Mechanism of Yes-Associated Protein 1 Ameliorating Aristolochic Acid 1-Induced Liver Injury in Mice Based on Untargeted Metabolomics Techniques / 中药新药与临床药理

Objective To investigate the mechanism of Yes-associated protein 1(YAP1)ameliorating aristolochic acid 1(AAI)-induced liver injury in mice based on untargeted metabolomics techniques.Methods There were 83-week-old male hepatocyte-specific Yap1 gene knockout mice(genotyped as Yap1Flox/Flox,Albumin-Cre,aka.Yap1LKO)were randomly selected as the Yap1LKO+AAI group,and 8 Yap1Flox control mice as the Yap1Flox+AAI group.Both groups were injected intraperitoneally with AAI at a dose of 2.5 mg·kg-1·d-1 for 14 consecutive days.Genotypes were identified by tail PCR;serum alanine transaminase(ALT)and aspartate transaminase(AST)activities were determined by microplate assay;histopathological changes of liver tissue were observed by HE staining;and the protein expression of YAP1 in liver tissue was determined by immunohistochemistry.The untargeted metabolomics approach was used to analyze the liver tissue differential metabolites,and the samples were analyzed by ultra performance liquid chromatography-quadrupole-electrostatic field orbit trap high-resolution mass spectrometry,and the differential metabolites were screened by principal component analysis(PCA),Partial least square-discriminant analysis(PLS-DA),and orthogonal partial least squares-discriminant analysis(OPLS-DA);using HMDB database and METLIN database to identify metabolites,and the pathway enrichment of differential metabolites was analyzed by KEGG database.Results(1)After 14 days of AAI induction,the increase of body mass in Yap1LKO mice was lower than that in Yap1Flox mice,but there was no statistical significance(P＞0.05).On day 14,compared with the Yap1Flox+AAI group,the serum ALT and AST enzyme activities in the Yap1LKO+AAI group of mice were significantly increased(P＜0.05),and the histopathological damage of the liver was significantly aggravated.The livers of the Yap1Flox mice had a positive protein expression of YAP1,whereas the Yap1LKO mice did not have a positive protein expression of YAP1.(2)A total of 139 differential metabolites with significant changes(VIP＞1 and P＜0.05)were screened by metabonomic analysis;compared with Yap1LKO+ AAI group,62 liver metabolites in Yap1Flox+AAI group were up-regulated,including choline,taurine,hypotaurine,α-linolenic acid,eleostearic acid,chenodeoxycholic acid and so on.Seventy-seven metabolites were down-regulated including glycerophosphocholine,L-phosphatidylcholine,L-glutamine,L-serine,L-glutathione,5-methionine,phenylalanine,glucose 6-phosphate,lactic acid,uric acid glycosides,etc..KEGG-enriched pathways were mainly choline metabolism,glycerophospholipid metabolism,insulin resistance,glutathione metabolism,etc..Conclusion Hepatocyte-specific Yap1 gene knockout exacerbated AAI-induced liver injury in mice,and YAP1 was involved in the regulation of choline metabolism and glycerophospholipid metabolism through the up-regulation of unsaturated fatty acids,such as choline and taurine,which ameliorated AAI-induced liver injury in mice.

Discussion and Concern on Animal Study for Orthopaedic Implantable Devices / 中国医疗器械杂志

In recent years, new orthopaedic implantable devices continue to emerge, which require higher requirements for technical evaluation. Animal study is an important part of the research and development process for the new orthopedic implantable devices, which provides relevant evidence for product design and stereotyping. By introducing the purpose of animal study, and the application of 3R principle (replacement, reduction, refinement) in this field, we summarize the concern on the animal study, in order to provide reference for the development and research of new orthopedic implantable devices and biomaterials. At the same time, the application of evidence-based research methods such as systematic review in the field is introduced, which provides new tools and approaches for the technical review and regulatory science.

Discussion of Application Status and Key Attentions on Registration for Ossicular Replacement Prosthesis / 中国医疗器械杂志

The ossicular replacement prosthesis should have good biocompatibility, stability, easy to install, and excellent sound transmission capacity. In this study, the characteristics of ideal materials for the ossicular replacement prosthesis were analyzed by searching the types of materials used in clinical practice and comparing the advantages and disadvantages of various materials and structures. At the same time, in combination with the current evaluation requirements and evaluation experience, the focus of the performance research project of ossicular replacement prosthesis in the process of registration is discussed to clarify the performance evaluation requirements of these products, so as to provide reference for the future work of manufacturers and regulators. The performance evaluation of ossicular replacement prosthesis focuses on its mechanical properties, fixation stability, sound transmission characteristics, biological characteristics, and magnetic resonance compatibility.

Analysis of Revision Content and Evaluation Attentions on Guidance for Registration of Metallic Bone Plate Internal Fixation System (Revised in 2021) / 中国医疗器械杂志

This study briefly introduces the revised content of Guidance for Registration of Metallic Bone Plate Internal Fixation System (Revised in 2021) compared to the original guidance, mainly including the principles of dividing registration unit, main performance indicators of standard specification, physical and mechanical performance research, and clinical evaluation. At the same time, in order to provide some references for the registration of metallic bone plate internal fixation system, this study analyzes the main concerns in the review process of these products based on the accumulation of experience combining with the current review requirements.

Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy / 医学前沿

The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8+ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

Bacterial Endotoxin for Intrathoracic Medical Devices Requirement Revisited / 中国医疗器械杂志

Bacterial endotoxin is considered as one of the critical risk factors in medical devices, especially implanted devices that directly or indirectly contact with blood circulating system. In that case, endotoxin limits for implanted medical devices is important in determine the safety of medical devices. According to GB/T 14233.2-2005, the requirements of endotoxin index for intrathoracic medical devices is 2.15 EU per device. However, the definition of "intrathoracic medical devices" is vague. Specifically, "for cardiovascular system application" instead of "intrathoracic application" is more reasonable. With the deeper understanding of the risk of endotoxin in medical devices and considering the internationally accepted standards, the limits of endotoxin in medical devices for cardiovascular system application is acceptable at 20 EU per device.

Effect of SABP, A Water-soluble Component of Salvia Miltiorrhiza, on Immune Microenvironment of Mice with Liver Cancer / 肿瘤防治研究

Objective To investigate the effect of SABP, a water-soluble component of Salvia miltiorrhiza, on the growth of orthotopic transplantation of H22 liver cancer and the immune microenvironment of liver cancer. Methods We established a mouse model of orthotopic transplantation of H22 cell liver cancer in BALB/c mice. ELISA was used to detect the expression of PD-L1, TGF-β, IL-1β, IL-10, IL-4, IFN-γ, IL-18, IL-7, IL-2, CCL-2 and CCL-21 in the liver. We counted the organ indexes of liver, spleen and kidney. Results SABP inhibited the growth of orthotopic transplantation tumors of H22 cell liver cancer, and increased the expression levels of PD-L1, TGF-β, IL-1β and IL-10 in the microenvironment of liver cancer, as well as the liver, spleen and kidney coefficients. Conclusion SABP could inhibit the growth of orthotopic transplantation tumors of H22 cell liver cancer and promote the expression of PD-L1, TGF-β, IL-1β and IL-10 in the microenvironment of liver cancer.

Regulatory Mechanism of PD-L1 Expression in Primary Liver Cancer / 肿瘤防治研究

The application of immunotherapy has become a hot spot in tumor research currently. In particular, immune checkpoint inhibitors have played an important role in the treatment of advanced unresectable primary liver cancer. However, the efficacy of immune checkpoint inhibitors varies greatly in the treatment of different patients, which has aroused people's attention to the regulatory mechanism of PD-L1 in the immune escape of liver tumors. PD-L1 is regulated by multiple levels and multiple signaling pathways in liver cancer, including gene mutation, epigenetic mechanisms, transcriptional regulation, post-transcriptional regulation and post-translational modification. Studies have also found that the high expression of PD-L1 may be the main factor affecting the immunotherapy of primary liver cancer. Therefore, it can provide more evidence for immunotherapy and immune combination therapy strategies of primary liver cancer by clarifying the regulatory mechanism of PD-L1.

Research on Registration System of Medical Device Master Files in China / 中国医疗器械杂志

The registration system of medical device Master Files is established to solve the problem that the outsourcing suppliers are not willing to cooperate with the device applicants in the process of providing medical device application documents. After a brief introduction of Master Files systems established by foreign regulatory agencies, this article focuses on the research of establishing a medical device Master Files registration system in China. The results show that the establishment of Chinese Master Files registration system can both improve the standardization and convenience of outsourcing activities of medical devices, and satisfy the needs of the development of medical device industry and regulatory system. At the same time, the probability of additional risk caused by the implementation of the system is low. Therefore, it is expected that the benefits of the system to promote public health outweigh the potential risks, which demonstrates that establishment of the system has important application values.

Nutlin-3 promotes pyroptosis in SMMC-7721 cells / 中国免疫学杂志

Objective:To evaluate the effect of Nutlin-3,a MDM2 antagonist,on the pyroptosis in SMMC-7721 cells.Methods: The expression of actived caspase-1(p20) and IL-1β was detected using Western blot analysis.Pyroptosis was investigated by a standard lactate dehydrogenase release assay(LDH).IL-1β content in the cell culture supernatant was quantified by ELISA.Results: Nutlin-3 up-regulated the expression level of actived caspase-1 and IL-1β in SMMC-7721 cells.Meanwhile,Nutlin-3 increased significantly the content of LDH and IL-1β in the cell culture supernatant(P<0.05).Conclusion: Nutlin-3 activated pro-caspase-1,promoted pyroptosis and IL-1β release in SMMC-7721 cells.

The authorized considerations on the pre-clinical study of drug-eluting coronary stent system / 中国医疗器械杂志

China Food and Drug Administration didn't issue any guideline on the pre-clinical study of drug-eluting coronary stent system, the basic requirement of the authorized administration was summarized to help manufacture prepare the document during the registration process.

The research progress of transcatheter aortic valve replacement / 中国医疗器械杂志

During the past years transcatheter aortic valve replacement has evolved to a promising technique for the treatment of the patients who suffered from severe aortic stenosis, the progress and basic consideration on clinical study have been summarized in the article.

Role of phosphorylation of p53 at Ser392 in cancer therapy / 解剖学报

Phosphorylation is the most common way of p 53 post-translational modifications .However , gaps still exist in our knowledge regarding the role and mechanism of phosphorylation of p 53 at Ser392 in carcinogenesis and cancer prevention.In the present study, we summarized the effect of phos-p53-Ser392 to wild-type and mutant p53, the regulation by DNA damage agents and protein kinase , and the significance of phosphorylation of p 53-Ser392 in cancer treatment .

Comparison among the immune effects of DNA-or protein-FimH of UPEC type 1 pilus / 中国免疫学杂志

Objective:To observe cellular,humoral and mucosal immune responses induced by DNA-or protein-based of FimH of UPEC type 1.Methods:After mice were immunized respectively with recombinant plasmid pcDNA3.1/fimH or pcDNA3.1/fimC,and the combinant FimH and FimC protein,the anti-FimH protein IgG of sera and SIgA in bladders were detected by ELISA.The lymphocyte phenotypes of CD3,CD4 and CD8 were analyzed by FCM.Results:The titers of IgG in sera and SIgA in the bladders were all low in the group immunized by recombinant FimH plamid,but the percentage of CD4+T cells in spleen was high,which revealed that recombinant FimH plamid was able to trigger better cellular immune response.The titers of IgG were very high in the group immunized by FimH protein,which suggested that the FimH protein was able to trigger better humoral immune response,but SIgA in the bladders was not detectable.Conclusion:The DNA for FimH can induce humoral,mucosal and cellular immune response.FimH protein can only induce humoral immune response.FimC protein is able to enhance the immunogenicity of FimH protein.