Journal of Hainan Medical University
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    2024(20):1521-1526, DOI: 10.13210/j.cnki.jhmu.20240603.001
    Abstract:
    Objective:Hepatitis E virus (HEV) is a member of Hepeviridae that has a positive sense, single‑stranded approximately 7 kb‑long RNA. HEV can be divided into four genera: HEV‑A, ‑B, ‑C and, ‑D. HEV‑A is known to be pathogenic to humans. However, the genetically highly divergent rat origin HEV (HEV‑C), which was originally considered only to infect rodents, was also reported to infect humans in Hong Kong China, Spain, and central Africa as well as in nonhuman primates, implying a possibility of rat HEV transmission to human. From our preliminary study, we have detected a HEV‑C gene in rat feces collected from Chengmai City, Hainan province. Here, we extensively studied the molecular characteristics of a rat HEV whole genome denoted ratHEV‑HMU‑8. Methods:Viral RNA was isolated from rat feces using Trizol reagent and was further reversely transcribed into cDNA using Oligo dT primer using commercial reagent according to the manufacturer’s instructions. Each ratHEV ORF region was amplified with PCR and the nucleotide sequences were determined by the Sanger sequencing method. Obtained ORF sequences were assembled to build a full‑length ratHEV genome. Sequence alignment was performed with the Clustal W method and the ratHEV‑HMU‑8 genotype was further verified by a maximum likelihood method with 1000 iterations of bootstrap sampling using DNAstar software. Results:Based on phylogenetic analysis, the HEV‑C gene studied here was identified as the genotype HEV‑C1 subgenotype and genetically close to the HEV‑C1 from Zhanjiang City (GenBank No. LC549184), the genetic identity is 93.1%. However, the genetic homology is low when compared with the reference from Yunnan Province, Hubei Province, and Hong Kong China, the genetic identity is 65.7%, 65.9%, and 85.4%, respectively. Conclusions:In our study, the first full‑length genome of rat HEV‑C1 from Hainan province was isolated and analysis by phylogenetic analysis, implying the potential risk of HEV‑C rat‑to‑human transmission that would cause rat HEV infection in Hainan. Thus, the prevalence of rat HEV in domestic animals and humans should be investigated to prevent or warn of a possible outbreak of rat HEV infection in the future.
    2024(20):1527-1534, DOI: 10.13210/j.cnki.jhmu.20240527.001
    Abstract:
    Objective:To explore the metabolic markers of acetaminophen-induced acute liver injury in rats through metabolomic analysis, and to evaluate the protective mechanism of wild pineapple fruit water extract on liver injury. Method:Thirty rats were randomly divided into 5 groups:control group, model group, wild pineapple extract high‑dose group (500 mg/kg), wild pineapple extract low‑dose group (200 mg/kg) and the positive drug group (silibinin, 30 mg/kg). The administration was continued for 7 days. One hour after each administration, except for the control group, the other groups were given acetaminophen 2 000 mg/kg via gavage. 24 H after the administration, blood samples were collected via the abdominal aorta to determine the levels of liver function indicators (ALT, AST) and to conduct histopathological observations. The biomarkers and metabolic pathways of serum samples were analyzed using H‑NMR. Results:Wild pineapple extract can significantly reduce the serum ALT and AST levels in rats with acute liver injury, and significantly alleviate the pathological damage of the liver, showing the protective effect on the liver, especially at low doses, and its liver protection effect is more prominent than that at high doses. Wild pineapple extract can regulate the metabolic disorder caused by liver injury and increase the levels of acetone and glutamine. Metabonomics analysis revealed 10 potential biomarkers and 6 metabolic pathways. Conclusion:Wild pineapple extract provides protection against acute liver injury caused by acetaminophen by regulating the metabolism of ketone bodies, sugars and amino acids and butyric acid in rat liver, thus effectively improving liver function and alleviating liver injury.
    2024(20):1535-1546, DOI: 10.13210/j.cnki.jhmu.20240618.001
    Abstract:
    Objective:To observe the effects of strengthening spleen and cleansing formula on adriamycin‑induced balb/c mice and mouse renal podocytes (MPC‑5) to explore the potential effect mechanism of its anti‑oxidative stress against focal segmental glomerulosclerosis (FSGS) to ameliorate podocyte injury. Methods:(1) In vivo experiments: balb/c mice were randomly divided into five groups:the blank group (CON),the model group (MOD),the low‑dose group (L: 1.13 g/kg),the medium‑dose group (Z: 2.26 g/kg) and the high‑dose group (H: 4.52 g/kg) of the strengthening spleen and clearing harmonizing formula. In the experimental group of balb/c mice, FSGS animal model was established by single tail vein injection of adriamycin (10.5 mg/kg), and the drug was administered by continuous gavage for 6 weeks after modeling. The 24‑h urine protein (quantitative), blood creatinine, and the levels of superoxide dismutase (SOD), malonaldehyde (MDA), catalase (CAT) in renal tissues were measured. H&E, Masson and PAS staining were used to observe the degree of renal histopathological damage. Transmission electron microscopy (TEM) was used to observe the morphological changes of podocytes. Immunofluorescence nephrine/p‑JAK2 double staining was used to observe the expression of p‑JAK2 on podocytes. The protein expression levels of p‑JAK2/JAK2, p‑STAT3/STAT3, and TGF‑β1 in renal tissues were detected by immunoblotting. (2) In vitro experiments: Experiment 1: The podocytes were divided into 5 groups:the control group (CON),the model group (MOD),the low‑dose group (L),the medium‑dose group (M), and the high‑dose group (H) of JianSheng QingHua Fang. Experiment 2: Foot cells were divided into the CON group (CON),the model group (ADR),the high dose group of strengthening the spleen and cleansing and harmonizing formula (ADR+H), and the C‑A1 group and the ADR+H+C‑A1 group. Experiment 1: The effects of adriamycin and spleen‑health clearing formula on cell viability were detected by CCK‑8 assay, and the intervention concentrations of modeling and spleen‑health clearing formula were screened. DCFH‑DA fluorescent probe was used to detect the content of cellular ROS in each group. Flow cytometry was used to determine the apoptosis of podocytes.Zmmunoblotting detected the protein expression levels of p‑JAK2/JAK2, p‑STAT3/STAT3, and TGF‑β1 as well as RT‑qPCR detected the downstream of STAT3 for the apoptotic factors BAX, BAD, Caspase3, p21, Blc‑2, and the inflammatory factors IL‑6, IL‑1β, and TNF‑α mRNA expression, Experiment 2: Zmmunoblotting was done to evaluate the effect of JAK2 agonist coumermycin A1 (C‑A1) on p‑JAK2/JAK2,p‑STAT3/STAT3 protein expression. Results:1. In vivo experiments: compared with the control group, glomerulosclerosis, basement membrane thickening, extensive fusion of podocytes, and p‑JAK2 fluorescence expression in renal tissues were significantly increased in the model group. 24 h urinary protein, blood creatinine, and MDA were elevated, and SOD, and CAT were decreased (P<0.05). The expression of p‑JAK2/JAK2, p‑STAT3/STAT3 and TGF‑β1 were elevated. Compared with the model group, foot cell injury was alleviated after the intervention of spleen‑enhancing and purifying formula, renal tissue p‑JAK2 fluorescence expression was reduced, 24 h urine protein, blood creatinine,and MDA were reduced as well as, SOD,and CAT were elevated. p‑JAK2/JAK2, p‑STAT3/STAT3,and TGF‑β1 expressions were reduced (P<0.05). 2. In vitro experiments: Experiment (1): CCK‑8 analysis showed that the modeling concentration of adriamycin was 0.4 μg/mL, and the intervening low, medium and high concentrations of the strengthening spleen and clearing harmonization formula were 1 mg/mL, 2 mg/mL and 4 mg/mL, respectively. compared with the control group, the apoptotic cell number and ROS content increased in the model group, and the expressions of p‑JAK2/JAK2, p‑STAT3/STAT3 and TGF‑β1 were elevated (P<0.05),mRNA expressions of BAX, BAD, Caspase3, p21, IL‑6, TNF‑α,and IL‑1β were decreased, and Blc‑2 mRNA expression was elevated (P<0.05); compared with the model group, after the intervention of the spleen‑strengthening and cleansing formula, the number of apoptotic cells,and the ROS content were decreased, JAK2/STAT3, TGF‑ β1 protein expressions were decreased,as well as mRNA expressions of BAX, BAD, Caspase3, p21, IL‑6, TNF‑α,and IL‑1β were elevated, while mRNA expression of Blc‑2 was decreased with a quantitative effect relationship (P<0.05). Experiment (2): Compared with the control group, p‑JAK2/JAK2 protein expression was elevated in the C‑A1 group (P<0.05); compared with the ADR+H group, p‑STAT3/STAT3 protein expression was elevated in the ADR+H+C‑A1 group (P<0.05). Conclusion:Strengthening spleen and clearing formula may improve podocyte injury in mice with focal segmental glomerulosclerosis by reducing oxidative stress through inhibiting the activation of TGF‑β1/JAK2/STAT3 signaling pathway.
    2024(20):1547-1556, DOI: 10.13210/j.cnki.jhmu.20240517.001
    Abstract:
    Objective:To investigate the anti‑hepatocellular carcinoma (HCC) effects of Ganning Decoction and its primary mechanisms. Methods:A total of 40 SD rats were given Ganning Decoction by gavage for 7 days, and serum samples were collected. CCK8 assay was used to detect the effect of serum concentration of Ganning Decoction on the viability of human hepatoma cell line HepG2 at 5%, 10%, 20% and 30%, respectively. HepG2 cells were divided into blank group and Ganning Decoction‑containing serum group. After 24 h of intervention with 5% serum containing Ganning Decoction, cellular proteins were extracted and processed for DIA quantitative proteomic analysis,including the establishment of atlas database and DIA data collection and analysis. The expression of TAGLN protein was detected by Western blot (WB). 10 BALB/c nude mice were divided into model group and Ganning Decoction group. The HCC model was established by subcutaneous injection of human liver cancer cell line MHCC‑97H. After successful modeling, 0.9% normal saline or Ganning Decoction was given by gavage for 14 days. The subcutaneous tumor volume was measured every one week from the beginning of modeling to the end of administration and the drew tumor growth curve. After the end of administration, the tumors were dissected, and the histopathological examination of the tumors were detected by hematoxylin‑eosin (HE) staining. Results:Ganning Decoction‑containing serum decreased HepG2 cell viability in a dose‑dependent manner (P<0.05,P<0.01). 5% Ganning Decoction‑containing serum was used for subsequent experiments. DIA quantitative proteomics analysis showed 36 up‑regulated proteins and 23 down‑regulated proteins (P<0.05). GO enrichment analysis showed cellular component, molecular function and biological process. KEGG enrichment analysis outcomes pointed out the discrepant proteins were closely related to complement and coagulation cascades, PPAR signaling pathway, etc. Reactome enrichment analysis revealed 20 signaling pathways including exocytosis of platelet alpha granule contents. PPI network showed that 38 proteins such as TGFB1, SERPINE1 and TAGLN were in the network nodes. WB validation results show that the expression of TAGLN in Ganning Decoction group was significantly higher than that in the blank group (P<0.01). The subcutaneous model of HCC in nude mice showed that Ganning Decoction could inhibit tumors growth (P<0.05), and HE staining showed that Ganning Decoction could promote tumor necrosis. Conclusion:Ganning Decoction can inhibit the proliferation of HepG2 cells and tumors, and promote the tumor necrosis. The mechanism involves multiple biological processes and signaling pathways, which may be related to the regulation of TAGLN protein expression.
    2024(20):1557-1563, DOI: 10.13210/j.cnki.jhmu.20240530.001
    Abstract:
    Objective:To explore the effect and mechanism of cigarette smoke-induced testicular injury in rats by activating NLRP3 inflammasome to induce pyroptosis. Methods:40 SPF healthy male Sprague-Dawley rats were randomly divided into a control group, a low-dose smoking group (10 cigarettes/day), a medium-dose smoking group (20 cigarettes/day), and a high-dose smoking group (30 cigarettes/day). The rats in the smoking group were sacrificed after 8 weeks of inhalation of cigarette smoke by respiratory static method. At the same time, the level of ROS in testicular tissue and the levels of inflammatory factors IL-1β, IL-18, TGF-β1, and MCP-1 in plasma were tested. The mRNA and protein expression levels of pyroptosis-related factors NLRP3, ASC, Caspase-1, GSDMD, IL-1β, and IL-18 were detected by RT-PCR and western blot. Results:After 8 weeks of cigarette smoke exposure, the testicular tissue of rats showed obvious pathological damage. The levels of ROS and pyroptosis in testicular tissue and the levels of IL-1β, IL-18, TGF-β1, and MCP-1 in plasma of rats in low-, medium- and high-dose smoking groups were significantly higher than those in the control group (P<0.05). With the increase of cigarette smoke exposure dose, the mRNA and protein expression levels of NLRP3, ASC, Caspase-1, GSDMD, IL-1β, and IL-18 in rat testis tissue increased gradually. Conclusion:Cigarette smoke exposure can cause testicular inflammatory injury in rats, and the mechanism may be related to pyroptosis caused by activation of NLRP3 inflammasome.
    2024(20):1564-1569, DOI: 10.13210/j.cnki.jhmu.20240531.003
    Abstract:
    Objective:To understand the prevalence and influencing factors of allergic rhinitis among children in Sanya,and to provide reference for the prevention and treatment of allergic rhinitis in children in Sanya. Methods:A stratified cluster sampling method was used to select 2051 children aged 6~14 years in five districts (Jiyang District,Tianya District,Yazhou District,Haitang District,Yucai Ecological District) of Sanya from September to December 2022 for epidemiological investigation.The self-reported prevalence and clinical symptoms of allergic rhinitis were analyzed,and the influencing factors were analyzed by binary logistic regression analysis. Results:A total of 2 051 questionnaires were collected,of which 1 765 were valid,with an effective rate of 86% (1 765/2 051).The mean age was 11.4 years. There were 895 boys (50.7%) and 870 girls (49.3%).The self-reported prevalence of allergic rhinitis in children in Sanya was 47.1%.The results of multi‑variate logistic regression analysis showed that:age ≥12 years[OR=1.497,95% CI(1.227‑1.825),P<0.001],passive smoking status at home[OR=1.451,95% CI(1.176‑1.790),P=0.001],using antibiotics≥5 times a year[OR=2.255,95% CI(1.616‑3.145),P<0.001],exercise <1 times per week[OR=1.656,95% CI(1.282‑2.139),P<0.001],less than 8h of daily sleep duration [OR=1.774,95% CI(1.438‑2.188),P<0.001],cleaning < 2 times a month at the place of residence [OR=1.423,95%CI(1.037‑1.953),P=0.029],frequent exposure to dust[OR=2.765,95% CI(2.020‑3.783),P<0.001],family history of allergic rhinitis [OR=2.687,95% CI(1.987‑3.634),P<0.001],history of food allergy[OR=1.538,95% CI(1.032‑2.294),P=0.035],history of chronic sinusitis[OR=6.633,95% CI(3.667‑11.998),P<0.001],history of adenoidal hypertrophy[OR=2.312,95% CI(1.282‑4.171),P=0.005]were risk factors for allergic rhinitis. Conclusion:The self‑reported prevalence of allergic rhinitis among children in sanya is higher than reported in most areas of China,age,passive smoking at home,use antibiotics,exercise frequency,daily sleep time,Frequency of living environment cleaning,frequent exposure to dust,family history of allergic rhinitis,history of food allergy,history of chronic sinusitis and history of adenoidal hypertrophy are all associated with allergic rhinitis disease. Among them,frequent exposure to dust,family history of allergic rhinitis, history of chronic sinusitis and history of adenoidal hypertrophy have the most obvious effect on allergic rhinitis.
    2024(20):1570-1578, DOI: 10.13210/j.cnki.jhmu.20230804.002
    Abstract:
    Objective:To systematically evaluate the efficacy and safety of PARPi in the treatment of metastatic castration resistance prostate cancer mCRPC to provide evidence-based medical evidence for clinical decision making. Methods:According to the inclusion and exclusion criteria, PubMed, Web of Science, Embace, and Clinicial.gov were searched for randomized controlled trials of PARPi for treating mCRPC from January 2015 to June 2023. A Meta-analysis was performed using RevMan5.4 and Stata17.0 software. Results:Seven randomized controlled trials involving 1 888 patients were included. The results of the meta-analysis showed that compared with the non-PARPi group, the PARPi group (PARPi with or without anti-hormone therapy)exhibited significantly improved radiological progression-free survival (HR: 0.52, 95% CI: 0.34–0.78) and overall survival (HR: 0.72, 95%CI: 0.60–0.86) of mCRPC (P<0.05). In terms of safety, the incidence of grades 1–2 bone pain, back pain, anemia, neutropenia, nausea, vomiting, diarrhea, and fatigue was significantly higher in the PARPi group than in the non-PARPi group (P<0.05). Only the incidences of nausea and anemia were significantly higher in the PARPi group than in the non-PARPi group (P<0.05), with no significant difference in bone pain, back pain, neutropenia, vomiting, diarrhea, and fatigue between the two groups (P>0.05). Conclusion:Compared with non-PARPi, the treatment of mCRPC with PARPi with or without anti-hormone therapy can improve radiological progression-free survival and overall survival, with a low incidence of grade 3 and above adverse reactions, which is worthy of clinical application.
    2024(20):1579-1587, DOI: 10.13210/j.cnki.jhmu.20240604.002
    Abstract:
    Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults, which leads to poor prognosis due to its high heterogeneity, rapid growth and intense aggressiveness. In recent years, the role of cell surface enzyme CD39 in the GBM tumor microenvironment has received widespread concern. CD39 produces the immunosuppressive molecule adenosine (ADO) by efficiently decomposing extracellular ATP and ADP, which significantly affects the anti-tumor immune response. This article reviewed the function of CD39 in regulating a variety of immune cells in GBM, such as MDSCs, TAMs, TILs, NKs and DCs, and discussed the therapeutic strategies for CD39, including the potential of inhibitor and antibody therapy, to provide new ideas for GBM therapy. This study provides a new perspective for the development of more effective GBM treatments and is expected to improve patient outcomes.
    2024(20):1588-1593, DOI: 10.13210/j.cnki.jhmu.20240530.003
    Abstract:
    G protein-coupled receptor 124(GPR124) can promote the expression of VEGF, NLRP3 and PPARγ to participate in the occurrence and development of periodontitis, and cause pathological changes such as gingival microcirculation deterioration and inflammatory injury of endothelial cells. This article will summarize the biological characteristics of GPR124 and elaborate the possible relationship between GPR124 and NLRP3, VEGF, and PPARγ in the deterioration of periodontitis, so as to provide new treatment ideas for patients with periodontitis or periodontitis accompanied by systemic diseases.
    2024(20):1594-1600, DOI: 10.13210/j.cnki.jhmu.20241011.003
    Abstract:
    Scrub typhus is a local epidemic disease infected by the bite of chigger larvae. It is an intracellular disease caused by rickettsia orientalis infection. It usually shows no obvious specificity at first, similar to the symptoms of influenza, such as fever, headache, cough, muscle aches, temporary hearing loss, etc. Some patients can find specific eschar and lymph node enlargement on physical examination, and the disease can involve multiple organs in the body. Severe patients often have acute respiratory distress syndrome (ARDS), acute renal failure, myocarditis, meningitis, DIC and other complications. At present, people have a poor understanding of this disease. Because the first doctors are mostly primary-level doctors, the rate of misdiagnosis and missed diagnosis of tsutsugamushi is still high. According to the different strains of tsutsugamushi disease in different regions, the difference in disease detection time, and the difference in population genetics, the positive rate of Weifi test is poor. Currently, there are few studies on Tsutsugamushi disease combined with acute respiratory distress syndrome. This paper reviews the latest research progress in diagnosis and clinical treatment of Tsutsugamushi disease combined with acute respiratory distress syndrome. The aim is to provide reference for clinical diagnosis and treatment of scrub typhus complicated with ARDS.
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    2021,27(13):1036-1040, DOI: 10.13210/j.cnki.jhmu.20200706.001
    Abstract:
    Hepatic fibrosis is a common pathological basis for all chronic liver diseases, and a necessary stage for the progression of chronic liver disease into cirrhosis. Since various cells and cytokines, as pathogenic factors, play a major role in hepatic fibrosis, the pathogenesis of hepatic fibrosis is extremely complicated. This review focuses on the role of different cells and cytokines (macrophages, natural killer cells and natural killer T cells, tumor necrosis factor, IL-22, transforming growth factor beta, connective tissue growth factor, vascular endothelial growth factor) in the progression of hepatic fibrosis.
    2021,27(21):1672-1676, DOI: 10.13210/j.cnki.jhmu.20200904.005
    Abstract:
    Parkinson's disease (PD) is a neurodegenerative disorder due to gradual loss of dopaminergic neurons in the substantia nigra in the midbrain, however, the pathogenesis is unclear. There is a correlation between the excitability of striatal neurons and PD. Ion channels are important to maintain membrane potential and regulate excitability of neurons, but ionic mechanisms for modulation of neurons excitability are not fully understood. This article reviews the relationship between ion channels and excitability of striatal neurons in PD and ion channel changes in the pathogenesis of PD, in order to find new targets to treatment PD by intervening ion channels.
    2021,27(17):1350-1354, DOI: 10.13210/j.cnki.jhmu.20200814.002
    Abstract:
    Cytokines play an important role in the pathological process of atherosclerosis (AS), affecting the progression and prognosis of AS-related cerebrovascular diseases. Cytokines mainly include C-reactive protein, interleukin, tumor necrosis factor, chemotactic cytokines, matrix metalloproteinases, etc. These cytokines promote or inhibit the inflammatory response and plaque formation during AS process through different targets and mechanisms. A comprehensive understanding of the cytokines in the occurrence and development of AS is conducive to search for new therapeutic targets and drugs.
    2021,27(17):1307-1311, DOI: 10.13210/j.cnki.jhmu.20200715.005
    Abstract:
    Objective: To explore the expression and prognostic significance of ADHs in hepatocellular carcinoma (HCC).Methods: The clinical data in this study were retrieved from The Cancer Genome Atlas (TCGA). The expression of ADHs was differentially analyzed in normal liver tissues and HCC by using the Metabolic gEne RApid Visualizer and the TCGA database, and the differentially expressed ADHs were selected for Kaplan‑Meier survival analysis. Cox analysis was performed to select factors that may influence the prognosis of HCC and to verify independent risk factors for HCC patients. The interaction among ADHs was explored at the gene level and protein expression level through GeneMAMIA and STRING, and the functional enrichment analysis of ADH family was carried out by using DAVID bioinformatics resources. Results: The expression levels of ADH1A, ADH1B, ADH1C, ADH4 and ADH7 in HCC were low. Patients with low expression level of ADH1A, ADH1B, ADH1C and ADH4 had poor survival rates, which may be related to the poor prognosis of HCC. Univariate Cox regression analysis showed that the expression levels of ADH1A, ADH1C and ADH4, as well as the clinical stage, T stage and M stage of the tumor were closely related to the overall survival rate of the patients. Multivariate Cox regression analysis further suggested that the low expression of ADH1A, ADH1C and ADH4 were independent risk factors affecting the prognosis of HCC patients. There was a pathway between ADH1A‑ADH1B, ADH1B‑ADH1C and ADH1A‑ADH1C, and ADHs were closely related to esterase D and aldehyde dehydrogenase. The ADHs were mainly involved in biological processes such as ethanol oxidation and retinol metabolism, and played a biological role in glycolysis/gluconeogenesis, chemical carcinogenesis and metabolism of xenobiotics by cytochrome P450. Conclusion: ADH1A, ADH1C and ADH4 may be biomarkers for the prognosis of HCC, providing reference value for the practical application of ADHs in HCC.
    2024(6):475-480, DOI: 10.13210/j.cnki.jhmu.20230804.003
    Abstract:
    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Its formation is a complex process, and the specific mechanism of its formation hasn't been cleared yet. Due to the fact that most HCC patients are diagnosed in the late stage, and they often lose good surgical opportunities. The emergence of targeted drugs has brought new hope to current HCC patients and can also serve as one of the measures for postoperative treatment, playing a huge role in treating HCC. Sorafenib is the first targeted drug used to treat HCC. It can induce apoptosis of liver tumor cells and inhibit proliferation and angiogenesis of liver tumor cells, so it can improve the survival rate of some patients. However, according to current research, 50% ⁃60% of HCC patients experience a decrease in sensitivity to the drug. It is mainly because Sorafenib will inhibit relevant signaling pathways in vivo after using, which leads to the occurrence of drug resistance, so further exploring the mechanism of Sorafenib resistance and reversing Sorafenib resistance have extremely important clinical value for improving the prognosis of liver cancer treatment. In recent years, many scholars have devoted themselves to studying the close relationship between Sorafenib mediated autophagy and drug resistance through Hippo/YAP and PI3K/Akt/mTOR signaling pathways. And exploring the molecular mechanisms of drug resistance has led to significant development in this field. Therefore, this article mainly discusses the relationship between Hippo/YAP and PI3K/Akt/mTOR signaling pathways and autophagy, as well as the mechanism of drug resistance mediated by them, so as to provide a reliable Scientific theory basis for drug resistance of Sorafenib in the treatment of liver cancer.
    2021,27(17):1281-1284, DOI: 10.13210/j.cnki.jhmu.20210716.002
    Abstract:
    The outbreak of COVID‑19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS‑CoV‑2) in 2019 threatens global public health. In the early stage, respiratory symptoms are the most common in patients with new coronal pneumonia, but with the spread of the disease around the world, gastrointestinal symptoms such as diarrhea, nausea and vomiting have attracted more and more attention. And some patients take diarrhea as the first symptom, which is easy to cause missed diagnosis. This paper expounds the close relationship between COVID‑19 and gastrointestinal tract, and reviews the research progress of COVID‑19's effect on gastrointestinal tract.
    2021,27(7):555-560, DOI: 10.13210/j.cnki.jhmu.20200930.003
    Abstract:
    Ulcerative colitis (UC) is a type of chronic inflammatory recurrent disease. The etiology and pathogenesis are still unclear by now. Among them, immune factors are usually considered to be the final link in the pathogenesis of UC. Due to the increasing incidence, long course of the disease, and difficult recovery, the relevant research is gradually deepened, and related research on intestinal flora, immunity, genetics, etc. has become a hot spot. A large amount of evidence indicates that regulatory T cells (Treg), helper T cells 17 (Th17), Th17/Treg immune axis and intestinal microbiota in UC patients play an important role in regulating the development of diseases. There is also a certain correlation between the bacterial flora and the Th17/Treg immune axis. Therefore, this article examines Th17/Treg cells, intestinal microbiota and the relationship between them by consulting a large number of relevant data at home and abroad in recent years. The formation of the immune axis and other issues are briefly summarized, with a view to providing more practical basis for clinical targeted therapy.
    Abstract:
    Endometriosis is not only a common disease in gynecology,but also a chronic and intractable disease in gy- necology.In recent years,with the increase of cesarean section rate and the increase of artificial abortion and hysteroscopic op- eration,the incidence of endometriosis has increased significantly,which impacts on women's health and quality of life.Treat- ments of endometriosis by western medicine mainly include hormone therapy and surgical treatment,which have many limita- tions and adverse reactions.In recent years,traditional Chinese medicine has shown more and more unique advantages,with di- versification.We summarized literatures about the treatment of endometriosis with traditional Chinese medicine in recent years.
    2021,27(11):872-875, DOI: 10.13210/j.cnki.jhmu.20200714.001
    Abstract:
    Drug resistance is a major problem when using molecular targeted drugs for tumors. Currently, functional gene screening is the most common strategy for screening drug resistance genes. In recent years, CRISPR‑Cas9 gene‑editing technology has been widely used in functional studies on tumor‑related genes because of its high accuracy, simplicity, and efficiency. In this paper, the principle of CRISPR‑Cas9 library screening technology and its application in functional gene screening are reviewed. At the same time, the application prospect of the CRISPR‑Cas9 technology is forecasted.
    2023(6):22-27, DOI: 10.13210/j.cnki.jhmu.20230217.001
    Abstract:
    Objective: A chiral resolution method for enantiomers of two chiral nitrogen⁃containing metabolites R⁃gentiandiol and S⁃gentiandiol of swertiamarin in plasma was developed, and the pharmacokinetics of the metabolites were studied. Methods: The metabolites of swertiamarin in vivo were detected by LC⁃MS/MS using Astec Cyclobond Ⅱ Cyclodextrin column (4.6 mm×100 mm, 5 μm), gradient elution with acetonitrile⁃water as mobile phase, and monitored by multiple reaction monitoring (MRM) method in positive mode. The ion pairs for quantitative analysis are R⁃gentiandiol (m/z 210.04→192.06), S⁃gentiandiol (m/z 210.04→192.06) and gentianone (m/z 192.02→162.08). Results: The linear correlation coefficients of the method developed were greater than 0.999, the precision was less than 7.00%, the recovery was 99.57%⁃102.65 %, and the matrix effect was 90.94%⁃91.34 %. The peak tmax of R⁃gentiandiol and S⁃gentiandiol in rat plasma after oral administration of swertiamarin were (1.63±0.23 h and (1.58 ± 0.21) h, t1/2 was (6.23±0.52) h and (5.46±0.38) h, Cmax was (86.79±20.81) ng/mL and (60.72±18.95) ng/mL, and the AUC0⁃24 were (1 094.58±86.37)) (ng·h)/mL and (724.67±58.38) (ng·h)/mL, respectively. Conclusion: The method was highly sensitive with good accuracy and precision, and it was successfully applied for chiral resolution and pharmacokinetics study of R⁃gentiandiol and S⁃gentiandiol in plasma. The method developed and experimental results will provide scientific basis for the study of pharmacodynamics and pharmacodynamic material basis of swertiamarin, and lay a foundation for clinical application and resource development of TCM monomer.
    2023(6):51-61, DOI: 10.13210/j.cnki.jhmu.20210713.001
    Abstract:
    Objective: To evaluate the clinical efficacy and safety of cinobufagin injection in the treatment of liver cancer. Methods: PubMed database, Embase database and Cochrane Library database, CNKI, Wanfang database, VIP database and Sinomed database were used to search for the randomized controlled trials of cinobufagin injection combined with Western medicine in the treatment of primary liver cancer. The retrieval time was from the establishment to December 15, 2020. Two independent researchers conducted systematic screening, literature inclusion and quality assessment of the articles according to the inclusion criteria, respectively. Meta‑analysis of the data was performed using RevMan 5.4 software. Results: A total of 30 studies with a total of 2 355 patients were included. Compared with conventional western medicine treatment, the clinical effective rate of Hububutin injection combined with western medicine was significantly higher [RR=1.16,95%CI=(1.11,1.22),P<0.000 01]. It could effectively reduce the tumor size [RR=1.33,95%CI=(1.17,1.51),P<0.000 01], prolong the survival time of patients [RR=1.41,95%CI=(1.31,1.52),P<0.000 01], improve the quality of life [RR=1.37,95%CI=(1.19,1.57),P<0.000 01], improve the liver function of patients [RR=-14.52,95%CI=(-16.15,-12.88),P<0.000 01], and reduce the occurrence of adverse reactions [RR=0.94,95%CI=(0.85,1.42),P=0.25] such as bone marrow suppression [RR=0.44,95%CI=(0.31,0.62),P<0.000 01]. Conclusion: Cinobufagin injection combined with western medicine therapy can effectively improve the clinical symptoms of primary liver cancer, and the safety is good. However, the methodological quality of the included literature is low, which affects the objectivity of the outcome, and it still needs to be verified by multi‑sample, multi‑center, randomized double‑blind controlled trial.
    2023(6):28-36, DOI: 10.13210/j.cnki.jhmu.20221125.001
    Abstract:
    Objective: To investigate the prognostic value of ORMDL2 in human glioma and its relationship with immune invasion. Methods: The clinical survival data from TCGA – LGG&GBM, CGGA and GEO were used to evaluate the clinical prognostic value of ORMDL2. The cut off value of ORMDL2 was detected with pROC package to draw ROC curve to prove its value in differential diagnosis of glioma. The first 300 genes with the most significant positive correlation with ORMDL2 were selected to establish PPI network through STRING database and conduct GO and pathway analysis. The relationship between the expression of ORMDL2 mRNA and immune cell infiltration was investigated by using ssGSEA and TIMER2.0 databases. Results: The expression of ORMDL2 mRNA in glioma was significantly higher than that in adjacent normal tissues, and the difference was most significant in high‑grade glioma. The expression of ORMDL2 was increased in human glioma, which was related to the clinicopathological characteristics and poor prognosis of glioma patients. In addition, the increased expression of ORMDL2 was associated with a series of immune infiltrating cells, including macrophages. Conclusion: ORMDL2 plays an important role in glioma immune cell infiltration and is a biomarker of prognosis of glioma patients.
    Abstract:
    Objective: To investigate the effect of mir⁃3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells, and to verify its target gene. Methods: The expression of mir⁃3168 in AGS and AGS/DDP gastric cancer cells was detected by qPCR, and mir⁃3168 mimic, inhibitor and negative control were synthesized. They were transfected into AGS and AGS/DDP gastric cancer cells, respectively. The expression of mir⁃3168 and TP53 mRNA was detected by qPCR. Cell viability was detected by CCK8 under gradient cisplatin treatment and non treatment, apoptosis was detected by flow cytometry, cell invasion was detected by Transwell, and TP53 protein expression was detected by western blot, The database predicted the binding sites of mir⁃3168 and TP53. According to the binding sites, the double luciferase experiment was used to verify the binding of mir⁃3168 and TP53. Results: Compared with cisplatin sensitive gastric cancer cell AGS, mir⁃3168 was significantly overexpressed in cisplatin resistant gastric cancer cell AGS/DDP; mir⁃3168 mimic promotes cisplatin resistance, proliferation and invasion of AGS and AGS/DDP gastric cancer cells, and inhibits apoptosis of AGS and AGS/DDP gastric cancer cells; mir⁃3168 inhibitor inhibits cisplatin resistance, proliferation and invasion of AGS and AGS/DDP gastric cancer cells, and promotes apoptosis of AGS and AGS/DDP gastric cancer cells; mir⁃3168 mimic inhibits the expression of TP53 mRNA and protein, and mir⁃3168 inhibitor promotes the expression of TP53 mRNA and protein; Targetscan database predicted that there was a binding point between mir⁃3168 and TP53, and the double luciferase experiment suggested that mir⁃3168 was bound to TP53 through the predicted binding site. Conclusion: mir⁃3168 may promote the malignant transformation of AGS and AGS/DDP gastric cancer cells and cisplatin resistance by targeting TP53.
    Abstract:
    Objective:To explore the establishment of an oxygen glucose deprivation/reperfusion model of senescent SH‑SY5Y cells. Methods: SH‑SY5Y cells were randomly divided into control (D‑galactose 0 mmol/L group), D‑galactose (25 mmol/L, 50 mmol/L, 100 mmol/L, 200 mmol/L, 400 mmol/L) groups, and treated with corresponding concentrations of D‑galactose for 48 h. The changes of cell morphology, β‑galactosidase, the cell morphology, β‑galactosidase activity by microscopic observation, cell proliferation rate by EdU kit and cell survival rate by CCK‑8 assay were used to determine the decaying concentration of D‑galactose and to establish the senescence model. The senescent SH‑SY5Y cells were randomly divided into control group (oxygen glucose deprivation without treatment group), oxygen glucose deprivation treatment (0.5 h, 1 h, 1.5 h, 2 h) group, followed by re‑glucose reoxygenation for 24 h, and CCK‑8 assay for the survival rate of senescent SH‑SY5Y cells. Results: There were no significant changes in cell morphology and β‑gal activity in the 25 mmol/L and 50 mmol/L groups compared with the control group (P>0.05), cytosolic hypertrophy was seen in the cells of the 100 mmol/L group, chromatin fixation in the cells of the 200 mmol/L group, and massive vacuolization in the cells of the 400 mmol/L group; the positive rate of β‑galactosidase staining in the cells of the (100-400 mmol/L) group was significantly higher compared with the control group (P< 0.05), with little difference between the 100 mmol/L and 200 mmol/L groups (P>0.05); the cell proliferation ability of the (100-400 mmol/L) group was significantly decreased in a concentration‑dependent manner (P<0.05); the cell survival rate was decreased in a concentration‑dependent manner (P<0.05), with IC50 between 100 mmol/L and 200 mmol/L. The survival of senescent SH‑SY5Y cells showed a time‑dependent decrease in oxygen‑glucose deprivation (P<0.05), with an IC50 close to 1 h. ConclusionD‑gal concentration of 100 mmoL/L and 48 h of cell action could establish a survival rate of about 50% of senescent SH‑SY5Y cells, and oxygen glucose deprivation of senescent SH‑SY5Y cells for 1 h and reperfusion for 24 h could establish an oxygen glucose deprivation/reperfusion model of senescent SH‑SY5Y cells with a survival rate close to 50%.
    2024(13):1035-1040, DOI: 10.13210/j.cnki.jhmu.20240005.001
    Abstract:
    Chronic wounds, as a long‑term wasting disease, are a long‑term clinical problem that is difficult to solve. Dysfunction of efferocytosis prevents apoptotic cells from being cleared from the wound in time, resulting in secondary cell necrosis and release of pro‑inflammatory cytokines, making it difficult for the wound to transition from the inflammatory phase to the proliferative phase. Macrophages and dendritic cells, as professional phagocytes, are the main bearers of efferocytosis. This article reviews the mechanism of action of these two types of professional phagocytes in the wound healing process and finds that in addition to efferocytosis‑related receptors, macrophages and dendritic cells also play a role in cytosis by acting on signaling molecules such as ICAM‑1, NK‑4, MIR‑21, CD36, etc., to accelerate the healing of chronic wounds. In addition, the efferocytosis function of dendritic cells may be limited by SLC7A11. Removing or inhibiting SLC7A11 can significantly enhance the efferocytosis of dendritic cells and promote chronic wound healing. This study is of great significance to further elucidating the healing process of chronic refractory wound and the development of new treatmentss.
    2023(6):15-21, DOI: 10.13210/j.cnki.jhmu.20211221.002
    Abstract:
    Objective: To investigate whether "Fuzheng Qingretonglin" decoction can reduce urinary tract damage caused by complex urinary tract infection caused by drug resistant Escherichia coli by regulating Nod‑like receptor pyrin domain3 inflammasome, and to explore the feasibility of this decoction combined with levofloxacin in the treatment of complex urinary tract infection caused by drug resistant bacteria. Methods: SD rats were divided into five groups: sham group, model group, levofloxacin group(Lev group), levofloxacin+Fuzheng Qingre Tonglin decoction group(FZ+lev group), and Fuzheng Qingre Tonglin decoction group(FZQRTL group). After the experiment, urine was taken for bacterial culture to determine the urinary tract infection of rats in each group; HE staining was used to observe the pathological changes of kidney and bladder tissues in rats; The expression of NLRP3 in kidney and bladder tissues was detected by immunohistochemistry; The expression of IL‑1β and IL‑18 in serum of rats was detected by ELISA; The expressions of NLRP3,ASC and Caspase‑1 were detected by Western blotting. Results: The positive rate of urine bacteria culture in the sham group was 0%, the positive rate of urine bacteria culture in the model group was 100%; and the positive rate of urine bacteria culture in the FZ+lev group was 37.50%, which was statistically different from that in the model group(P<0.05). A large number of inflammatory cells were observed in the kidney and bladder tissues of the model group by HE staining, while the number of inflammatory cells in the kidney and bladder tissues of the Lev group and FZQRTL group was significantly reduced compared with that of the model group. The FZ+lev group in the number and structure of inflammatory cells in kidney and bladder were similar to the sham group. The NLRP3 immunohistochemistry of kidney and bladder tissue in FZ+lev groups and FZQRTL groups was significantly different from that in model group(P<0.001). The levels of IL‑1β and IL‑18 in serum of Lev group,FZQRTL group and FZ+lev group were significantly decreased by ELISA compared with model group(P<0.001). The levels of IL‑1β and IL‑18 in the FZ+lev groups were significantly lower than in the Lev group and FZQRTL group, and the differences were statistically significant(P<0.05). The protein expressions of NLRP3, ASC and Caspase‑1 in the Lev group, FZQRTL group and FZ+lev group were significantly lower than those in the model group(P<0.001). The protein expressions of NLRP3, ASC and Caspase‑1 in the FZ+lev groups were significantly lower than in the Lev group and FZQRTL group, and the differences were statistically significant(P<0.05). Conclusion: "Fuzheng Qingretonglin" decoction may have a protective effect on the kidney and bladder of rats with complex urinary tract infection caused by drug‑resistant Escherichia coli by inhibiting the activation of NLRP3 inflammatory bodies, and TCM combined with levofloxacin has a better therapeutic effect than TCM or levofloxacin alone.
    2023(6):43-50, DOI: 10.13210/j.cnki.jhmu.20230116.001
    Abstract:
    Objective: To study the position and the grade of screw perforation in the apical region of adolescent idiopathic scoliosis (AIS) surgery using a calibration technique for the intraoperative navigation error, and to analyze the related factors of navigation deviation and the clinical significance of the calibration technique. Methods: From 2017 to 2020, a total of 60 Lenke 1 AIS surgical cases were enrolled in this research. The 30 cases received surgery using the intraoperative navigation system (Navigation group) and another 30 cases were assisted with intraoperative navigation system with calibration technique (Calibration group) for the intraoperative navigation error. The basic information and radiological data of the both groups were all recorded. According to the Fu Chang⁃feng’s pedicle channel classification system, the pedicle on the apical region of the two groups was classified. And then the accuracy of screw placement of the two groups was evaluated according to the Rao’s classification. Results: A total of 600 screws were placed in the two groups. The 297 and 303 pedicle screws were implanted in the navigation group and the calibration group, respectively. In the apical region of the calibration group, the rates of the grade 0 screw placement in type A, B and C pedicle were 95.7%, 86.7% and 68.9% respectively. It was a statistically significant difference from the 73.9%, 66.9% and 30.0% in the navigation group respectively (P<0.05). In the calibration group, the rates of the medial cortical perforation in the type A, B, C and D pedicle were 0%, 1.6%, 1.6% and 0%, respectively. The corresponding rates were 16.3%, 16.9%, 30.0% and 47.6% in the navigation group, respectively. Moreover, in the concave side of the apical region of the calibration group, the rates of the medial cortical perforation in the type A, B, C and D pedicle were 0%, 3.6%, 2.6% and 0%, respectively. Compared with the calibration group, the corresponding rates were higher in the navigation group (34.4%, 25.9%, 37.2% and 60.0%, respectively). No serious complications such as spinal cord or neurovascular injury occurred for the two groups. Conclusion: Compared with the intraoperative navigation system, the calibration technique for the intraoperative navigation error could provide the higher accuracy of pedicle screw placement in the apical region of the major curve, the lower medial cortical perforation rate, the less screws misplacement rate on the concave side and the less complication rate of the severe Lenke 1 AIS patients.
    2021,27(21):1652-1658, DOI: 10.13210/j.cnki.jhmu.20210609.001
    Abstract:
    Objective: To further understand the pathogenesis of psoriasis based on bioinformatics, gene set enrichment analysis (GSEA) and immune infiltration analysis were carried out on the microarray data of psoriasis expression profile. Methods: GSE6710 chip data were obtained from gene expression database (GEO), and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using GSEA software. A total of 22 kinds of immune cell gene expression matrices and R packages were downloaded from CIBERSOFT official website, and the immune cell infiltration matrix was obtained by R software and related graphs were drawn. Results: The pathways related to cell proliferation and innate immunity were highly expressed in psoriatic lesions, and some cancer‑related pathways were highly expressed in psoriatic lesions. Immunized cell infiltration analysis showed that activated memory T cells, follicular helper T cells, M0 macrophages and activated dendritic cells were up‑regulated in the psoriatic skin lesion group, and inactive mast cells were down‑regulated in the psoriatic skin lesion group. Activated dendritic cells were positively correlated with follicular helper T cells, activated mast cells were positively correlated with M0 macrophages. Inactivated mast cells were negatively correlated with activated memory T cells, M1 macrophages were negatively correlated with regulatory T cells, M0 macrophages were negatively correlated with inactive mast cells.Conclusion: Cell proliferation and innate immunity are of great significance in the pathogenesis of psoriasis. Immune cell infiltration analysis is generally consistent with the current psoriasis pathogenesis model. Macrophages and mast cells also play a certain role in psoriasis.
    2023(6):73-78, DOI: 10.13210/j.cnki.jhmu.20210701.001
    Abstract:
    Coronary no‑reflow phenomenon belongs to a type of coronary microcirculation disturbance, and its main pathogenic factors are vascular endothelial cell injury, microembolism and inflammatory reaction, which are corresponding to the pathogenesis of choroid injury, blood stasis and heat toxin in traditional Chinese medicine, such as NO, ET‑1, chemokine, IL and other cytokines. The degree of improvement of patients' symptoms and laboratory examination data provide a basis for traditional Chinese medicine compound prescription, monomer and traditional Chinese medicine characteristic therapy for the treatment of no-reflow phenomena(NRP). Combined with related factors, the author summarizes the research progress of traditional Chinese medicine treatment of NRP in recent years, in order to provide clinical reference.
    2021,27(7):481-487, DOI: 10.13210/j.cnki.jhmu.20200914.003
    Abstract:
    Objective: To investigate to the effect of hypoxia and hypoxia/reoxygenation on ROS, MAPKs and cell apoptosis in H9c2 cardiomyocytes. Methods: H9c2 cells were treated with cobalt chloride (CoCl2) at different concentrations (150, 300, 450, 600, 900, 1 200, 2 400 µmol/L) for 4-48 h to establish the hypoxia and hypoxia/reoxygenation-induced cardiomyocyte injury model. H9c2 cell viability was detected by MTT, and the intracellular ROS level was measured by 2',7'-dichlorofluorescin diacetate and dihydroethidium. In addition, the expression level of mitogen-activated protein kinases (MAPKs) (including phosphorylated JNK, ERK and p38) and caspase-3 was determined by Western blotting. Results: At 300-12 00 µmol/L, CoCl2 inhibited the cell viability in H9c2 cells in a concentration and time-dependent manner (P<0.01). Compared with the control group, the ROS levels under hypoxia condition were significantly increased (P<0.05) at 4 and 16 h. Moreover, the expression levels of p-JNK, p-p38 and caspase-3 were increased (P<0.05). However, the expression of p-ERK remained unchanged. Furthermore, the expression levels of ROS, p-JNK, p-ERK1/2, p-p38 and caspase-3 in the hypoxia/reoxygenation group were significantly increased compared with the hypoxia group (P<0.01). Conclusion: Reoxygenation further aggravates hypoxia-induced oxidative stress injury in cardiomyocyte by activating ROS/MAPKs signaling pathway, suggesting the role of myocardial ischemia/reperfusion injury in the pathogenesis of ischemic heart disease.

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