZKG) for acute tracheobronchitis

KAN Hongwei, TIAN Jun

2024, 29(1):  61-67.  doi:10.12092/j.issn.1009-2501.2024.01.006

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AIM: To observe the effect of Su Bei Zhi Ke granules (SBZKG) on acute tracheobronchitis (Syndrome of Wind-cold Attacking Lung). METHODS: Mouse ear swelling experiment and mouse abdominal capillary permeability experiment was used to observe its anti-inflammatory effect. Cough test in mice induced by ammonia water, and phlegm test in rats were used to observe the expectorant and antitussive effects of phenol red test in mice. We used the mortality rate experiment of infected mice to observe its antibacterial and antiviral effects. RESULTS: Compared with the contral group, the large and medium dose groups of SBZKG both reduced mouse auricle swelling (P<0.05) and increased swelling inhibition rate, reducing mouse abdominal capillary permeability (P<0.05, P<0.01). SBZKG can increase the phenol red sputum output in the respiratory tract of mice (P<0.01), prolong the cough incubation period of mice, reduce the number of coughs in mice (P<0.05, P<0.01), and increase the sputum output in rats (P<0.05, P<0.01). SBZKG can reduce the mortality rate of mice infected with bacteria and viruses. CONCLUSION: SBZKG has certain anti-inflammatory, antitussive, expectorant, antibacterial and antiviral effects, and has certain therapeutic effects on acute tracheobronchitis.

Clinical value of genetic polymorphism analysis of hypertension drugs for individualized treatment of hypertension patients in the southern Anhui region

WAN Shujun, ZHANG Mengying, CHEN Qilei, ZHONG Min, ZHU Xiaolong, ZHANG Yingying, LV Kun

2024, 29(1):  68-75.  doi:10.12092/j.issn.1009-2501.2024.01.007

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AIM: To analyze the distribution frequency of gene polymorphisms of β receptor blockers, angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, calcium antagonists, and diuretics in hypertensive patients from southern Anhui province, and provide a theoretical basis for gene detection of hypertension drugs and personalized medication. METHODS: Drug gene testing information from 839 hospitalized patients with hypertension at Yijishan Hospital of Wannan Medical College from July 2021 to April 2023 were collected, and  the distribution frequency of each gene locus were analyzed. RESULTS: The genotype frequencies of ACE (I/D) I/I, I/D, and D/D were 42.1%, 46.0%, and 11.9%, respectively. the genotype frequencies of ADRB1 (1165G>C) G/G, G/C, and C/C were 8.3%, 40.0%, and 51.6%, respectively. The genotype frequencies of AGTR1 (1166A>C) A/A, A/C, and C/C were 90.2%, 9.8%, and 0.0%. The genotype frequencies of CYP2C9*3 (1075A>C) *1/*1, 

*1/*3, and *3/*3 were 91.3%, 8.7%, and 0.0%, respectively; the genotype frequencies of CYP2D6* 10 (100C > T) *1/*1, *1/*10, and *10/*10 were 25.0%, 36.6%, and 38.4%, respectively. The genotype frequencies of CYP3A5*3 (6986A>G) *1/*1, 
*1/*3, and *3/*3 were 7.0%, 39.0%, and 54.0%, respectively. The frequencies of NPPA (2238T>C) T/T, T/C, and C/C genotypes were 97.9%, 2.1%, and 0.0%, respectively. In addition, there was a significant difference in the genotype distribution frequency of multiple drug related gene loci in southern Anhui compared to other regions in China (P<0.05). CONCLUSION: The genotype distribution frequency of hypertensive drug related gene loci had certain bias in southern Anhui, and were significant different from other regions in China, indicating that conducting genetic polymorphism testing of hypertensive drugs had certain guiding significance for the individualized application of hypertensive drugs in southern Anhui. 


Efficacy and safety of interventional therapy combined with drug injection under bronchoscope in the treatment of central non-small cell lung cancer

XU Ling, YE Wei, LV Liping, WANG Hua

2024, 29(1):  76-81.  doi:10.12092/j.issn.1009-2501.2024.01.008

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AIM: To evaluate the efficacy and safety of interventional therapy combined with tumor drug injection under bronchoscope for central non-small cell lung cancer (NSCLC). METHODS: Sixty-four patients who met the test admission criteria were randomly assigned to the experimental group and the control group according to the ratio of 1:1, and were given bronchoscopic interventional therapy combined with local drug injection of recombinant human endostatin combined with platinum-containing dual-drug chemotherapy and platinum-containing dual-drug alone, respectively. The curative efficiency and safety of the two groups were compared. RESULTS: Compared with the control group, the KPS score, dyspnea grading were significantly improved (P<0.05). The effective rate of the test group was 78.12%, which was higher than 37.5% in the control group, the difference between the two groups was significant (P<0.05). Moreover, there was also a significant difference in the 1-year survival rate between the experimental group and the control group (P<0.05). CONCLUSION: The treatment of central NSCLC by interventional therapy combined with tumor drug injection through fiberoptic bronchoscope has obvious clinical efficacy, which can effectively alleviate the clinical symptoms and improve the quality of life of patients. There is no significant difference in adverse reactions between the two groups, and is worthy of popularization and application.

Research progress on drug treatment and drug resistance mechanism of gastrointestinal stromal tumors

ZHAO Quanming, YANG Mandou, HU Yibo, SU Youtong, PU Li, ZHANG Yu, LI Wenliang

2024, 29(1):  82-89.  doi:10.12092/j.issn.1009-2501.2024.01.009

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Gastrointestinal stromal tumors (GIST) are the most common mesenchymal-derived tumors of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) are the cornerstone of GIST therapy, but mutations in resistance genes pose many problems for treatment, especially the heterogeneity of KIT resistance mutations. In recent years, with the release of a number of GIST related drug research and experimental results, the great potential of targeted therapy, immunotherapy and combination therapy to treat GIST in different directions has been revealed, providing more therapeutic directions for GIST. This article will review the experimental research and future direction in recent years.

Research progress of FLT3 inhibitors and drug resistance mechanisms in acute myeloid leukemia

WU Tingkai, REN Chongchong, ZHANG Wanwan, LIU Bei

2024, 29(1):  90-98.  doi:10.12092/j.issn.1009-2501.2024.01.010

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The FMS-like tyrosine kinase 3 (FLT3) gene mutation is the most common genetic mutation in acute myeloid leukemia (AML) and is associated with poor prognosis. Various targeted inhibitors have been developed for FLT3 mutations and have shown promising clinical efficacy. However, the emergence of resistance poses new challenges for targeted therapy in AML. This article provides an overview of the pathological and prognostic role of FLT3 mutations in AML, the current research progress on commonly used FLT3 inhibitors (type I and type II), the mechanisms of FLT3 inhibitor resistance, and strategies for overcoming resistance.

Research progress on molecular mechanism of traditional chinese medicine active ingredients interfering bone marrow mesenchymal stem cells senescence

YU Miaoying, WANG Yanhui, YAN Shi

2024, 29(1):  99-106.  doi:10.12092/j.issn.1009-2501.2024.01.011

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The senescence of bone marrow mesenchymal stem cells (BM-MSCs) will induce age-related bone tissue degeneration and chronic inflammation, and reduce its application effect for cell therapy. More and more active ingredients of traditional chinese medicine have been proved to intervene BM-MSCs senescence, playing an important role in bone diseases prevention and treatment, and improving the therapeutic effect of BM-MSCs. In this paper, the latest research progress on the molecular mechanism of traditional chinese medicine active ingredients interfering BM-MSCs senescence was summarized, in order to provide new direction and reference basis for senescence intervention research and clinical application improvement of BM-MSCs.

Advances in the study of mesenchymal stem cells in obstructive sleep apnea hypoventilation syndrome

XU Jinhui, YUE Hongmei, LI Yating, LIU Miaomiao, WU Xingdong, ZHU Haobin

2024, 29(1):  114-120.  doi:10.12092/j.issn.1009-2501.2024.01.013

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Mesenchymal stem cells (MSCs) are self-regenerating, rapidly proliferating pluripotent stem cells that depend primarily on their derived pro-angiogenic, inflammatory regulatory, and trophic factors to exert beneficial effects that attenuate deleterious inflammatory responses, reduce vascular damage, and promote tissue repair and regeneration. Obstructive sleep apnea hypoventilation syndrome (OSAHS) is a chronic disorder marked by oropharyngeal collapse during sleep, resulting in transient reduced airflow, large fluctuations in intrathoracic pressure, and intermittent hypoxia and hypercapnia. OSAHS subsequently cytokine-mediated inflammatory cascades, oxidative stress, and ischemia, recruit MSCs from inflamed and damaged tissues through MSCs-derived of anti-inflammatory and pro-angiogenic factor activity, reduce hypoxia, suppress inflammation, promote regeneration, and prevent fibrosis in OSAHS-injured tissues. In this paper, we will describe the pathogenesis of inflammation, oxidative stress, fibrosis and ischemia from the perspective of OSAHS, highlighting the current research progress on MSCs-dependent regulation of OSAHS-related pathology.