摘要
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world, and it is also one of the main causes of liver cirrhosis and hepatocellular carcinoma, so it is particularly important to curb the development and progression of NAFLD in a timely manner. However, due to its complex pathogeneses, there are currently no effective methods for radical treatment. As a new generation of probiotics, Akkermansia muciniphila (Akk bacteria) can improve metabolic disorders of the body, and more and more studies have shown that Akk bacteria have a potential therapeutic effect on metabolic diseases, especially NAFLD. Therefore, this article briefly reviews the mechanism of action of Akk bacteria in NAFLD, in order to provide new ideas for improving the treatment of NAFLD and creating new therapies.
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Retiform hemangioendothelioma (RH) is a rare vasogenic malignancy with a high local recurrence rate and rare distant metastasis. Hepatic RH in infants is extremely rare. Here we report a case of liver RH in a 7-month-old infant.
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Autoimmune hepatitis (AIH) is a type of chronic hepatitis caused by the attack of hepatocytes by the autoimmune system, and with the prolongation of disease course, it may gradually progress to liver cirrhosis and even hepatocellular carcinoma. Although great achievements have been made in the understanding and treatment of AIH, its etiology and pathogenesis still remain unclear. T cells play a crucial role in the development and progression of AIH, and by focusing on follicular helper T cells, this article elaborates on the research advances in follicular helper T cells in AIH, in order to provide new ideas and strategies for the clinical treatment of AIH.
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ObjectiveTo investigate the prevalence of liver cirrhosis and the changing trend of the disease burden of liver cirrhosis in the Chinese population from 1990 to 2019, and to provide a data reference for formulating the prevention and treatment strategies for liver cirrhosis in China. MethodsThe Global Burden of Disease Study 2019 was used to collect the data on the incidence rate, mortality rate, disability-adjusted life years (DALY), years of life lost (YLL), and years lived with disability (YLD) of liver cirrhosis. The Joinpoint regression model was used to analyze the changing trend of disease burden; the age-period-cohort (APC) model was used to evaluate age, period, and cohort effects; R software BAPC package was used to predict future changes in disease burden. ResultsFrom 1990 to 2019 in China, there were increases in the numbers of liver cirrhosis cases and prevalent cases in the general population, as well as in the male and female populations, while there was a reduction in the number of deaths. From 1990 to 2019, the standardized incidence rate, standardized prevalence rate, and standardized mortality rate of liver cirrhosis in the Chinese population showed a downward trend, with a mean annual reduction of 0.62% (95% confidence interval [CI]: -0.74% to -0.50%, t=9.99, P<0.001), 0.44% (95%CI: -0.53% to -0.35%, t=13.18, P<0.001), and 3.02% (95%CI: -3.12% to -2.93%, t=7.58, P<0.001), respectively. From 1990 to 2019, the standardized DALY, YLL, and YLD rates of liver cirrhosis in the Chinese population also showed a downward trend, with a mean annual reduction of 3.27% (95%CI: -3.37% to -3.18%, t=6.22, P<0.001), 3.32% (95%CI: -3.42% to -3.22%, t=9.31, P<0.001), and 1.42% (95%CI: -1.49% to -1.34%, t=4.93, P<0.001), respectively. From 1990 to 2019, the incidence rate of liver cirrhosis in the Chinese population first increased and then decreased with age, while the mortality rate showed an increasing trend, and the risks of disease onset and death showed a decreasing trend with time and birth cohort. The predictive model showed that the standardized incidence rate, prevalence rate, mortality rate, and DALY rate of liver cirrhosis in China will show a decreasing trend from 2020 to 2030. Alcohol was the most important risk factor for both male and female populations, followed by medication. ConclusionThe disease burden of liver cirrhosis in China shows a decreasing trend from 1990 to 2019, with sex and age differences, especially in the middle-aged male population. Effective measures should be taken for intervention.
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Objective To investigate the expression of Sema4D in peripheral blood T cells and serum of patients with hepatitis B cirrhosis and its correlation with clinical indicators. Methods A total of 20 patients with chronic hepatitis B (CHB), 68 patients with hepatitis B cirrhosis, and 20 healthy controls who attended The 940 th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army from October 2020 to November 2021 were enrolled. According to Child-Pugh class, the patients with hepatitis B cirrhosis were divided into Child-Pugh class A group with 24 patients, Child-Pugh class B group with 24 patients, and Child-Pugh class C group with 20 patients. After peripheral blood samples were collected to isolate serum and peripheral blood mononuclear cells (PBMCs), flow cytometry was used to measure the expression of membrane-bound Sema4D (mSema4D) + CD4 + T cells and mSema4D + CD8 + T cells in PBMCs, and ELISA was used to measure the expression of soluble Sema4D (sSema4D) in serum; their correlation with viral replication and liver inflammation markers was analyzed. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups, and the Mann-Whitney U test was used for further comparison between two groups; a Spearman correlation analysis was also performed. Results There were significant differences in the expression of mSema4D + CD4 + T cells and mSema4D + CD8 + T cells between the CHB group, the hepatitis B cirrhosis group, and the control group ( F =43.092 and 13.344, both P < 0.001), while there were significant differences between any two groups ( P < 0.05). The expression levels of mSema4D + CD4 + T cells and mSema4D + CD8 + T cells gradually decreased with increasing Child-Pugh class ( F =14.093 and 17.154, both P < 0.05), and there were significant differences between any two groups ( P < 0.05). The content of sSema4D was 1.54(1.42-1.71) ng/mL in the control group, 1.08(1.07-1.38) ng/mL in the CHB group, and 4.87(2.13-14.97) ng/mL in the hepatitis B cirrhosis group, with a significant difference between the three groups ( H =32.366, P < 0.001) and between any two groups ( P < 0.05). The content of sSema4D was 2.42(0.59-5.65) ng/mL in the Child-Pugh class A group, 4.92(2.75-12.73) ng/mL in the Child-Pugh class B group, and 14.18(4.59-18.43) ng/mL in the Child-Pugh class C group, with a significant difference between the three groups ( H =11.889, P =0.003) and between any two groups ( P < 0.05). In patients with hepatitis B cirrhosis, the level of sSema4D was positively correlated with the levels of alanine aminotransferase (ALT) and HBV DNA quantification ( r =0.294 and 0.430, both P < 0.05). Conclusion Sema4D is lowly expressed on T cell membrane and highly expressed in serum of patients with hepatitis B cirrhosis, and sSema4D may be involved in the development and progression of hepatitis B cirrhosis by affecting the levels of ALT and HBV DNA.
摘要
Liver transplantation, as one of the radical treatment strategies for hepatocellular carcinoma, has a good clinical effect in patients meeting the Milan criteria; however, the high recurrence rate and metastasis rate after surgery bring great challenges to the long-term survival of such patients. Therefore, how to improve long-term survival rate and reduce postoperative tumor metastasis has become a key problem that needs to be solved urgently. In recent years, immune checkpoint inhibitors (ICIs), with their good safety and objective reactivity, have provided a new opportunity for the treatment of patients with advanced liver cancer and have become potential candidates for improving the therapeutic effect of liver transplantation. At present, early clinical studies have reported the unique advantages of ICIs used alone or in combination in downstaging or bridging therapy before liver transplantation for hepatocellular carcinoma and adjuvant therapy after liver transplantation. Therefore, this article reviews the clinical trials of ICIs in liver transplantation for hepatocellular carcinoma and the advances in the application of ICIs in recent years and discuss its safety and efficacy, in order to provide a certain reference for clinical medication.
摘要
Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.
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Persistent HBV infection alters the expression of receptors on the surface of innate and acquired immune cells, which may cause a variety of immune disorders and finally lead to immune escape and disease chronicity. Studies have shown that the upregulation of inhibitory receptors is the main cause of immune disorders in patients, and blocking inhibitory receptors can restore immune function to a certain extent. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a new type of inhibitory receptor attracting much attention at present, and it is highly expressed in NK cells and T cells. It has been found that TIGIT plays an important role in chronic viral infection, and this article briefly reviews the research advances in the association between TIGIT and immune disorders in chronic HBV infection.
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In recent years, monotherapy and combination therapy with immune checkpoint inhibitors (ICIs) have achieved good efficacy in a variety of malignancies from solid tumors to lymphomas and have become a standardized and systematic treatment modality for many cancers. However, there is still a lack of studies on the safety of ICIs in hepatitis B virus (HBV)-infected patients with malignancies, and early studies have reported HBV reactivation due to ICI antitumor therapy in clinical practice. With reference to related literature, this article reviews the recent clinical trials and application of ICIs in cancer patients with chronic viral infection and clarifies the efficacy and safety of ICIs in this special population, in order to provide a reference for clinical medication.
摘要
Autoimmune hepatitis (AIH) is a type of chronic hepatitis caused by the autoimmune system attacking hepatocytes, and its chronic progression may lead to liver cirrhosis and even hepatocellular carcinoma. Currently, pharmacotherapy and liver transplantation are the main treatment methods for AIH, but both methods have their own limitations, which limits the clinical benefits of patients. Therefore, it is a critical issue to search for new therapeutic agents and methods. Recent studies have shown that mesenchymal stem cells (MSC) and their exosomes can improve the symptoms of patients with AIH by suppressing inflammatory response, enhancing the regeneration of hepatocytes, and regulating the immune system and thus have wide application prospects in the treatment of AIH. By summarizing related articles, this article reviews the possible mechanisms and application of MSC and their exosomes in the treatment of AIH, in order to provide new ideas for the clinical treatment of AIH.
摘要
N7-methylguanosine (m7G) is one of the most popular RNA modifications at present and has attracted wide attention from researchers in China and globally. By influencing the metabolism of various RNA molecules (including messenger RNA, ribosomal RNA, microRNA, and transfer RNA), m7G modification actively participates in many biological processes such as cell proliferation, differentiation, and apoptosis. More and more evidence has shown that m7G plays a key role in the development of cancer, and abnormal m7G levels are closely associated with the development and progression of cancer by regulating the expression of multiple oncogenes and tumor suppressor genes. Hepatocellular carcinoma is the most common gastrointestinal tumor in China, and current treatment methods tend to have an unsatisfactory therapeutic effect. At present, the potential molecular mechanism of m7G modification in hepatocellular carcinoma remains unclear. This article reviews the potential mechanism of action of m7G modification in hepatocellular carcinoma and the m7G-related diagnosis and treatment strategies.
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Objective:To discusse the value of pituitin in laparoscopic ovarian cyst removal.Methods:From October 2015 to June 2018 in Dalian Medical University Affiliated Dalian Maternity Hospital, useing prospective research methods, 90 patients with unilateral ovarian cyst (except endometriomas) were randomly divided in 3 groups of pituitrin group,control group 1 and control group 2. The pituitrin group: laparoscopic cystectomy with the injection of diluted pituitrin 6 U, the total amount of diluted pituitrin 10 - 20 ml, ovarian hemostasis was achieved by sutura. The control group 1: ordinary laparoscopic cystectomy without injection suture hemostasis. The control group 2: laparoscopic cystectomy with the injection of normal saline 10 - 20 ml, ovarian hemostasis was same to pituitrin group. The operation time and the amount of bleeding were compared among the three groups. The ovarian reserve was compared between before and 3 months after operation by estradiol (E 2), follicle-stimulating hormone (FSH), luteinizing hormone (LH). Results:The amount of bleeding in the pituitrin group was less than that in the control group1: (14.00 ± 5.48) ml vs. (18.33 ± 6.99) ml, P<0.05. The operation time in the pituitrin group and control group 2 was less than that in the control group1: (43.50 ± 7.21) min, (45.00 ± 10.29) min vs. (50.17 ± 8.95) min, P<0.05. The level of FSH after operatiaon in the pituitrin group and control group 2 was less than that in the control group1: (7.20 ± 1.55) U/L, (7.43 ± 1.52) U/L vs. (8.31 ± 0.97) U/L, P<0.05. The level of E 2 3 months after operation in the pituitrin group was higher than that in the control group 1 and control group 2: (54.20 ± 10.90) ng/L vs. (46.63 ± 10.76) ng/L, (43.90 ± 18.23) ng/L, P<0.05. There was no significant difference of LH 3 months after operation among the three groups ( P>0.05). Conclusions:This study shows that diluted pituitrin decreases operation time and the amount of bleeding during operation, at the same time,the pituitrin injection is valued of ovarian reserve.
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Objective:To compare the efficacy and safety of endoscopic sclerotherapy with polycinnamol solution and foam in the treatment of grade II hemorrhagic internal hemorrhoids.Methods:From September 2020 to June 2021, 81 patients with grade II hemorrhagic internal hemorrhoids were collected from the Department of Gastroenterology, the First Affiliated Hospital of University of Science and Technology of China. They were randomly divided into an observation group and a control group. The observation group was injected with polycinnamol solution, and the control group was injected with polycinnamol foam. All of them were treated with endoscopic sclerotherapy. The clinical data of the two groups were compared and analyzed. The operation time, immediate hemostasis rate, incidence of postoperative complications (such as fever, pain, bleeding and Urinary retention), recurrence and rebleeding rate of the two groups were observed, and the efficacy and safety of the two groups in the treatment of grade II hemorrhagic internal hemorrhoids were compared.Results:There was no statistically significant difference in basic data between the two groups of patients (all P>0.05), indicating comparability. The surgical operation time of the observation group patients [(7.40±1.18)min] was shorter than that of the control group [(13.88±0.95)min] ( P<0.05); The injection dose of polycinnamol [(5.79±1.61)ml] in the observation group was higher than that in the control group [(4.38±1.92)ml] ( P<0.05). The immediate postoperative hemostasis rate in the observation group was the same as that in the control group (100%). The incidence of postoperative fever (7.32%), perianal pain (4.88%), bleeding (7.32%), and urinary retention (4.88%) complications in the observation group had no significant difference from that in the control group [postoperative fever (5.00%), anal pain (7.50%), bleeding (7.50%), and urinary retention (2.50%)] (all P>0.05). Two months after surgery, the rebleeding rate in the observation group (4.88%) was not significantly different from that in the control group (7.50%) ( P>0.05), but the rebleeding score in the observation group (1.21±0.63) was lower than that in the control group (2.62±0.71), with a statistically significant difference ( P<0.05). The rebleeding rate (2.44%) and the rebleeding score (2.33±1.51) in the observation group were lower than those in the control group [the rebleeding rate (12.50%) and the rebleeding score (5.54±2.42)] at 12 months after follow-up, and the differences were statistically significant ( P<0.05). Conclusions:Endoscopic sclerotherapy is effective in the treatment of grade II hemorrhagic internal hemorrhoids. There is no significant difference in the immediate and short-term hemostasis rate and the incidence of complications between two different dosage forms of sclerotherapy, namely, polycinnamol solution and foam, but the operation of the solution injection is more time-saving and the long-term recurrence rate is lower, which is worthy of clinical application.
摘要
Objective To investigate the effect and mechanism of acteoside (ACT) in inhibiting epithelial-mesenchymal transition (EMT) in human hepatoma HCCLM3 cells by regulating the ERK1/2 pathway. Methods CCK-8 assay was used to detect the effect of hepatocellular carcinoma cell proliferation. The invasion and migration of HCC cells were detected by scratch and Transwell tests. The mRNA and protein expression levels of the ERK1/2 signaling pathway and EMT-related genes (E-cadherin and N-cadherin) were detected by real-time PCR and Western blot analyses. Results ACT reduced the activity of HCCLM3 cells and inhibited the proliferation of HCC cells, and the effects had certain correlation with drug concentration and time. ACT inhibited the migration and invasion process of HCCLM3 cells in a concentration-dependent manner. ACT downregulated the mRNA and protein expression of genes related to the ERK1/2 signaling pathway. It increased the mRNA and protein expression levels of the EMT-related gene E-cadherin but decreased those of N-cadherin. Conclusion ACT could inhibit EMT and the invasion and migration of HCCLM3 cells in human hepatoma, and the underlying mechanism is closely related to the downregulation of the ERK1/2 signaling pathway.
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Gastric cancer is one of the most common cancers in the world,and with the rise of immune-targeted therapy,it has provided new treatment options for many patients with advanced gastric cancer.However,not all cancer patients can benefit from monoclonal antibody therapy against programmed death-1 and its ligand and against cytotoxic T lymphocyte associated antigen-4.Therefore,the discovery of new immune checkpoints has become a future therapeutic trend.In this review,we summarized and analyzed the biological characteristics of V-domain Ig suppressor of T cell activation,B7 homolog 3 and lymphocyte-activation gene 3 of novel immune checkpoint T cell activation,as well as their effects on the occurrence and development of gastric cancer.At the same time,the effectiveness of corresponding immunosuppressants in preclinical and clinical trials was also evaluated,in order to provide a theoretical reference for the targeted therapy of gastric cancer.
摘要
Programmed death-1 and programmed death-ligand 1(PD-1/PD-L1)are regulatory immune checkpoint molecules that inhibit T cell activation and,therefore,play an important role in tumor immunotherapy.In recent years,increasing numbers of targeted therapeutic agents have been developed,but single immune checkpoint blockers cannot completely inhibit tumor occurrence,and tumor escape sporadically occurs.Consequently,combination therapy of targeted drugs is considered a useful method to inhibit tumorigenesis and tumor development.T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif(ITIM)domain(TIGIT)is an inhibitory type 1 poliovirus receptor that has recently been a hotspot of targeted drug therapy research.It has been shown that the combination therapy of TIGIT plus PD-1/PD-L1 can reduce tumor escape and inhibit tumorigenesis more effectively.Therefore,this review summarizes and discusses the progress on the dual blockade of TIGIT and PD-1/PD-L1 pathways in tumor immunotherapy to provide a theoretical basis for tumor im-munotherapy.
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Nonalcoholic fatty liver disease is a common chronic liver disease with the risk of progression to nonalcoholic hepatitis, liver fibrosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease has various pathogeneses, among which abnormal metabolism of branched-chain amino acids can induce oxidative stress, autophagy, and mitochondrial dysfunction in hepatocytes and is the most important mechanism in the development and progression of nonalcoholic fatty liver disease. This article reviews related research advances and analyzes the possible role of abnormal metabolism of branched-chain amino acids in the development and progression of nonalcoholic fatty liver disease, in order to improve clinical awareness and diagnosis.
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Objective:To investigate the expression of Macrophage migration-inhibitory factors (MIF) in hepatocellular carcinoma (HCC) tissues and its interaction with ERK1/2 signaling pathway, so as to establish a theoretical basis for further studying the molecular mechanism of MIF promoting HCC.Methods:From February 2020 to August 2021, 52 cases of hepatocellular carcinoma (HCC) tissues based on hepatitis B cirrhosis (HBV-LC) and 52 cases of adjacent tissues in Tianjin Medical University Cancer Hospital and 940th Hospital of Joint Logistic Support Force of PLA were collected as the experimental group, including 39 males and 13 females, aged 35-65 years. And 20 cases of normal liver tissue were selected as the control group. Immunohistochemistry was used to detect the expression of MIF, ERK1/2 and p-ERK1/2 proteins in liver tissues of the two groups, and in situ hybridization was used to detect the expression of ERK1/2 nucleic acid in liver tissues of the two groups.HepG2 HCC cells and L-02 normal hepatocytes were co-cultured with different concentrations of rMIF, the expression and phosphorylation levels of ERK1/2 and JNK1 proteins in the two kinds of liver cells were detected by Western-blot, and the expression levels of ERK1/2 nucleic acids in the two kinds of liver cells were detected by RT-PCR. One-way ANOVA was used for measurement data and χ 2 test was used for counting data. Results:The expressions of MIF, ERK1/2, p-ERK1/2 and ERK1/2 mRNA were significantly increased in HCC and para-cancer tissues (the expression of MIF in HCC group was 78.8%, and that in adjacent group was 75.0%; ERK1/2 80.8% in HCC group and ERK1/2 71.8% in paracancerous group. The expression of p-ERK1/2 75.0 % in HCC group and 46.2% in paracancerous group were respectively detected. ERK1/2 mRNA was expressed in HCC group 76.9%, ERK1/2 mRNA expression in paracancerous group 78.8%), and the differences were statistically significant compared with normal liver tissues ( P<0.05), but there was no significant difference between HCC and para-cancer tissues ( P>0.05). The expressions of ERK1/2, p-ERK1/2 and ERK1/2 mRNA in HepG2 HCC cells were significantly increased with the increase of rMIF concentration, and the increase was most obvious when rMIF concentration was 200 ng/ml, and the difference was statistically significant compared with L-02 normal hepatocytes ( P<0.05). Conclusion:MIF, ERK1/2 and p-ERK1/2 are highly expressed in HCC tissues and HepG2 HCC cells, suggesting that MIF promotes the occurrence and development of hepatocellular carcinoma through ERK1/2 signaling pathway.
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Objective To evaluate the safety and efficacy of irreversible electroporation (IRE) combined with neoadjuvant chemotherapy in patients with locally advanced pancreatic cancer. Methods We searched PubMed, Embase, Cochrane Library, Web of Science, China Biomedical Literature Database, CNKI, Wanfang, and VIP databases for articles dated from the establishment of each database to March 2022. Meta-analysis was performed using RevMan5.4 software. Results A total of 3970 patients with locally advanced pancreatic cancer were enrolled in eight studies, including one randomized controlled trial, four retrospective studies, and three prospective studies. The patients were divided into the combined therapy group with 344 patients and the chemotherapy-only group with 3626 patients. Meta-analysis showed that the overall survival of patients in the combined therapy group was significantly higher than that in the chemotherapy-only group (OR=4.52; 95%CI: 2.63-7.77; P < 0.00001). However, no significant difference existed in the disease control rate between the combined therapy group and the chemotherapy-only group (OR=0.58; 95%CI: 0.02-18.74; P=0.76). Moreover, no significant difference existed in the disease progression between the two groups (OR=0.49; 95%CI: 0.23-1.02; P=0.06). The combination of neoadjuvant chemotherapy and IRE had no significant effect on the incidence of adverse reactions of gastrointestinal reaction (OR=0.37; 95%CI: 0.10-1.34; P=0.13) and bone marrow suppression (OR=0.61; 95%CI: 0.26-1.40; P=0.24). Conclusion IRE combined with neoadjuvant chemotherapy can remarkably improve the prognosis of patients with locally advanced pancreatic cancer, and significantly prolong the overall survival.
摘要
Objective: To research the effect of matrine on the proliferation and migration of HepG2 cells through extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Methods: HepG2 cell was selected and divided into blank control group, experimental group (matrine 1, 2, and 4 mg/mL), and positive control group (PD98059, ERK1/2 inhibitor). MTT measure was used to detect the effective time and concentration which matrine inhibits HepG2 cells. After 24 h, the effect of effective concentration of matrine on the of morphological changing HepG2 cells was observed. The invasion ability was assayed by transwell method, the expression of ERK1/2 and pERK1/2 were detected through Western blot, and reverse transcription polymerase chain reaction was used to test the expression level of ERK1/2 mRNA. Results: With the increase of matrine concentration, the number of adherent HepG2 cells gradually decreased, the morphologic changes gradually became spherical, some cell morphology was incomplete, and even cell fragments appeared. The proliferation and invasion ability of HepG2 cells decreased. The expression of ERK1/2, pERK1/2, and ERK1/2 mRNA downregulated with the increase of matrine concentration (P < 0.05). Conclusion: Matrine inhibits the proliferation and migration of HepG2 cells by downregulating the ERK1/2 signaling pathway.