GPR126, also known as ADGRG6, is one of the most deeply studied aGPCRs. Initially, GPR126 was thought to be a receptor associated with muscle development and was primarily expressed in the muscular and skeletal systems. With the deepening of research, it was found that GPR126 is expressed in multiple mammalian tissues and organs, and is involved in many biological processes such as embryonic development, nervous system development, and extracellular matrix interactions. Compared with other aGPCRs proteins, GPR126 has a longer N-terminal domain, which can bind to ligands one-to-one and one-to-many. Its N-terminus contains five domains, a CUB (complement C1r/C1s, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a SEA (Sperm protein, Enterokinase, and Agrin) domain, a hormone binding (HormR) domain, and a conserved GAIN domain. The GAIN domain has a self-shearing function, which is essential for the maturation, stability, transport and function of aGPCRs. Different SEA domains constitute different GPR126 isomers, which can regulate the activation and closure of downstream signaling pathways through conformational changes. GPR126 has a typical aGPCRs seven-transmembrane helical structure, which can be coupled to Gs and Gi, causing cAMP to up- or down-regulation, mediating transmembrane signaling and participating in the regulation of cell proliferation, differentiation and migration. GPR126 is activated in a tethered-stalk peptide agonism or orthosteric agonism, which is mainly manifested by self-proteolysis or conformational changes in the GAIN domain, which mediates the rapid activation or closure of downstream pathways by tethered agonists. In addition to the tethered short stem peptide activation mode, GPR126 also has another allosteric agonism or tunable agonism mode, which is specifically expressed as the GAIN domain does not have self-shearing function in the physiological state, NTF and CTF always maintain the binding state, and the NTF binds to the ligand to cause conformational changes of the receptor, which somehow transmits signals to the GAIN domain in a spatial structure. The GAIN domain can cause the 7TM domain to produce an activated or inhibited signal for signal transduction, For example, type IV collagen interacts with the CUB and PTX domains of GPR126 to activate GPR126 downstream signal transduction. GPR126 has homology of 51.6%-86.9% among different species, with 10 conserved regions between different species, which can be traced back to the oldest metazoans as well as unicellular animals.In terms of diseases, GPR126 dysfunction involves the pathological process of bone, myelin, embryo and other related diseases, and is also closely related to the occurrence and development of malignant tumors such as breast cancer and colon cancer. However, the biological function of GPR126 in various diseases and its potential as a therapeutic target still needs further research. This paper focuses on the structure, interspecies differences and conservatism, signal transduction and biological functions of GPR126, which provides ideas and references for future research on GPR126.

Aim To investigate the enhanced efficacy and reduced toxicity of GanoExtra in combination with cyclophosphamide(CTX)on inhibiting lung metastasis and immune function in mice.Methods The CCK-8 method was used to verify the cytotoxic effects of Gano-Extra on MCF-7 and 4T1 tumor cells.In vivo experi-ment,a mouse model of lung metastasis of breast canc-er was established by injecting 4T1 tumor cells into the tail vein,which was divided into four groups including 4T1 model group,CTX group,GanoExtra group and GanoExtra+CTX group.The control group was set.After 21 days,the mice were euthanized under anes-thesia,and the body weight of the mice was recorded.Average lung index and spleen index were calculated.The mouse spleen lymphocyte transformation experi-ment was used to determine the activity of spleen cells.The NK cell activity assay was used to determine the activity of NK cells.Blood cells were determined in mouse blood samples.Flow cytometry was used to de-termine the levels of CD4+and CD8+T cells in blood samples.ELISA was used to measure the levels of TNF-α and IL-6 in serum.HE staining was used to ob-serve the pathological morphological changes in tumors and various tissues;and CFSE staining was used to de-termine the proliferative effect of GanoExtra on CD8+cells.Results In vitro GanoExtra at 50 mg·L-1 sig-nificantly inhibited the activity of MCF-7 and 4T1 tumor cells.In the breast cancer pulmonary metastasis model,compared with the model group,the spleen in-dex and blood WBCs content were significantly re-duced,while the activity of NK cells,spleen cells,and the proportion of RBCs,CD 3+and CD 8+T cells in the blood were significantly increased.At the end of the treatment,compared with the CTX group,the number of lung metastases and lung index of the Gano-Extra+CTX group were significantly reduced,and the levels of HGB,CD8+cells,IL-6,and TNF-α in the blood of mice were significantly increased.GanoExtra at 10 mg·L-1 significantly promoted the proliferation of CD8+T cells in vitro.Conclusions GanoExtra can enhance the inhibitory effect of CTX on tumor metasta-sis,alleviate adverse reactions such as splenomegaly and pulmonary enlargement caused by CTX,and have a health-promoting function of promoting the prolifera-tion of CD8+T cells to enhance the immune efficacy of the body.

Objective:To investigate the role of serum adenosine deaminase(ADA)combined with globulin(GLB),creatinine(CREA),β2-microglobulin(β2-MG)and hemoglobin(HGB)in the initial screening of multiple myeloma(MM),in order to reduce missed diagnosis and misdiagnosis of MM.Methods:A retrospective analysis was performed on 62 newly diagnosed multiple myeloma(NDMM)patients who were admitted to the Department of Hematology of the First Affiliated Hospital of Chengdu Medical College from April 2018 to December 2021,and 33 patients with benign hematologic diseases and 30 healthy subjects were selected as the control group.The expression of ADA in pan-cancer was analyzed using TCGA and GTEx databases.The general data and laboratory indicators of the subjects were collected,and the differences of ADA activity and other laboratory indicators in each group were compared.The relationship between serum ADA activity and clinical data of NDMM patients was analyzed.The changes of ADA activity before and after chemotherapy in NDMM patients and the differences of ADA activity in NDMM patients with different DS and ISS stages were compared.Multivariate logistic regression was used to analyze the risk factors of NDMM.The receiver operating characteristic(ROC)curve was used to evaluate the diagnostic efficacy of ADA and other laboratory indicators in MM.Bioinformatics method was used to analyze the co-expression networks and enrichment pathways of ADA.Results:ADA level was significantly upregulated in tissues of 14 types of cancer in TCGA database,and ADA was highly expressed in 11 types of cancer in TCGA combined with GTEx databases.The serum levels of ADA,GLB,uric acid(UA),cystatin C(CysC)and β2-MG in the NDMM group were significantly higher than those in benign hematologic disease group and healthy control group(P＜0.05),while the levels of ALB and the value of albumin to globulin ratio(A:G)in the NDMM group were significantly lower than those in the other two groups(P＜0.001).There were significant differences in DS stage(P=0.036),ISS stage(P=0.019)and the levels of CREA(P=0.036),UA(P=0.034),β2-MG(P=0.019)in NDMM patients with different ADA activity levels.After primary chemotherapy,ADA activity and(32-MG concentration were decreased in NDMM patients(P＜0.01).The comparison results of patients in different stages showed that ADA activity of patients in DS stage I+11 was significantly lower than that of patients in DS stage Ⅲ(P＜0.05),and ADA activity of patiens in ISS stage Ⅰ+Ⅱ was significantly lower than that of patients in ISS stage Ⅲ(P＜0.01).Multivariate logistic regression analysis showed that increased GLB,increased ADA activity,increased CREA,increased β2-MG and decreased HGB were independent risk factors for NDMM.The area under the curve(AUC)of ADA in the diagnosis of MM was 0.847,and the AUC of ADA combined with GLB,CREA,(32-MG and HGB in the diagnosis of MM was 0.940.The results of co-expression network and enrichment pathway analysis showed that ADA bounded to 20 proteins and it was significantly associated with the metabolic pathways of purine,pyrimidine,nicotinate and nicotinamide.Conclusion:The detection of ADA activity in serum is of positive significance for the auxiliary diagnosis,therapeutic evaluation and monitoring the progress of NDMM patients.ADA combined with GLB,CREA,β2-MG and HGB can improve the detection rate of MM,and reduce missed diagnosis and misdiagnosis to a certain extent.

Objective:To screen interleukin(IL)-1β secretion-related membrane transporters by macrophage experiment in vitro and conventional knockout mice.Methods:THP-1 cell line was differentiated to obtain human THP-1-derived macrophages,and the primary macrophages were obtained from human peripheral blood.FVB wild-type mice with the same sex and age were used as the controls of MRP1 knockout mice.The macrophages in abdominal cavity and bone marrow of mice were cultivated.The cells were treated with ABCC1/MRP1,ABCG2/BCRP,ABCB1/P-gp,OATP1B1,and MATE transporter inhibitors,then stimulated by lipopolysaccharide and adenosine triphosphate.The secretion level of IL-iβ was detected by ELISA,Western blot,and immunofluorescence.Results:After inhibiting ABCC1/MRP1 transporter,the secretion of IL-1β decreased significantly,while inhibition of the other 4 transporters had no effect.In animal experiment,the level of IL-1 β secreted by macrophages in bone marrow of MRP1 knockout mice was significantly lower than control group(P＜0.05).Conclusion:ABCC1/MRP1 transporter is a newly discovered IL-1β secretion pathway,which is expected to become a new target for solving clinical problems such as cytokine release syndrome.

Objective:To investigate the reversal effect and mechanism of asiatic acid (AA)on multidrug resistance in human adriamycin (ADR)chronic myeloid leukemia K562/ADR cells.Methods:CCK-8 assay was used to detect the resistance of K562 cells and K562/ADR cells to ADR.CCK-8 assay was used to detect the effect of AA on K562/ADR cell viability and adriamycin sensitization.After K562/ADR cells were treated with non-toxic doses of AA(10,20μmol/L),the average fluorescence intensity of ADR was detected by flow cytometry.Real-time quantitative PCR was used to detect the expression levels of MRP1,P-gp,β-catenin,C-myc and cyclinD1 mRNA.Western blot was used to detect the expression levels of MRP1,P-gp,β-catenin,C-myc and cyclinD1 proteins.Western blot assay was used to detect the expression levels of MRP1,P-gp,β-catenin,C-myc and cyclinD1 proteins in K562/ADR cells treated with 20μmol/L AA and Wnt/β-catenin pathway agonist WAY-262611 (5 μmol/L).Results:The CCK-8 assay showed that the drug resistance of K562/ADR cells was 56.57 times that of K562 cells,showing stable drug resistance,and the difference was statistically significant (P<0.05 ).AA inhibited the proliferative activity of K562/ADR cells in a concentration-dependent manner(r=0.9666).Compared with 0 μmol/L AA group,the 10 and 20 μmol/L AA groups could significantly enhance the average fluorescence intensity of intracellular ADR (P<0.05 ),and reverse the cell resistance to ADR (P<0.05).The mRNA and protein expressions of MRP1,P-gp,β-catenin,C-myc and cyclinD1 in cells were down-regulated (P<0.05).Compared with 20μmol/L AA group,the expression levels of MRP1,P-gp,β-catenin,C-myc and cyclinD1 protein in 20 μmol/L AA+WAY group were significantly increased (P<0.05 ). Conclusion:AA inhibits K562/ADR cell proliferation in a concentration-dependent manner and reverse their resistance to ADR,the reversal mechanism may be related to the down-regulation of MRP1 and P-gp expression after inhibiting Wnt/β-catenin signaling pathway.

Objective:To investigate the effect of genetic polymorphism of MTHFR C677T (rs1801133) on methotrexate (MTX) related toxicity in pediatric mature B-cell lymphoma patients. Methods:Fifty-eight intermediate and high risk patients under 18 years of age with mature B-cell lymphoma who received 5 g/m2 MTX (24 h intravenous infusion) in Sun Yat-sen University Cancer Center from August 2014 to December 2021 were included,and their toxicity of high-dose MTX (HD-MTX) were monitored and analyzed. Results:Among the 58 pediatric patients,the number of CC,CT,and TT genotypes for MTHFR C677T was 33,19 and 6,respectively. A total of 101 courses of HD-MTX therapy were counted,of which plasma MTX level>0.2 μmol/L at 48 h post-MTX infusion were observed in 35 courses,≤0.2 μmol/L in 66 courses. Inter-group comparison showed that plasma MTX level>0.2 μmol/L at 48 h post-MTX infusion increased the risk of developing oral mucositis (P<0.05). Compared with wild-type (CC genotype),patients in the mutant group (CT+TT genotype) were more likely to develop myelosuppression,manifested as anemia,leucopenia,neutropenia and thrombocytopenia. However,plasma MTX level at 48 h was not associated with MTHFR C677T gene polymorphism. Conclusion:The risk of developing oral mucositis in children with mature B-cell lymphoma is associated with plasma MTX concentration. Polymorphism of MTHFR C677T gene is not related to plasma MTX concentration in children with mature B-cell lymphoma,but is related to grade Ⅲ to Ⅳ hematological toxicity.

Objective:To explore the influence of whole-course one-stop management intervention on mental state,blood pressure in patients undergoing nuclide myocardial perfusion imaging and its safety.Methods:A total of 100 patients with coronary heart disease(CHD)who underwent nuclide myocardial perfusion imaging in Second Affiliated Hospital of Chi-nese Peoples Liberation Army Air Force Military Medical University between January 2018 and January 2023 were selected and divided into control group(n=50)and whole treatment group(n=50)according to random number table method.The control group received conventional intervention,while the whole treatment group received one-stop management in-tervention.The scores of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Symptom Checklist-90(SCL-90),systolic blood pressure(SBP)and diastolic blood pressure(DBP)before and after intervention,and inci-dence of adverse reactions after intervention were compared between the two groups.Results:Compared with the control group,there were significant reductions in SBP[(127.80±7.07)mmHg vs.(118.64±7.31)mmHg]and DBP[(83.80±2.78)mmHg vs.(74.76±2.74)mmHg],scores of HAMA[(22.96±3.23)points vs.(11.94±4.52)points],HAMD[(19.30±3.85)points vs.(9.62±3.79)points]and SCL-90[(103.06±8.02)points vs.(72.56±10.74)points]in the whole treatment group after intervention(P＜0.001 all).Compared with the control group,there was significant re-duction in the total incidence rate of adverse reactions(46.00％vs.18.00％)in the whole treatment group(x2=9.007,P=0.003).Conclusion:Whole-course one-stop management during nuclide myocardial perfusion imaging can improve blood pressure stability,reduce the negative emotions of the patients and the risk of clinical adverse reactions.Our findings suggest the clinical utility of the whole-course one-stop treatment.

Objective:To analyze the clinical phenotypes and genotypes of a family with posterior segment microphthalmia-retinoschisis and drusen syndrome.Methods:A pedigree investigation study was conducted.A family with four members across two generations treated at Shenzhen Eye Hospital in July 2021 was enrolled.Detailed ophthalmic examinations, including best corrected visual acuity (BCVA), intraocular pressure, slit-lamp microscopy, color fundus photography, optical coherence tomography (OCT), anterior segment OCT, fundus fluorescein angiography (FFA), and visual field tests were performed in the four members.Peripheral venous blood samples were collected from members for whole exome sequencing and data analysis.The pathogenicity of novel variant sites was assessed according to the ACMG guidelines.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Shenzhen Eye Hospital (No.22KYPJ018).Written informed consent was obtained from each subject or the guardian.Results:The proband is a 14-year-old female with high hyperopia since childhood, BCVA of + 9.75 DS-0.75 DC×150°=0.9 and + 11.75 DS-1.25 DC×30°=0.7, corneal transverse diameters of 12.1 and 12.2 mm, anterior chamber depths of 2.56 and 2.92 mm, lens thicknesses of 3.92 and 3.94 mm, and axial lengths of 17.47 and 17.01 mm in the right and left eyes, respectively.Fundus photography revealed diffuse yellow-white drusen-like lesions with unclear borders in the mid-peripheral retina, while OCT showed retinoschisis in the inner nuclear layer and homogeneous mound-like elevations with hyperreflective dense spots under the retinal pigment epithelium.FFA demonstrated diffuse punctate transilllumination of the mid-peripheral retina in both eyes, and visual field tests revealed a general decrease in visual acuity.The proband's 8-year-old brother exhibited similar signs to the proband.The consanguineously married parents were phenotypically normal.Whole exome sequencing identified compound heterozygous mutations in the membrane frizzled-related protein ( MFRP) gene in the proband and her brother, c.1150_1151insC (p.His384Profs*8) in exon 5 and c. 498_499insC (p.Asn167Glnfs*34) in exon 10.The father carried the c. 498_499insC mutation, while the mother carried the c.1150_1151insC mutation.Both were frameshift mutations predicted to alter gene function.These novel mutations had not been reported in the ESP, 1 000 Genomes (Phase 3), or ExAC databases, indicating they are novel variants.The variants co-segregated with the disease and both were classified as pathogenic according to ACMG guidelines.Based on the clinical and genetic findings, the family was diagnosed with posterior segment microphthalmia-retinoschisis and drusen syndrome, inherited in an autosomal recessive manner. Conclusions:The MFRP gene mutations c. 1150_1151insC and c. 498_499insC are the pathogenic variants for the posterior segment microphthalmia-retinoschisis and drusen syndrome in this family, and these compound heterozygous mutations are reported for the first time.

Objective:To compare the accuracy of dynamic navigation system,fully-guided and Pilot-drill guided implant surgery in anterior dental aesthetic area.Methods:45 patients underwent single tooth implantation in anterior dental aesthetic area were random-ly divided into 3 groups(n=15).Dynamic navigation system imlanting(A),3D printing fully-guided template with ASTRA EV assis-ted orthopedic implantation(B)and Pilot-drill guided implantation(C)were respectively used for the patients in group A,B and C.The deviation between the preoperative design and actual results were measured by CBCT and/or 3D reconstruction with navigation de-sign software or 3SHAPE software.SPSS 25.0 software package was used and(x)±s was used for descriptive analysis,results were pair-wise compared among the 3 groups using ANOVA.Results:Data were normally distributed and the variance of the data was homoge-neous.In group A,the distance deviation of implant top center was(0.571±0.196)mm,the horizontal deviation was(0.405±0.222)mm,the distance deviation of implant apical center was(0.449±0.267)mm,the vertical deviation was(0.312±0.223)mm,the de-viation of the connection angle between the two centers was 2.257°±0.989°.In group B,those were(0.520±0.242)mm,(0.219±0.201)mm,(0.643±0.284)mm,(0.464±0.292)mm and 1.272°±0.951° respectively.In group C those were(1.179±0.365)mm,(0.667±0.276)mm,(1.518±0.566)mm,(0.967±0.444)mm and 2.568°±0.632°.The deviation of all the measurments of group A and B was lower than those of group C(P＜0.05).The deviation of the connection angle between the 2 centers of group B was less than that of group A(P＜0.05),but no statistical significance(P＞0.05)was found in other 4 measured items.Conslusion:The accuracy of the dynamic navigation system and the fully-guided implantation is significantly higher than that of the Pilot-drill guided implantation,but is not statistically significant between dynamic navigation and the fully-guided system.

Chronic hepatitis B virus (HBV) infection is one of the major public health issues of ongoing global concern. Due to inadequate understanding of the HBV life cycle, there is a lack of effective drugs to cure chronic hepatitis B. During HBV replication, covalently closed circular DNA (cccDNA) serves as the template for viral replication and can be transcribed to produce five viral RNAs of 3.5, 2.4, 2.1 kb and 0.7 kb in length, which are translated to produce HBeAg, core protein, polymerase (P) protein, HBsAg and HBx proteins, respectively. Among them, the 3.5 kb pregenomic RNA (pgRNA) is also the template for viral reverse transcription. Polymerase protein recognizes and binds to the capsid assembly signal on the pgRNA to initiate capsid assembly and reverse transcription. Recent studies have revealed that the processes of splicing, nuclear export, stability, translation, and pgRNA encapsidation of HBV RNAs are regulated by a post-transcriptional regulatory network within the host cell and depend on unique post-transcriptional regulatory elements in the HBV RNA structure. The aim of this review is to overview the post-transcriptional regulatory mechanisms of HBV RNA and their applications in the study of HBV antiviral therapeutics, with the aim of providing new ideas for the development of new drugs targeting HBV RNA.