Table of Content

Volume 28 Issue 7
26 July 2023

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Mechanism of neuroprotective effect of ginsenoside Rg1 regulating Epac1/Rap1 signaling pathway in rats with ischemic stroke

WANG Kun, XU Peipei, ZHOU Lanlan, LU Sheng

2023, 28(7):  721-727.  doi:10.12092/j.issn.1009-2501.2023.07.001

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AIM: To investigate the neuroprotective effect of ginsenoside Rg1 on rats with ischemic stroke and to investigate its mechanism of action. METHODS: Eighty-four SPF-grade SD male rats at about 13 weeks of age were randomly divided into 7 groups (n=12): sham-operated group, model group, Rg1 low-dose group, Rg1 medium-dose group, Rg1 high-dose group, Epac1 agonist group, and Epac1 inhibitor group. The model group, Rg1 low, medium and high dose groups, Epac1 agonist group and Epac1 inhibitor group were all used to establish a permanent focal cerebral ischemia rat model. Rats in the Rg1 low, medium and high dose groups were treated with 60, 120 and 240 μmol/L Rg1 administered by gavage at a fixed time every morning. The rats in the Epac1 agonist and Epac1 inhibitor groups were administered intraperitoneally at a fixed time each morning with a concentration of 1.0×104 μmol/L for the Epac1 agonist 8-CPT and 1.0×105 μmol/L for the inhibitor ESI-09. After two weeks of continuous administration, the rats in each group were decapitated. The brain infarct volume, number of intact neurons, oxidative damage index, apoptosis, and protein expression levels of NOX2, Epac1, Rap1, and caspase3 in each group of rats were detected by TTC staining, Nissler staining, TUNEL staining, microenzyme labeling, and Western blotting method, respectively. RESULTS: Compared with the sham-operated group, the brain infarct volume of rats in the model group and Epac1 agonist group was significantly larger, the number of intact neurons in brain tissue was significantly reduced, the oxidative damage of neurons in brain tissue was significantly aggravated, the apoptosis rate of neuronal cells was significantly higher, and the expression of NOX2, Epac1, Rap1, and caspase3 was significantly higher, with statistically significant differences (P<0.05); compared with the model group, the brain infarct volume was significantly reduced in the Rg1 low, medium and high dose groups and Epac1 inhibitor group, the number of intact neurons in brain tissue was significantly increased, the apoptosis rate of neuronal cells was significantly reduced, and the expression of NOX2, Epac1, Rap1 and Caspase3 was significantly reduced, and the differences were statistically significant (P<0.05). CONCLUSION: Ginsenoside Rg1 can regulate the Epac1/Rap1 signaling pathway after ischemic stroke and attenuate the oxidative stress of brain neurons, thus reducing neurological impairment and exerting a protective effect on neuronal cells.


Effects of Ginkgo biloba extract on renal injury in rats with experimental renal failure through miR-145/FOXO1 axis

LI Shixu, LI Linyun, WANG Xin, LI Ke, BIAN Hua

2023, 28(7):  728-735.  doi:10.12092/j.issn.1009-2501.2023.07.002

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AIM: To investigate the effect of Ginkgo biloba extract (GBE) on kidney injury in rats with chronic renal failure (CRF) and its potential molecular mechanism. METHODS: SD rats were given 5/6 nephrectomy to construct CRF models and divided into model group, GBE group (100 mg/kg), GBE+Agomir-NC group, and GBE+Agomir-145 group, 12 per group; another 12 were selected as the sham group, with only the kidney exposed and no nephrectomy. Rats in the GBE group were given GBE 100 mg/kg gavage daily, once a day, for 4 consecutive weeks; rats in the GBE+Agomir-NC group and GBE+Agomir-145 group were given GBE 100 mg/kg gavage daily, and then Agomir-NC and Agomir-145 were injected via the tail vein every 3 days for 4 weeks; the sham group and the model group were given the same amount of normal saline by gavage and injection through the tail vein respectively. The general state of the rat was observed, and the renal function indicators [24 h urine microalbumin (24 h UAlb), blood urea nitrogen (BUN), blood creatinine (SCr)] and oxidative stress indicators [malonaldehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)] were detected, Masson staining was used to observe the fibrosis of kidney tissue, real-time fluorescent quantitative PCR (RT-qPCR) was used to detect the mRNA expression levels of microRNA-145 (miR-145), transforming growth factor-β1 (TGF-β1) and forkhead box O1 (FOXO1) in renal tissue, Western blot was used to detect the protein levels of TGF-β1 and FOXO1 in kidney tissue. RESULTS: The general state of CRF rats improved significantly after GBE intervention, the body weight, renal tissue SOD and GSH-Px activities, and FOXO1 mRNA and protein levels were significantly higher than those in the model group (P<0.05); the 24 h UAlb, serum BUN, SCr and renal tissue MDA levels, the relative area of renal interstitial fibrosis, and renal tissue miR-145, TGF-β1 mRNA and protein levels were significantly lower than those in the model group (P<0.05); and on the basis of GBE intervention, up-regulating the expression of miR-145 could significantly weaken the protective effect of GBE on renal injury in CRF rats (P<0.05). CONCLUSION: GBE can alleviate kidney damage in CRF rats, and its mechanism of action may be related to down-regulation of miR-145, up-regulation of FOXO1 expression, and inhibition of renal fibrosis.

Molecular mechanism of lncRNA HOTAIR regulating miR-206 on the proliferation and apoptosis of rheumatoid arthritis synovial cells

FAN Jie, JIN Yongming, JIANG Xiaolong, JIANG Guohua

2023, 28(7):  736-742.  doi:10.12092/j.issn.1009-2501.2023.07.003

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AIM: To investigate the molecular mechanism of lncRNA HOTAIR regulating miR-206 on the proliferation and apoptosis of rheumatoid arthritis synovial cells. METHODS: The synovial tissue from 30 cases of rheumatoid arthritis were collected. Rheumatoid arthritis synovial cells MH7A were cultured. The experiment was divided into si-NC group, si-HOTAIR group, miR-NC group, miR-206 mimic group, si-HOTAIR+NC inhibitor group, si-HOTAIR+miR-206 inhibitor group. Real-time fluorescent quantitative PCR (RT-qPCR) was used to detect the expression levels of HOTAIR and miR-206 in cells. CCK-8 method to detect cell proliferation; flow cytometry to detect cell apoptosis; Western blot to detect cell protein expression of CyclinD1, p21, Bax and Bcl-2; dual luciferase reporter assay to detect HOTAIR and miR-206 targets To combination relationship. RESULTS: Compared with the healthy control group, the expression level of HOTAIR in patients with rheumatoid arthritis was significantly up-regulated, and the expression level of miR-206 was significantly down-regulated (P<0.05). Compared with the si-NC group, the HOTAIR expression level in the si-HOTAIR group was significantly down-regulated, the cell survival rate were significantly down-regulated, and the apoptosis rate were significantly up-regulated (P<0.05). Compared with the miR-NC group, the expression level of miR-206 in the miR-206 mimic group was significantly up-regulated, the cell survival rate were significantly down-regulated, and the apoptosis rate were significantly up-regulated (P<0.05). Compared with the si-HOTAIR+NC inhibitor group, the cell survival rate in the si-HOTAIR+miR-206 inhibitor group were significantly up-regulated, and the apoptosis rate were significantly decrease (P<0.05). CONCLUSION: Inhibiting the expression of HOTAIR and up-regulating the expression of miR-206 can reduce the proliferation of rheumatoid arthritis synovial cells and promote apoptosis.

Effects of scacia honey on serum uric acid level and renal injury in rats

XU Xiuhe, HE Xiaoli, ZHOU Jiashun, PAN Lizhu, ZHOU Zhuojun, LI Jiayue, WANG Caixia, YUAN Wei, ZHU Guiqi

2023, 28(7):  743-750.  doi:10.12092/j.issn.1009-2501.2023.07.004

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AIM:To observe the effect ofacacia honey (AH) on serum uric acid level and renal function in potassium oxonate modelrats after drinking AH aqueous solution. METHODS: Sixty male SD rats were selected and randomly divided into control group (CON group), potassium oxonate model group (OA model group), 10% fructose group (10% F group) and different concentration honey groups (25%, 12.5% and 6.25% AH groups). All rats were fed with normal diet.The rats in CON group were subcutaneously injected with 5% sodium carboxymethyl cellulose (CMC-Na) solution and drunk sterile water every day, while rats in other groups were injected with 100 mg/kg OA solution suspended with 5% CMC-Na subcutaneouslyand drunksterile water orfructose solution or AH solution of different concentrations every day. Before and during the 4-week test, rats were weighed and blood was taken once a week. At the end of test, urine and feces specimens or kidney tissues were collected and blood was taken from the abdominal aorta. The uric acid content in blood, urine, and feces and the levels of serum creatinine (Cre) and blood urea nitrogen (BUN) or inflammatory factors in kidney tissues were measured.Renal function and histology were evaluated. RESULTS: Compared with CON group, AH could significantly reduce the body weight of rats (P<0.05), increase the kidney organ coefficient, the levels of serum uric acid, and uric acid in urine or feces, and reduce the level of fecal uric acid (FUA) in rats.AH can down regulate the level of tumor necrosis factor alpha (TNF-a) (P<0.05) and up regulate the expression of monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor β-1 (TGF-β1) in rats kidneys; AH can cause slight to mild dilatation of renal tubules and mild to moderate basophilic lesions of renal rubules in rat kidney in a dose dependent manner.CONCLUSION: In the doses rang of present study, AH can cause hyperuricemia,renal tubular dilatation and basophilic lesions, and lead to renal function damage in rats.

Study of the improvement effect of "DuZhong-DangGui" on osteoarthritis rats via regulating NLPR3 inflammasome

WANG Xinyu, CHEN Yipeng, MA Yongli, HE Junfei

2023, 28(7):  751-757.  doi:10.12092/j.issn.1009-2501.2023.07.005

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AIM: To investigate the protective effect of "DuZhong-DangGui"(DZ-DG) on the knee tissue of rats with osteoarthritis (OA) and its regulation role on NLPR3 inflammasome. METHODS: Twenty-four SPF male SD rats, eighteen rats were randomly selected to establish OA model by anterior cruciate ligament amputation (ACLT) method, and rats were divided into control group, OA model group, DZ-DG group and positive drug group, 6 in each group, treatment for 8 weeks. The peripheral blood were collected, ELISA was used to detect the levels of IL-1β, IL-6, IL-18, and TNF-α; cartilage tissue of knee joint were collected, HE staining was used to observe pathology changes, OARSI staining was used to observe cartilage calcification and preform quantitative OARSI scoring; immunohistochemistry and TUNEL staining were used to detect the contents of Caspase1 and Collagen II and the number of apoptosis in the tissue, respectively, and western blot was used to detect the protein expressions of matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), p53, p21, NLPR3, apoptosis-associated speck-like protein containing a CARD (ASC) and Pro-Caspase-1. RESULTS: Compared to control group, OA model group rats serum levels of IL-1β, IL-6, IL-18, and TNF-α significantly increased (P<0.01), OARSI scores significantly increased (P<0.01), chondrocyte apoptosis was increased (P<0.01), Caspase-1 content and MMP-13, p53, p21, NLPR3, ASC, Pro-Caspase-1 protein expressions significantly increased (P<0.01), while Collagen II content and TIMP-1 protein expression significantly decreased (P<0.01). Compared with the OA model group, DZ-DG group and positive drug group rats serum levels of IL-1β, IL-6, IL-18 and TNF-α significantly decreased (P<0.05), chondrocyte apoptosis were significantly decreased (P<0.01), Caspase1 content, MMP-13, p53, NLPR3, Pro-Caspase-1 significantly decreased (P<0.05), Collagen Ⅱ content and TIMP- 1 protein expression (P<0.01); DZ-DG group rats protein expression of p21 and ASC were decreased (P<0.01). CONCLUSION: The DZ-DG have protection role on cartilage of OA rats, its effect may related to mediation of NLPR3/ASC/Pro-Caspase-1 pathway, to decrease of IL-1β, and inhibition of cell apoptosis.

Analysis of reasons for screening failure of healthy subjects in clinical trials of orally inhaled drug products

LIU Min, KONG Xiang, ZHANG Ye, GU Yifei, XIANG Xuemei, HE Qing, HUANG Kai

2023, 28(7):  758-766.  doi:10.12092/j.issn.1009-2501.2023.07.006

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AIM: To explore the reasons for screening failure of healthy subjects in clinical trials of orally inhaled drug products (OIDPs). METHODS: Screening data of 1 432 healthy subjects who participated in clinical trials of OIDPs were collected. The main reasons for the screening failure, gender differences in screening failure rate and the correlation between age and screening failure rate were summarized and analyzed. RESULTS: The screening failure rate was 72.4 % and increased with age. The failure rate was slightly higher in females than in males. Besides abnormal vital signs (17.3%), abnormal laboratory test results (16.5%) and withdrawal of consent (7.6%), poor venous condition (13.9%), positive for cigarette test results (12.6%) and failure in inhalation training (7.1%) were also the other three main reasons affecting the screening success rate. Abnormal vital signs and poor venous conditions were the primary screening failure reasons for males and females, respectively. CONCLUSION: The screening success rate could be improved by informing fully and communicating effectively, selecting young subjects with strong understanding abilities, and enhancing the training skills of investigators.

Effects of glycaemic control and CYP3A5 polymorphisms on tacrolimus trough concentrations after adult kidney transplantation

LI Kun, LI Lulu, LI Nannan, HU Weihong, ZHOU Jianchao

2023, 28(7):  767-774.  doi:10.12092/j.issn.1009-2501.2023.07.007

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AIM: Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4/5 (CYP3A4/5) substrates. We evaluated the relationship between haemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus. METHODS: This retrospective observational cohort study included kidney transplant recipients (>18 years) receiving controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized by body weight (C/D) ratio of tacrolimus at 7 days, 6 months and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline, 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction. RESULTS: Out of 42 patients (CYP3A5 expressers, n=56, and non-expressers, n=83), the multiple linear regression analysis showed that the C/D ratio on Day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers. Factors affecting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers and increased HbA1c levels and CYP3A5 non-expressers, respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y=54.6x+194.6, R=0.63, P=0.004, Bonferroni correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y=54.5x+20.2, R=0.41, P=0.036, Bonferroni correction). CONCLUSION: HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post-kidney transplantation.

Immunotherapy combined with anti-angiogenic drugs and chemotherapy in negative driver gene and advanced non-small cell lung cancer

HOU Qiong, LIU Fei, CHEN Chuanrong

2023, 28(7):  775-779.  doi:10.12092/j.issn.1009-2501.2023.07.008

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AIM: To investigate the application value of immunotherapy combined with anti-angiogenic drugs and chemotherapy in negative driver gene and advanced non-small cell lung cancer (NSCLC). METHODS: A total of 48 patients with advanced NSCLC and negative driver genes were included and randomly divided into two groups according to 1:1. The observation group received immunotherapy combined with anti-angiogenic drugs and chemotherapy. The control group received conventional standard chemotherapy. The differences between the two groups were analyzed in drug toxicity, side effects and survival status. RESULTS: Objective response rate (ORR) and disease control rate (DCR) were compared to evaluate the short-term efficacy. There was no statistical difference in ORR between the two groups. DCR in the observation group was higher than that in the control group, the difference was significant (P<0.05). The probability of hypertensive proteinuria and hand-foot syndrome in the observation group was significantly higher than that in the control group (P<0.05). Compared with the control group, the observation group could prolong the mPFS mOS of the patients (P<0.05). CONCLUSION: Immunotherapy combined with anti-angiogenic drugs and chemotherapy can improve the efficacy of negative driver gene and advanced NSCLC, which is tolerated by patients and worthy of clinical application.

Establish and implement a pre-prescription system for outpatient based on Six Sigma DMAIC model

WANG Lin, YU Jianguo, LI Xiao, LUAN Jiajie

2023, 28(7):  780-787.  doi:10.12092/j.issn.1009-2501.2023.07.009

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AIM: The pre-prescription system of outpatient was established and implemented based on six sigma DMAIC model to ensure the safety of drug use and promote rational of drug use. METHODS: The rules database was made scientifically and precisely, according to DMAIC model of Six Sigma--define, measure, analyze, improve and control. The pre-prescription system of our hospital was established and improved,through adopting the prescription review mode of interception and Intervention.And the process management was continued to optimize. RESULTS: The rule-making of pre-trial system for outpatient prescription in our hospital was reasonable, and the rate of clinical approval and acceptance was high. After the system audit, the average rate of doctor's revision was 76.32%, and the average rate of Pharmacist's intervention was 63.23%, the effective rate and qualified rate of pharmacist intervention were 97.23% and 96.87%, respectively. CONCLUSION: Based on Six Sigma DMAIC model, the pre-trial system for outpatient prescription was established and implemented, which improved the level of rational drug use, effectively ensured the safety of drug use, and improved the satisfaction of patients.

Advances in venlafaxine-related PK-PD relationship and influencing factors

WANG Xin, WU Guodong, AN Ming, LI Gang, LIU Yang

2023, 28(7):  788-795.  doi:10.12092/j.issn.1009-2501.2023.07.010

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Venlafaxine (VEN) is a new antidepressant drug that can effectively antagonize the reuptake of serotonin (5-HT) and norepinephrine (NE), compared with other antidepressants, venlafaxine pharmacokinetics/pharmacodynamics (PK-PD) is more regular and has the characteristics of less toxic side effects, fast oral absorption, and high bioavailability. This article reviews the PK-PD modelling of venlafaxine and its quantitative relationship, as well as the factors affecting the process in vivo of venlafaxine, including sex, body weight, individual genotype, liver and kidney function impairment, drug-drug interaction and other related factors.

Research progress on mechanisms and therapeutic drugs of peroxisome proliferator-activated receptor in treatment of cholestatic liver disease

WANG Anjing, WANG Yaya, LIANG Xuan, YAN Yajie, SU Jing, LI Caidong

2023, 28(7):  796-808.  doi:10.12092/j.issn.1009-2501.2023.07.011

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Cholestatic liver disease is a common disease that causes bile flow dysfunction due to various reasons. The etiology of cholestatic liver disease is complexed, and therapeutic drugs are extremely limited. To date, ursodeoxycholic acid is the only FDA-approved drug for treating primary biliary cirrhosis, whereas its efficacy is limited to early stage of the disease, therefore novel drugs are urgently needed. Nuclear receptors become therapeutic hotspot target in cholestasis since these receptors play a key role in regulating bile acid homeostasis. Peroxisome proliferator-activated receptor (PPAR) is an important nuclear receptor involved in regulating multiple mechanisms of cholestasis in vivo. It can improve intrahepatic cholestasis by inhibiting bile acid synthesis, reducing bile acid toxicity, affecting the expression of bile acid metabolic enzymes and transporters, and can play an anti-inflammatory, anti-oxidation and anti-fibrosis role. A number of studies have shown that PPAR agonists represented by fibrates alone or in combination can improve liver function indexes, inflammatory factors and fibrosis markers in patients with cholestasis. This review analyzes and summarizes the lastest advances in the molecular mechanism of PPAR as a therapeutic target for cholestasis and drug treatment in development or have been used in clinical.

Research progress in plasma concentration monitoring of rivaroxaban

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

2023, 28(7):  809-817.  doi:10.12092/j.issn.1009-2501.2023.07.012

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Rivaroxaban, a novel oral anticoagulant drug, is widely prescribed in clinical practice. Rivaroxaban offers predictable pharmacokinetic and pharmacodynamic properties, a lowprobability of drug-drug and food-drug interactions. Compared with warfarin, rivaroxaban does not require continuous therapeutic monitoring and can be administered in fixed doses.However,in certain emergency clinical situations, such as bleeding, acute stroke, acute kidney injury, prior to urgent surgery and in the suspected accumulation of durg, plasma concentration monitoring of rivaroxaban is necessary and important for patients. Existing studies proved that there were significant individual variability and wide range in the plasma rivaroxaban concentration, which increased the risk of clinical use. Therefore, Data in the degree of rivaroxaban concentration may provide recommendations for the clinical application to promote medication safety and individuality in the future. This article collected the latest literatures and case reports related to research progress of rivaroxaban plasma concentration monitoring, and Summarized influencing factors, monitoring methods, so as to provide a basis for further study on rational use of rivaroxaban in clinical.

The possibility of phosphodiesterase 4 inhibitors as drug therapy for idiopathic pulmonary fibrosis

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

2023, 28(7):  818-823.  doi:10.12092/j.issn.1009-2501.2023.07.013

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Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and typical chronic fibrotic lung disease. In recent years, significant progress has been made in the pathophysiology, clinical diagnosis and treatment of IPF. However, to date, there is still no cure for IPF. The second messenger cyclic adenosine monophosphate (cAMP) inhibits fibroblast proliferation or differentiation into myofibroblasts during the development of IPF. Phosphodiesterase 4 (PDE4) is a major camp-degrading enzyme in lung fibroblasts, which is up-regulated during the progression of fibrosis. PDE4 inhibitors have anti-fibrosis effects in vivo and in vitro in IPF models. In addition, PDE4 is widely involved in inflammatory processes, which are also active in the pathogenesis of IPF. Thus, PDE4 inhibition is a potential therapeutic approach for IPF. This article reviews the pathogenesis of IPF and the physiological function of PDE subtype 4 inhibitors in the treatment of IPF. 

Application of sodium-glucose cotransporter 2 inhibitors in acute myocardial infarction

HAO Xiao, ZHAO Mei, WANG Wenjing, ZHANG Feifei, LIU Huiliang, DANG Yi, LI Shuren, QI Xiaoyong

2023, 28(7):  824-831.  doi:10.12092/j.issn.1009-2501.2023.07.014

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SGLT2 inhibitors currently have clear benefits in the treatment of heart failure whether combined with diabetes or not. Ventricular remodeling after myocardial infarction leads to the occurrence and development of heart failure, and eventually leads to death. There are relatively few studies on SGLT2 inhibitors in patients with myocardial infarction. The purpose of this article is to review the research progress of SGLT2 inhibitors application before and after myocardial infarction.

Research progress on therapeutic role of recombinant human soluble thrombomodulin in atherosclerosis

ZHAO Lingzhi, HE Yanjun, XIE Jianqin, YOU Chongge

2023, 28(7):  832-840.  doi:10.12092/j.issn.1009-2501.2023.07.015

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Atherosclerosis is a multifocal, smoldering, immunoinflammatory disease caused by lipid accumulation. Acute cardio-cerebrovascular disease caused by AS is one of the most serious life threats in the world. Endothelial cell injury, vascular inflammatory stimulation, abnormal lipid metabolism and coagulation disorder are the main pathological mechanisms of AS. Thrombomodulin (TM) is a transmembrane glycoprotein mainly expressed on the surface of endothelium. It plays a key role in maintaining the dynamic equilibrium of the vascular system through its functions of anti-coagulation, anti-inflammation and cell protection. Recombinant human soluble thrombomodulin (rhsTM), a soluble form of human TM containing the extracellular domain of TM, might be effective in the treatment of AS. This review summarizes the structure and function of TM and the mechanism of rhsTM in the treatment of AS. Aiming to provide new ideas for the prevention and treatment of AS.