Safety, tolerability, and immunogenicity of a CpG/Alum adjuvanted SARS-CoV-2 recombinant protein vaccine (ZR202-CoV) in healthy adults: Preliminary report of a phase 1, randomized, double-blind, placebo-controlled, dose-escalation trial.

This was a phase 1 dose-escalation study of ZR202-CoV, a recombinant protein vaccine candidate containing a pre-fusion format of the spike (S)-protein (S-trimer) combined with the dual-adjuvant system of Alum/CpG. A total of 230 participants were screened and 72 healthy adults aged 18-59 years were enrolled and randomized to receive two doses at a 28-day interval of three different ZR202-CoV formulations or normal saline. We assessed the safety for 28 days after each vaccination and collected blood samples for immunogenicity evaluation. All formulations of ZR202-CoV were well-tolerated, with no observed solicited adverse events ≥ Grade 3 within 7 days after vaccination. No unsolicited adverse events ≥ Grade 3, or serious adverse events related to vaccination occurred as determined by the investigator. After the first dose, detectable immune responses were observed in all subjects. All subjects that received ZR202-CoV seroconverted at 14 days after the second dose by S-binding IgG antibody, pseudovirus and live-virus based neutralizing antibody assays. S-binding response (GMCs: 2708.7 ~ 4050.0 BAU/mL) and neutralizing activity by pseudovirus (GMCs: 363.1 ~ 627.0 IU/mL) and live virus SARS-CoV-2 (GMT: 101.7 ~ 175.0) peaked at 14 days after the second dose of ZR202-CoV. The magnitudes of immune responses compared favorably with COVID-19 vaccines with reported protective efficacy.

Neuron-Derived Exosomes Promote the Recovery of Spinal Cord Injury by Modulating Nerve Cells in the Cellular Microenvironment of the Lesion Area.

During spinal cord injury (SCI), the homeostasis of the cellular microenvironment in the injured area is seriously disrupted, which makes it extremely difficult for injured neurons with regenerative ability to repair, emphasizing the importance of restoring the cellular microenvironment at the injury site. Neurons interact closely with other nerve cells in the central nervous system (CNS) and regulate these cells. However, the specific mechanisms by which neurons modulate the cellular microenvironment remain unclear. Exosomes were isolated from the primary neurons, and their effects on astrocytes, microglia, oligodendrocyte progenitor cells (OPCs), neurons, and neural stem cells were investigated by quantifying the expression of related proteins and mRNA. A mouse SCI model was established, and neuron-derived exosomes were injected into the mice by the caudal vein to observe the recovery of motor function in mice and the changes in the nerve cells in the lesion area. Neuron-derived exosomes could reverse the activation of microglia and astrocytes and promote the maturation of OPCs in vivo and in vitro. In addition, neuron-derived exosomes promoted neurite outgrowth of neurons and the differentiation of neural stem cells into neurons. Moreover, our experiments showed that neuron-derived exosomes enhanced motor function recovery and nerve regeneration in mice with SCI. Our findings highlight that neuron-derived exosomes could promote the repair of the injured spinal cord by regulating the cellular microenvironment of neurons and could be a promising treatment for spinal cord injury.

Role of Oxidative Stress in Ulcerative Colitis and Traditional Chinese Medicine Prevention and Treatment： A Review / 中国实验方剂学杂志

Ulcerative colitis （UC） is a commonly seen digestive system disease with unclear pathogenesis. The condition is complex and variable， often chronic， and has a long treatment period with no specific cure. Currently， the treatment of UC often involves the use of corticosteroids， aminosalicylates， and biologics in western medicine， which provide fast-acting and definite efficacy in the short term. However， with prolonged medication， some patients may develop drug resistance and worsening of the disease， leading to the occurrence of colon cancer. Research has found that oxidative stress is one of the important pathogenic factors in UC and influences its onset and development. Oxidative stress is a state of imbalance between oxidative products and the antioxidant system in the body， characterized by overexpression of oxidative products such as malondialdehyde （MDA）， reactive oxygen species （ROS）， nitric oxide （NO）， or deficiency of antioxidant enzymes such as superoxide dismutase （SOD）， catalase （CAT）， and glutathione （GSH）. It is worth noting that traditional Chinese medicine （TCM）， as a unique characteristic medicine of China， has achieved significant efficacy in the treatment of UC. Studies have shown that TCM effectively inhibits the occurrence of UC by suppressing the accumulation of metabolites and antagonizes the development of UC by enhancing the antioxidant system. Therefore， using TCM to regulate the oxidative balance as a diagnostic and therapeutic approach may be a new method and direction for the treatment of UC in the future. Based on the above research， this article summarized the mechanisms of key pathogenic proteins in oxidative stress and the occurrence and development of UC， and compiled the effective ingredients of Chinese medicine， single drugs， prescriptions， and acupuncture and moxibustion in regulating upstream and downstream target proteins of oxidative stress. These interventions can reduce pathological damage to the intestinal mucosa， lower the colon injury index， enrich the intestinal microbiota， increase colon length， and improve clinical symptoms of UC. The article is expected to expand the application of TCM in the treatment of UC and provide a reliable scientific theoretical basis.

Association of folic acid with the development and progression of liver cancer / 临床肝胆病杂志

So far, liver cancer is still a highly malignant tumor with a high incidence rate in China, and it seriously affects the life and health of Chinese people. Previous studies have shown that the development of liver cancer is associated with various factors such as virus, smoking, drinking, and nonalcoholic fatty liver disease. With continuous exploration, more and more studies have pointed out that nutritional factors and living environment are associated with the development and progression of liver cancer. Folic acid is a necessary nutrient for cell growth and reproduction, and its level in human body has an impact on the growth of tumor cells and is closely associated with liver cancer. This article reviews the research advances in the association between folic acid and liver cancer in recent years, so as to provide new reference and basis for the prevention and treatment of liver cancer.

Effect of potassium-competitive acid blockers on human gut microbiota: a systematic review and meta-analysis.

Background: Vonoprazan has been reported to exert more potent and long-lasting gastric acid inhibition than proton pump inhibitors, potentially leading to a greater impact on the gut microbiota. This study aimed to clarify changes in microbial diversity and bacterial composition after VPZ treatments. Methods: We searched from PubMed, Embase, WOS, Scopus, Cochrane Library, and ClinicalTrials.gov (all years up to May 2023). The primary outcomes were alpha and beta diversity, as well as differences in gut microbiota composition between before and after VPZ treatments. We performed a meta-analysis to uncover the potential changes in human gut microbiota among VPZ users by pooled mean difference (MD) with a 95% confidence interval (CI). The risk of bias was assessed using the ROBINS-I tool. Results: A total of 12 studies were included to compare differences before and after VPZ treatments. Compared with baseline, alpha diversity was significantly reduced after VPZ treatments and gradually returned to baseline with longer follow-up. At the phylum level, there was a decrease in the relative abundance of Firmicutes and Actinobacteria, while Bacteroidetes increased compared with baseline. At the genus level, we found a significant decrease in the relative abundance of Coprococcus and Bifidobacterium and a significant increase in the relative abundance of Bacteroides compared with those before treatment. In subgroup analyses according to country and participants, we found differences in microbial changes after VPZ treatments. Conclusion: Vonoprazan can affect the changes of gut microbiota, which may be potentially associated with its strong ability of acid inhibition. However, due to the large heterogeneity, further studies are required to validate these findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023412265.

Impact of Antimicrobial Stewardship Programs on Antibiotic Use and Drug Resistance: Analysis of Data from Maternal and Child Health Care Hospitals in Hubei Province, China.

OBJECTIVE: To evaluate the impact of Antimicrobial Stewardship Programs (ASPs) on antibiotic use and drug resistance. METHODS: This was a retrospective, multicenter, management intervention study. The data from 85 maternity hospitals (maternal and child health care hospitals) in Hubei province from 2012 to 2019 were collected. The indicators related to antimicrobial drug use included the utilization rate of different grades of antimicrobial drugs, the intensity of antimicrobial agent use, the rational use of prophylactic antimicrobial agents before class I surgical incision, and pathogenic detection and consultation rates before antimicrobial drug use. RESULTS: Since the implementation, the purchase of antimicrobial agents in hospitals has been maintained within the prescribed range, and the defined daily dose system (DDDs) of antimicrobial agents has been reduced, prophylactic use and accurate treatment of antimicrobial agents related to class I surgical incision have been more reasonable. With the implementation of ASPs, the detection rate of imipenem-resistant Acinetobacter baumannii, cefotaxime-resistant Escherichia coli, and methicillin-resistant Staphylococcus aureus has been decreased in China from national bacterial resistance surveillance data. CONCLUSION: ASPs have positive effects on antibiotic use and drug resistance in 85 maternity hospitals (maternal and child health care hospitals).

Optimization of Heat Treatment for 38Si7 Spring Steel with Excellent Mechanical Properties and Controlled Decarburization.

Optimizing the heat treatment procedure with 13 mm diameter 38Si7 spring steel is critical for developing high-performance, low-cost, large spring steel for railway clips. The effects of quenching temperature, holding time, tempering temperature, and tempering time on the microstructure and mechanical properties were investigated using an orthogonal experiment, designed with four factors and three levels. The best heat treatment settings were explored, as well as the variation laws of mechanical properties, decarburization behavior, and fracture morphology. The results demonstrated that quenching temperature and tempering temperature had the most impact on plasticity and tempering temperature, while time had the most effect on strength. The optimized heat treatment schemes made the elongation increase by up to 106% and the reduction in area increase by up to 67%, compared with the standard BS EN 10089-2002, and there were mixed fractures caused by ductility and brittleness. The fracture tests showed a good performance of 20.2 GPa·%, and the heat treatment processes' minimum decarburization depth of 93.4 µm was determined. The optimized process would obtain stronger plastic deposition and better decarburization performance. The microstructure was simply lightly tempered martensite, and the matrix still retained the acicular martensite. The optimal heat treatment process is quenching at 900 °C for 30 min (water cooling), followed by tempering at 430 °C for 60 min (air cooling). The research led to a solution for increasing the overall mechanical characteristics and decreasing the surface decarburization of 38Si7 spring steel with a diameter of 13 mm, and it set the foundation for increasing the mass production of railway clips of this size.

Role of platelets in the development and progression of hepatocellular carcinoma / 临床肝胆病杂志

Hepatocellular carcinoma is one of the common causes of tumor-related death, and it has high morbidity and mortality rates in China. Recent studies have shown that platelets are closely associated with the development of hepatocellular carcinoma. Literature review shows that platelets not only participate in hemostasis, but also act on liver cells and tumor microenvironment, promote the formation of new blood vessels, and participate in the development and progression of hepatocellular carcinoma as a cell mediator through immune response and other pathways. In addition, platelets and their derivatives can be used as potential therapeutic targets for hepatocellular carcinoma. Therefore, antiplatelet therapy is expected to become a new adjuvant strategy for the treatment of hepatocellular carcinoma, which has important clinical significance.

Research progress of miRNA involvement in plant polyphenols in regulating lipid metabolism / 中国药理学通报

Lipid metabolism disorder is an important risk factor for obesity,type 2 diabetes mellitus,non-alcoholic fatty liver disease and other chronic metabolic diseases.Micro RNAs(miRNAs)are short stranded RNA molecules with the size of 19 to 25 nucleotides that regulate lipid metabolism,within a number of physiological functions.Studies have shown that miRNAs can participate in the regulation of lipid metabolism by polyphenolic phytochemicals.In this paper,the mechanism of plant polyphenols improving lipid metabolism disorders and maintaining lipid balance through miRNA is summarized from the synthesis of triglyceride,fatty acid β oxidation,cholesterol efflux and cholesterol esterification,aiming to provide a new thought for the application and development of plant polyphenols to improve the diseases related to lipid metabolism disorders,and offer theoretical basis for the research and development of miRNA as a potential target for the prevention and treatment of diseases related to lipid metabolism disorders.

Advances in the treatment of potassium-competitive acid blockers in reflux esophagitis / 中国临床药理学与治疗学

Reflux Esophagitis (RE) is a gastroesophageal motility disorder mainly caused by lower esophageal sphincter disorder caused by a variety of injury factors, acid-suppressing drugs such as Proton Pump Inhibitors (PPIs) are often used clinically. With the increase of PPIs-resistant reflux esophagitis cases, the demand for the pharmacokinetics and pharmacodynamics of acid-suppressing drugs is higher. In recent years, the emergence of a new class of acid-suppressing drugs, potassium-competitive acid blockers (P-CABs), has solved some clinical deficiencies of traditional proton pump inhibitors. It has the characteristics of effective, longer-lasting acid suppression, the inhibitory effect on gastric acid secretion is not affected by the state of gastric acid secretion, the individual differences in drug metabolism and efficacy are smaller, and the drug efficacy is not affected by food intake or not. It has obvious advantages in the efficacy of severe erosive esophagitis and PPIs-resistant severe erosive esophagitis, and is more cost-effective, and is expected to replace PPI as the first-line treatment for reflux esophagitis.

[Characteristics and Ecological Risk Assessment of POPs Pollution in Sediments of Xiaoxingkai Lake in the Northeast China].

The pollution characteristics of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and phthalate esters (PAEs) in the surface sediments of Xiaoxingkai Lake were analyzed by GC-MS, and the main sources and biological toxicity risks of the pollutants were discussed. The results show that:① The content of PAHs in the sediments of xiaoxingkai lake ranged from 82.1 to 534.6 ng·g-1, and the concentration of PAHs in the northwestern port of the lake was higher. The content of OCPs and PAEs in the sediments ranged from 4.8 to 50.4 ng·g-1 and 33.3 to 401.6 ng·g-1, respectively. The concentration was higher in the southeastern lakes. ② PAHs in the sediments were dominated by 3-5-ring compounds (accounting for more than 85%), which were mainly combustion sources, among which the combustion of coal and firewood contributed 47%, the combustion of gasoline and diesel contributed 39%, and the oil product leakage contributed 14%. The OCPs were mainly HCHs (78%) from the use of new lindane and the input of a small amount of industrial HCHs. The PAEs were mainly dibutyl phthalate (DBP) and diethyl phthalate (2-ethyl hexyl) ester (DEHP; 94%), which were mainly derived from household garbage and common human articles. ③ Compared with other lakes in China, PAHs and PAEs in the sediments of Xiaoxingkai Lake are at a low pollution level, and there is no ecological risk at present, but some OCPs at some points present a moderate ecological risk.

Research progress in clinical trials of targeted drugs for gastric cancer / 中国临床药理学与治疗学

In the past several years, chemotherapy, as the best treatment option for advanced gastric cancer, however, was associated with adverse events and high resistance rates. Recently, molecular targeted drugs have gradually come into notice of clinical researchers due to the advantages of selectively killing tumor cells and less adverse events. Many clinical trials have confirmed targeted drugs targeting receptor tyrosine kinases combined with chemotherapy drugs could provide more survival benefits and might be effective for the treatment of gastric cancer. This article aims to demonstrate the progress in clinical trials of targeted therapeutic drugs for gastric cancer.

Pediatric tuina for the treatment of attention deficit hyperactivity disorder (ADHD) symptoms in preschool children: study protocol for a pilot randomized controlled trial.

BACKGROUND: Medication and behavior therapy are the conventional treatments for attention deficit hyperactivity disorder (ADHD), but they have limitations for preschool children. Evidence suggests that pediatric tuina, which is a modality of traditional Chinese medicine, might have beneficial effects on this condition. OBJECTIVE: To assess the feasibility of conducting an RCT in terms of recruitment, use, and acceptability of the parent-administered pediatric tuina for ADHD symptoms in preschoolers. METHODS: It is a single-center, two-arm, parallel, open-label, pilot randomized controlled trial (RCT). Sixty children with pre-specified ADHD symptoms (hyperactivity, anxiety, and sleep disturbance) together with one of their parents will be recruited and randomized into two groups at a 1:1 ratio. Parents in the parent-administered tuina group (intervention group, n = 30) will attend an online training program to learn pediatric tuina skills for ADHD symptoms and conduct this treatment on their children at home. Parents in the parent-child interaction group (comparison group, n = 30) will attend an online training about progressive muscle relaxation exercise and do this exercise with their children at home. Additional teaching materials will be provided to the participants in both groups. Both interventions should be carried out every other day during a 2-month treatment period, with each time around 20 min. Assessment will be performed at baseline, week 4, and week 8. The primary outcome measure is the Swanson, Nolan, and Pelham parent scale; the secondary outcomes include preschool anxiety scale, children's sleep habits questionnaire, and parental stress scale. A process evaluation embedded within the outcome evaluation will be performed. Differences in the scale scores and test parameters between groups will be examined using a linear mixed-effects model. Qualitative data will be analyzed using thematic content analysis, facilitated by QSR NVivo. DISCUSSION: This study will provide evidence on the acceptability and feasibility of pediatric tuina for ADHD in preschool children. The process evaluation will help to better understand the facilitators and barriers of the intervention functioning. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (Identifier: NCT04237259 ) on 14 February 2020. Protocol version: 2; date, 23 June 2020.

Safety and Efficacy of the Metabolic Profiling of the BIMRT Utilizing 18F FDG PET-CT.

AIM: This study aims to evaluate the safety and efficacy of fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) guided intensity-modulated radiation therapy (IMRT) for patients with peritoneal metastases. PATIENTS AND METHODS: A total of 55 patients with peritoneal metastases were treated with 18F-FDG-PET/CT-guided IMRT (BIMRT) from January 2012 to January 2019. They were prescribed with a fraction of the median dose of 2 Gy to a total dose of 50.4 Gy. The multivariate analysis was used the Cox proportional hazard model and the Kaplan-Meier plot was used to perform local control rate (LCR), progression-free survival (PFS), and overall survival (OS) analysis. RESULTS: The 1-year, 2-year, and 3-year LCR were 72.7%, 36.4%, and 9.1%, respectively; the 1-year, 2-year, and 3-year PFS were 69.1%, 30.9%, and 7.3%, respectively, and the median PFS time was 18 months. The 1-year, 3-year and 5-year OS were 70.9%, 28.7%, and 4.2%, respectively. Based on the multivariate analysis using the Cox proportional hazard model, the Karnofsky performance status (KPS) score and radiotherapy joint chemotherapy (RJC) method were independent prognostic-related indicators (P < 0.0001). CONCLUSION: BIMRT may be a safe and effective treatment for patients with peritoneal metastases, especially for patients who cannot undergo surgery. In addition, the results indicated that the patient's KPS score and RJC method were independent prognostic-related indicators for patients survival time.

Advances in miRNA regulation of Th17/Treg balance / 医学研究生学报

T helper 17 (Th17) and regulatory T cells (Tregs) are two distinct subsets of T cells that play a key role in the development of autoimmunity and inflammation. Th17 cells are thought to be the key effector T cells that induce inflammatory responses while Tregs inhibit the development of inflammation by regulating effector T cell activity to maintain peripheral immune tolerance. Th17/Treg imbalance can lead to the development of autoimmune diseases. MicroRNAs (miRNAs) are small endogenous non-coding RNA molecules in eukaryotes that play important regulatory roles in the maintenance of homeostasis in the immune system and the development of autoimmune diseases. Abnormal expression of miRNA will result in a broken or dysfunctional balance of differentiation between Th cell subsets, leading to inflammation or autoimmune diseases. This article provides an overview of the research advances in miRNA regulation of Th17/Treg balance to explore the role and clinical significance of miRNAs in Th17/Treg balance and maintenance of immune system balance.

Advances in miRNA regulation of Th17/Treg balance / 医学研究生学报

T helper 17 (Th17) and regulatory T cells (Tregs) are two distinct subsets of T cells that play a key role in the development of autoimmunity and inflammation. Th17 cells are thought to be the key effector T cells that induce inflammatory responses while Tregs inhibit the development of inflammation by regulating effector T cell activity to maintain peripheral immune tolerance. Th17/Treg imbalance can lead to the development of autoimmune diseases. MicroRNAs (miRNAs) are small endogenous non-coding RNA molecules in eukaryotes that play important regulatory roles in the maintenance of homeostasis in the immune system and the development of autoimmune diseases. Abnormal expression of miRNA will result in a broken or dysfunctional balance of differentiation between Th cell subsets, leading to inflammation or autoimmune diseases. This article provides an overview of the research advances in miRNA regulation of Th17/Treg balance to explore the role and clinical significance of miRNAs in Th17/Treg balance and maintenance of immune system balance.

18F-FDG-PET/CT-guided intensity-modulated radiotherapy for 42 FIGO III/IV ovarian cancer: A retrospective study.

The aim of the present study was to evaluate the curative effect of fludeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT)-guided intensity-modulated radiotherapy (IMRT) for 42 patients with International Federation of Gynecology and Obstetrics (FIGO) stage III/IV ovarian cancer. Between January 2012 and December 2015, 42 patients with FIGO stage III/IV ovarian cancer who were treated with 18F-FDG-PET/CT-guided IMRT at the Department of Radiation Oncology were analyzed. A total of 21 patients who exhibited recurrence following surgery and 11 patients who were unable to tolerate or rejected surgery received 5-10 cycles of chemotherapy only. A total of 10 patients, who were either older (>70 years) or in poor general health were unable to undergo surgery and only received IMRT. The patients received a total radiation dose of 5,040 cGy (range, 4,500-5,500 cGy), with a dose fraction of 200 cGy/fx, administered a total of 10-14 times, 5 times/week, prior to being rested for half an hour to relocate lesions and undergoing a second round of radiotherapy for 10-14 cycles. The 1-, 2- and 3-year progression-free survival (PFS) rates of the patients were 66.7, 33.3 and 21.4%, respectively, and the median PFS time was 20.3 months. The 1-, 2- and 3-year local control rates of the patients were 90.5, 83.3 and 69.0%, respectively, and the 1-, 2- and 3-year overall survival (OS) rates were 73.8, 64.3 and 52.4%, respectively. According to the results of multivariate analysis using the Cox proportional hazards model, the Karnofsky performance status (KPS) score (1) was the only index associated with prognosis (P<0.003). The study concluded that for patients with advanced ovarian cancer, particularly for patients unable to undergo surgery or chemotherapy, 18F-FDG PET/CT-guided IMRT is a safe and effective treatment method, and it may be considered as an equally effective treatment option. Furthermore, the results of the present study suggested that the KPS score of a patient is the only factor affecting the OS time.

Study on network pharmacology of Gualou Guizhi Decoction in treatment of lower limb spasm after cerebral apoplexy / 中草药

Objective: The mechanism of Gualou Guizhi Decoction (GGD) in the treatment of lower limb spasm after stroke was analyzed based on network pharmacology. Methods: Using the TCMSP and SwissTarget Prediction platform to screen the main components and targets of GGD, the obtained target information was imported into Gephi software to build the active components-targets network of GGD. Genecard, DisGeNET, and TTD disease databases were used to screen target genes for stroke and lower limb spasm; Target protein interaction network was constructed by using STRING platform; KEGG pathways, and GO (Gene Ontology) function were analyzed by using ClueGO software and DAVID v 6.8 platform. Results: Flavonoids, organic acids, and saponins of GGD was applied to 49 key target genes, such as IL6, TNF, EGFR, ESR1, TP53, STAT3, and F2, etc; Forteen category biological processes including proliferation of striated muscle cells, bone remodeling, smooth muscle cells, muscle cells and endothelial cells proliferation were involved; Thirty signaling pathways, including TNF, MAPK, PI3K-Akt, ALS, serotonergic synapse, and neurotrophin, etc, were regulated. Conclusion: Various active ingredients of GGD has pharmacological effects such as anti-inflammatory, antioxidant, neurotrophic, and participate in some biological processes, such as muscle cell proliferation, so as to treat lower limb spasm after stroke from central nervous system and peripheral muscle tissue two-ways.

Advances in the antitumor activities and mechanisms of action of steroidal saponins.

The steroidal saponins are one of the saponin types that exist in an unbound state and have various pharmacological activities, such as anticancer, anti-inflammatory, antiviral, antibacterial and nerves-calming properties. Cancer is a growing health problem worldwide. Significant progress has been made to understand the antitumor effects of steroidal saponins in recent years. According to reported findings, steroidal saponins exert various antitumor activities, such as inhibiting proliferation, inducing apoptosis and autophagy, and regulating the tumor microenvironment, through multiple related signaling pathways. This article focuses on the advances in domestic and foreign studies on the antitumor activity and mechanism of actions of steroidal saponins in the last five years to provide a scientific basis and research ideas for further development and clinical application of steroidal saponins.

ADAM17 promotes cell migration and invasion through the integrin ß1 pathway in hepatocellular carcinoma.

ADAM17 is believed to promote tumor development by facilitating both cell proliferation and migration. In this study, we investigated the involvement of ADAM17 and the activation of the integrin pathway in the regulation of the malignant properties of hepatocellular carcinoma cells and tissues. ADAM17 was positively correlated with active integrin ß1, which was determined using a human tissue microarray and an N-nitrosodiethylamine-induced HCC mouse model. We found elevated ADAM17 and active integrin ß1 levels in HCC tissues compared with adjacent liver tissues, and the active integrin ß1 levels were associated with tumor size and TNM grade. High ADAM17 and active integrin ß1 levels in tumor tissues were significantly associated with poor survival of HCC patients. RNAi-mediated ADAM17 knockdown and integrin ß1 blockade significantly attenuated the migration and invasion of HCC cells, and overexpression of ADAM17 showed the reverse effects. ADAM17 interference attenuated the intrahepatic growth and metastasis of HCC cells in an orthotopic xenograft model. ADAM17-knockdown cells showed diminished levels of active integrin ß1, p-FAK, p-AKT, MMP-2 and MMP-9. ADAM17 knockdown significantly attenuated the translocation of the Notch1 intracellular domain into the nucleus, whereas overexpression of the Notch1 intracellular domain rescued the translocation and enhanced the activation of integrin ß1. Our data provide evidence for ADAM17 as an important determinant of malignant properties via regulation of integrin ß1 activation and Notch1 signaling. Inhibition of ADAM17 may provide viable therapeutic potential for preventing HCC metastasis.