THE THREE KEY PLAYERS IN OSTEOIMMUNOLOGY: RANK, RANKL AND OSTEOPROTEGERIN.

The RANK, RANKL and OPG interaction plays a major role in bone resorption and remodelling. The history dates back to mid 1990s when the RANK/ RANKL interaction was found to mediate osteoblastic stromal cells to stimulate osteoclastic bone resorption. This interaction was found to induce several cytokines including the TNF superfamily, thereby activating the pathways of bone remodelling. The Osteoprotegerin (OPG) prevents the binding of RANKL to RANK, thereby preventing the excessive bone resorption. When there is an imbalance in the levels of RANK/RANKL/OPG, the metabolic activity of the bone cells gets altered and thus there is loss of balance between bone formation and resorption. Thus, studying the inter – relationship between RANK, RANKL and OPG becomes critical for assessing the osteoblastic and osteoclastic activity

Establishment and validation of OX40/FcγR-humanized mice for the study of agonistic anti-OX40 antibody / 上海交通大学学报（医学版）

Objective • To establish a rapid method to evaluate the activity of agonistic antibody using OX40 (tumor necrosis factor receptor superfamily member 4)/FcγR (Fcγ receptor)-humanized mice. Methods • Bone marrow cells from OX40-humanized mice and FcγR-humanized mice were collected and mixed with equal ratio. Then the mixed bone marrow cells were administrated into irradiated wild-type mice through the tail veins. The reconstruction efficiency of the immune system was confirmed by detecting the expression of hOX40 and hFcγR in the immune cells of chimera mice. After the chimera mice were generated successfully, they were used to evaluate the immunostimulatory activity of anti-hOX40 antibodies to CD4+ or CD8+ T cells. The results of flow cytometry were statistically analyzed. The unpaired t-test was used to compare the means between the two groups, and oneway ANOVA was used to compare the means between multiple groups. Results • Flow cytometry analysis showed that wild-type recipient mice were efficiently reconstituted with hFcγR expressing cells and hOX40 expressing cells to generate OX40/FcγR-humanized bone marrow chimera mice. In these mice, B cells and myeloid cells expressed hFcγRs (P<0.05), and T cells expressed hOX40 upon in vitro stimulation (P<0.05). When these mice were used to evaluate the immunostimulatory activity of anti-hOX40 antibody, significant expressions of IFN-γ and hOX40 were observed (P<0.05). Conclusion • OX40/FcγR-humanized bone marrow chimera mice are generated based on hFcγR expressing cells and hOX40 expressing cells, suggesting a rapid method to build a mouse model with both hFcγR and hOX40 expression. These mice are suitable for evaluating the immunostimulatory activity of agonistic human anti-hOX40 antibodies.

Study of tumor necrosis factor receptor superfamily 1B gene polymorphism in relation to the outcomes of HCV infection / 中华肝脏病杂志

Objective@#To investigate the tumor necrosis factor receptor superfamily 1B gene (TNFRSF1B) polymorphism in relation to the outcomes of hepatitis C virus (HCV) infection.@*Methods@#One thousand six hundred and forty-five cases without HCV infection, 545 cases with HCV clearance, and 783 cases with chronic HCV infection were enrolled. TaqMan probe method was used to investigate genotype rs1061622 (T > G) and rs1061624 (G > A). Two single nucleotide polymorphisms (SNPs) sites were genotyped and haplotypes were constructed to evaluate their relation with the outcome of HCV infection.@*Results@#Logistic regression analysis showed that there was no relation to the two SNPs with HCV infection susceptibility and chronicity (P > 0.05). Haplotype analysis showed that carrier TA had an increased susceptibility to HCV infection [adjusted odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.01 to 1.30, P = 0.038)]. Carrier TA and GG haplotypes were conducive to chronic HCV infection (adjusted OR = 1.28, 95% CI: 1.08 to 1.53, P = 0.006; OR = 1.31, 95% CI: 1.03 to 1.66, P = 0.026).@*Conclusion@#The combinational effects of rs1061622 and rs1061624 in TNFRSF1B gene may increase the risk of HCV chronicity and infection.

Association between TNFRSF11A and TNFRSF11B gene polymorphisms and the outcome of hepatitis C virus infection / 中华流行病学杂志

Objective@#To explore the relationship between the tumor necrosis factor receptor superfamily members 11A (TNFRSF11A) and 11B (TNFRSF11B) gene polymorphisms and the outcome of hepatitis C virus (HCV) infection.@*Methods@#In this case-control study, 749 cases of persistent HCV infection, 494 cases of spontaneous clearance and 1 486 control subjects were included from 2008 to 2016. TaqMan-MGB probe method was used to detect the genotype of TNFRSF11A rs1805034 and TNFRSF11B rs2073617. The genotypes distribution of the two single nucleotide polymorphisms (SNP) were analyzed in different populations.@*Results@#Co-dominant model showed that individuals carrying the rs2073617 CC genotype were prone to have chronic HCV infection, compared with individuals carrying the rs2073617 TT genotype (OR=1.517, 95%CI: 1.055-2.181, P=0.024). Recessive model results showed that individuals carrying rs2073617 CC genotype were more likely to develop chronic HCV infection compared with individuals carrying rs2073617 TT or TC genotype (OR=1.435, 95%CI: 1.033-1.996, P=0.032). Additive model showed that the risk for chronic HCV infection increased with the increase of the number of rs2073617 C alleles (OR=1.204, 95%CI: 1.013-1.431, P=0.035).@*Conclusion@#The genetic polymorphism of TNFRSF11B rs2073617 might be related with the chronicity of HCV infection.

Expressions of CMTM6 and PD-L1 protein in glioma tissues and their correlation with clinicopathological characteristics of patients / 中国肿瘤生物治疗杂志

@# Objective: : To investigate the expressions of chemokine-like factor superfamily 6 (CMTM6) and programmed cell death ligand 1 (PD-L1) in glioma tissues and their correlation with clinicopathological features of patients. Methods： ：From January 2012 to December 2015, 86 brain glioma tissues and 30 brain tissues (Control group) from patients operated with decompressive of craniotomy were collected from the FifthAffiliated Hospital of Zhengzhou University. The distribution and expressions of CMTM6 and PD-L1 protein in brain glioma tissues were detected by immunohistochemistry and WB methods. The differential expression of CMTM6 and PDL1 between glioma tissues and normal brain tissues was analyzed by t test of two independent samples. Single variant χ2 test was used to analyze the relationship between the expression of CMTM6, PD-L1 and the clinicopathological features of patients. Results: The expression of CMTM6 in glioma tissues was significantly higher than that in control tissues (P<0.01). The expression levels of CMTM6 and PD-L1 in high pathological grade (WHO III-IV) glioma tissues were significantly higher than those in low pathological grade (WHO I-II) glioma tissues (all P<0.01). The expression of CMTM6 was correlated with pathological grade, dizziness history, epilepsy seizure and PD-L1 expression (all P<0.05), while the expression of PD-L1 was correlated with pathological grade, epilepsy seizure and CMTM6 expression (all P<0.05). Conclusion: There is a correlation between the expression of CMTM6 and PD-L1 in glioma tissues, both of which are highly expressed and are expected to be used to study glioma signaling pathways.

Expression of TM6SF2 in hepatocellular carcinoma tissue and its bioinformatics functions / 临床肝胆病杂志

ObjectiveTo investigate the expression of TM6SF2 in hepatocellular carcinoma (HCC) tissue and its biological functions by data mining in tumor databases. MethodsThe GEPIA database was applied to measure the change in the mRNA expression level of TM6SF2 in HCC tissue, and OncoLnc was used to analyze the association of TM6SF2 expression with the survival time of HCC patients. The cBioPortal and LinkedOmics databases were used to analyze the genes associated with the expression of TM6SF2 in HCC tissue, and the DAVID6.8 and STRING databases were used to perform a bioinformatics analysis of TM6SF2 and the genes associated with its expression. The t-test was used to investigate the difference in the mRNA expression of TM6SF2 between HCC tissue and adjacent tissue. The Spearman correlation coefficient was used to analyze the correlation of gene expression. The Kaplan-Meier method was used to calculate survival percentage, and the log-rank test was used to analyze the difference in survival percentage. ResultsCompared with the normal liver tissue, the HCC tissue had low mRNA expression of TM6SF2 (｜log2FC｜cut-off = 0.5, P＜0.01). Compared with those with high expression of TM6SF2, the patients with low expression had a significant reduction in overall survival time (χ2=9.897，P＜0.01). Data analysis showed that a total of 49 genes were associated with the expression of TM6SF2 in HCC tissue, and the gene ontology analysis showed that these genes were enriched in the biological processes and functions including fatty acid synthesis, fatty acid ligase activation, and thrombin regulation (P＜0.05). The Kyoto Encyclopedia of Genes and Genome pathway analysis showed that these genes were mainly involved in the signaling pathways of alanine metabolism, peroxisome proliferator-activated receptor signaling pathway, and bile secretion (P＜0.05). The protein-protein interaction network analysis showed that the genes of SERPINC1, NR1I2, SERPINA10, and SLC10A1 had marked or potential interaction with TM6SF2 (P＜0.01). ConclusionTumor data mining can quickly obtain the information on the expression of TM6SF2 in HCC tissue and provide a bioinformatics basis for exploring the role of TM6SF2 in the development and progression of HCC.

Pathophysiologic mechanism of CMTM5 low expression in multiple myeloma progression / 中华血液学杂志

Objective@#To investigate the mechanism of chemokine-like factor superfamily member (CMTM) 5 on the proliferation of multiple myeloma cells.@*Methods@#RT-qPCR method was used to detect the expression and correlation of CMTM5, caspase3 and caspase9 in U266 after decitabine demethylation treatment; U266 transfected with pcDNA3.1 plasmid overexpressed CMTM5, then cell proliferation activity was detected by CCK-8 assay.@*Results@#Compared with the control group, the low-dose demethylation treatment increased mRNA expression of CMTM5, caspase3, and caspase9 in U266, and showed a time-dependent (P<0.01). The up-trend of CMTM5, caspase3, and caspase9 in the high-demethylation drug treatment group was more significant and also showed time-dependent (P<0.001); There was a significant positive correlation between CMTM5 and caspase3 (r=0.937) and caspase9 (r=0.945) in each group (P<0.001). After transfection of U266 with the pcDNA3.1-CMTM5 plasmid, overexpression of CMTM5 inhibited the cell proliferation activity compared with the control and pcDNA3.1-vector group.@*Conclusion@#Decitabine has a reductive effect on the low level of CMTM5 in U266 cells, and its recovery level is significantly positively correlated with caspase 3 and caspase9. Re-expression of CMTM5 inhibits the proliferative activity of U266.

Pathophysiologic mechanism of CMTM5 low expression in multiple myeloma progression / 中华血液学杂志

Objective: To investigate the mechanism of chemokine-like factor superfamily member (CMTM) 5 on the proliferation of multiple myeloma cells. Methods: RT-qPCR method was used to detect the expression and correlation of CMTM5, caspase3 and caspase9 in U266 after decitabine demethylation treatment; U266 transfected with pcDNA3.1 plasmid overexpressed CMTM5, then cell proliferation activity was detected by CCK-8 assay. Results: Compared with the control group, the low-dose demethylation treatment increased mRNA expression of CMTM5, caspase3, and caspase9 in U266, and showed a time-dependent (P<0.01). The up-trend of CMTM5, caspase3, and caspase9 in the high-demethylation drug treatment group was more significant and also showed time-dependent (P<0.001); There was a significant positive correlation between CMTM5 and caspase3 (r=0.937) and caspase9 (r=0.945) in each group (P<0.001). After transfection of U266 with the pcDNA3.1-CMTM5 plasmid, overexpression of CMTM5 inhibited the cell proliferation activity compared with the control and pcDNA3.1-vector group. Conclusion: Decitabine has a reductive effect on the low level of CMTM5 in U266 cells, and its recovery level is significantly positively correlated with caspase 3 and caspase9. Re-expression of CMTM5 inhibits the proliferative activity of U266.

Factores de crecimiento incluidos en terminologia embryologica: análisis crítico / Growth factors included in terminologia embryologica: critical analysis

Cada término incluido en Terminologia Embryologica (TE), publicada en 2013 y con una segunda edicición en 2017 sujeta a aprobación por la Federación Internacional de Programas de Terminología Anatómica (FIPAT), se debe estructurar en base a sus principios: los nombres deben tener un valor informativo, se suprimen los epónimos, homónimos y nombres concordantes. Sin embargo, esto no ocurre en algunos términos. Es por ello que se analizaron los términos incluidos en el ítem "Factores de Crecimiento" (Factores crescentiae, E.4.0.1.0.0.0.1) en la forma en que se presentan, se contrastó su concordancia con lo publicado en revisiones de la base de datos PubMed y se describió la forma de nomenclatura de ellos en base a lo utilizado por el Comité de Nomenclatura de Genes de la Organización del Genoma Humano (HGNC). Se evidenció que en los términos Familia Hedgehog (Familia erinacea, E.4.0.1.0.0.0.6) y Superfamilia del Factor de Crecimiento Epidermal (EGF) (Superfamilia factoris epidermalis [EGF] crescentiae, E.4.0.1.0.0.0.10) no concuerdan con la clasificación propuesta por TE en base al receptor que se ve involucrado en la actividad del factor de crecimiento, ya que en el caso de la familia Hedgehog no sólo participa el receptor patched, sino también el smoothened. En el EGF hay actividad del receptor tirosina kinasa y no del serina/treonina kinasa, como se presenta en el documento oficial. También, aparecen los ligandos fibronectina/laminina y delta/serrate como factores de crecimiento, pese a no ser catalogados como tal. Por otra parte, la forma en la que se construyen este tipo de términos muchas veces no es como la plantea la FIPAT, sino que obedece a la línea de trabajo que del HGNC. TE debiese modificar el criterio empleado en el ítem factores de crecimiento.

Each term included in Terminologia Embryologica (TE), published in 2013 and with a second edition in 2017 subject to approval by the Federative International Programme For Anatomical Terminology (FIPAT), must be structured based on its principles: Names must have an informative value, eponyms, homonyms and concordant names are deleted. However, this does not happen in some terms. That is why the terms included in the section "Growth Factors" (Factores crescentiae, E.4.0.1.0.0.0.1) were analyzed in the way they are presented, their concordance with what was published in reviews of PubMed database, and their naming form was described based on what was used by the Genes Nomenclature Committee of the Human Genome Organisation (HGNC). It was evidenced that in the terms Family Hedgehog (Familia erinacea, E.4.0.1.0.0.0.6) and Superfamily of the Epidermal Growth Factor (EGF) (Superfamilia factoris epidermalis [EGF] crescentiae, E.4.0.1.0.0.0.10) these do not agree with the classification proposed by TE based on the receiver that is involved in the activity of the growth factor, since in the case of Hedgehog family not only does the patched receptor participate, but the smoothened one does as well. In EGF there is tyrosine kinase receptor activity and not serine/threonine kinase, as presented in the official document. Also, the ligands fibronectin/laminin and delta/serrate appear as growth factors, despite not being catalogued as such. Furthermore, oftentimes the way in which such terms are constructed is contrary to the FIPAT presentation, but follows the HGNC line of work that holds the HGNC.

Anti-inflammatory mechanism of Scutellarlae Radix based on network pharmacology / 中草药

Objective: To explore the anti-inflammatory mechanism of Scutellarlae Radix (SR) by the network pharmacology. Methods: Firstly, the components in SR were searched through TCMSP database and screened with “Lipinski rule” and “Oral Bioavailability > 30%” rules. The targets of above components selected by PharmMapper web server and Cytoscape 3.4.0 was used to build a network between components and targets (component-target network, CTN). Secondly, “anti-inflammatory” targets was searched from Therapeutic Target Database (TTD) with keyword “anti-inflammatory”, and targets retrieved were used to build a protein-protein interaction (PPI) network based on the analysis by String database. To obtain anti-inflammatory targets of the active components in SR, the PPI network was fused with the CTN. Finally, the DAVID database was used to perform KEGG pathway enrichment analysis in order to explore the anti-inflammatory mechanism of SR. Results: Twenty-eight components in SR were obtained, including flavonoids such as baicalin, baicalein, wogonin, wogonoside, etc, alkaloids such as berberine, and epiberberine, and phenols such as dihydromyricetin, etc. Mitogen-activated protein kinase (MAPK14), tumor necrosis factor receptor superfamily 1A (TNFRSF1A), epidermal growth factor receptor (EGFR), and E-selectin (SELE) were the main targets of SR' anti-inflammatory effect. Salvigenin, epicatechin, and astragalusine mainly acted on MAPK14; Carthamidin acted on TNFRSF1A; Dihydromubutin A, 5,7,4’-trihydroxy-8-methoxyflavone, 5,7,4’-trihydroxy-8-methoxyflavanone, baicalin, and other components mainly acted on EGFR. There were 11 KEGG pathways, mainly related to TNF signaling pathways, MAPK signaling pathway, etc. Conclusion: There are three main anti-inflammatory mechanisms in SR, which can inhibit the production of inflammatory factors, inhibit the binding of inflammatory factors to their respective receptors, and block the initiation of inflammatory reactions.

An association of ulcerative colitis with tumor necrosis factor superfamily member 15 gene polymorphisms in Chinese patients / 中华内科杂志

Objective To explore the relationship between ulcerative colitis (UC) susceptibility and tumor necrosis factor superfamily member (TNFSF) 15 gene polymorphisms and haplotypes in Han nationality in Zhejiang province of China. Methods A total of 408 UC patients and 574 healthy controls were recruited in this study. Three single nucleotide polymorphisms of TNFSF15 (rs3810936, rs4263839, rs4979462) were examined by improved multiple ligase detection reaction (iMLDR) technique. Analyses of linkage disequilibrium (LD) and haplotype were performed by Haploview 4.2 software in all study subjects. Results The variant allele A and genotype (GA+AA) of rs4263839 were less frequent in UC patients than in controls (45.34% vs. 50.17%, P=0.035; 68.38% vs. 76.66%, P=0.004). According to the severity and location of disease, UC patients were divided into different subgroups. After multiple comparison correction (α=0.012 5), the frequencies of variant allele A and genotype (GA+AA) of rs4263839 were lower in patients with severe UC than in the controls (37.69% vs. 50.17%, P=0.007;60.00% vs. 76.66%, P=0.004). Similar findings were also drawn for patients with extensive colitis in contrast with the controls (42.22% vs. 50.17%, P=0.009; 63.33% vs. 76.66%, P<0.001). Furthermore, the haplotype analysis indicated that three SNPs above were in a strong LD. The frequency of haplotype TAC was lower in UC patients than in the controls (40.83% vs. 46.04%, P=0.023). Also it was less prevalent in patients with severe UC and patients with extensive colitis when compared with controls respectively (33.38% vs. 46.04%, P=0.005;37.22% vs. 46.04%, P=0.003). Conclusions TNFSF15 (rs4263839) variation might not only reduce the risk of UC, but also affect the severity and lesion location of UC. The haplotype TAC formed by rs3810936, rs4263839 and rs4979462 might be related to a lower risk of UC, especially in patients with severe colitis or patients with extensive colitis.

Effects of PNPLA3, TM6SF2 gene polymorphisms and its interactions with smoking and alcohol drinking on hepatitis B virus-associated hepatocellular carcinoma / 中华流行病学杂志

Objective To explore the SNP effects ofpatatin-like phospholipase domain which containing 3 (PNPLA3),transmembrane 6 superfamily member 2 (TM6SF2) gene,environmental effects of smoking,alcohol drinking and interaction between gene-gene,gene-environment and drinking-smoking on hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC).Methods We collected anticoagulant peripheral blood from patients of HBV-HCC,chronic hepatitis B (CHB),liver cirrhosis (LC) and from healthy controls to detect the single nucleotide polymorphism (SNP) of patatin-like phospholipase domain containing 3 (PNPLA3) gene loci rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) gene loci rs58542926,using the flight mass spectrometry method.The optimal assignment value of gene polymorphisms was defined by using the online SNP stats.Hardy-Weinberg (H-W) balance was tested for SNP.Effects of the genetic and environmental factors to HBV-HCC were analyzed by using the multiple classification logistic regression method.The gene-gene,gene-smoking and alcohol drinking interaction effects were investigated by Fork-Life analysis and binary logistic regression methods.Results The frequency distribution of CHB group rs738409 loci seemed not in conformity with the H-W balance (x2=11.980,P＜0.005).Two loci frequency distributions in the other groups were all in accordandce with the H-W balance.After adjusting for influences on age and sex and comparing to the healthy group,the rs58542926 mutation appeared as OR=1.659,95％CI:1.026-2.684,P=0.039,in the HBV-HCC group.When comparing to CHB group,the HBV-HCC group presented that drinking as OR=1.680,95％CI:1.121-2.519,P=0.012.When comparing to the LC group,the ORs of drinking and smoking were 1.539 (1.071-2.213) and 1.453 (1.005-2.099) respectively,in the HBV-HCC group.When comparing to the CHB + LC group,interactions between the HBV-HCC group were found rs738409 and rs58542926 on additive model OR=1.548 (U=1.885,P=0.029) and OR=1.658 (P=0.024) on logistic regression model while drinking was rs738409 on interaction additive model with OR=1.811(U=1.965,P=0.024).As for drinking and mutation of rs738409,the multiplication model of logistic regression showed no statistically significant differences.Interaction between smoking and drinking appeared as OR=1.756 (P＜0.001) in the logistics regression multiplication model.Conclusions Factors as mutation of TM6SF2,smoking and drinking all appeared as risk factors for HBV-HCC.Mutations of both PNPLA3 and TM6SF2,together with smoking and drinking all served as risk factors for HBV-HCC.However,the mutation of single PNPLA3 appeared as a protective factor on HBV-HCC.

Effects of PNPLA3, TM6SF2 gene polymorphisms and its interactions with smoking and alcohol drinking on hepatitis B virus-associated hepatocellular carcinoma / 中华流行病学杂志

Objective To explore the SNP effects ofpatatin-like phospholipase domain which containing 3 (PNPLA3),transmembrane 6 superfamily member 2 (TM6SF2) gene,environmental effects of smoking,alcohol drinking and interaction between gene-gene,gene-environment and drinking-smoking on hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC).Methods We collected anticoagulant peripheral blood from patients of HBV-HCC,chronic hepatitis B (CHB),liver cirrhosis (LC) and from healthy controls to detect the single nucleotide polymorphism (SNP) of patatin-like phospholipase domain containing 3 (PNPLA3) gene loci rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) gene loci rs58542926,using the flight mass spectrometry method.The optimal assignment value of gene polymorphisms was defined by using the online SNP stats.Hardy-Weinberg (H-W) balance was tested for SNP.Effects of the genetic and environmental factors to HBV-HCC were analyzed by using the multiple classification logistic regression method.The gene-gene,gene-smoking and alcohol drinking interaction effects were investigated by Fork-Life analysis and binary logistic regression methods.Results The frequency distribution of CHB group rs738409 loci seemed not in conformity with the H-W balance (x2=11.980,P＜0.005).Two loci frequency distributions in the other groups were all in accordandce with the H-W balance.After adjusting for influences on age and sex and comparing to the healthy group,the rs58542926 mutation appeared as OR=1.659,95％CI:1.026-2.684,P=0.039,in the HBV-HCC group.When comparing to CHB group,the HBV-HCC group presented that drinking as OR=1.680,95％CI:1.121-2.519,P=0.012.When comparing to the LC group,the ORs of drinking and smoking were 1.539 (1.071-2.213) and 1.453 (1.005-2.099) respectively,in the HBV-HCC group.When comparing to the CHB + LC group,interactions between the HBV-HCC group were found rs738409 and rs58542926 on additive model OR=1.548 (U=1.885,P=0.029) and OR=1.658 (P=0.024) on logistic regression model while drinking was rs738409 on interaction additive model with OR=1.811(U=1.965,P=0.024).As for drinking and mutation of rs738409,the multiplication model of logistic regression showed no statistically significant differences.Interaction between smoking and drinking appeared as OR=1.756 (P＜0.001) in the logistics regression multiplication model.Conclusions Factors as mutation of TM6SF2,smoking and drinking all appeared as risk factors for HBV-HCC.Mutations of both PNPLA3 and TM6SF2,together with smoking and drinking all served as risk factors for HBV-HCC.However,the mutation of single PNPLA3 appeared as a protective factor on HBV-HCC.

Expression and effect of THEM4/Akt on extracellular matrix deposit in kidney of diabetic mice / 临床与实验病理学杂志

Purpose To investigate the relations of THEM4/Akt expression and extracellular matrix deposit in kidney of diabetic mice. Methods Diabetic mice models were successfully established by intraperitoneally injected STZ. Both normal control mice and diabetic mice were raised for 8 week until they were sacrificed. Western blot, immunohistochemistry and realtime PCR were used to detect the expression of THEM4, phospho-Akt (Ser 473), TGF-β1, a-SMA, Col Ш, FN protein and THEM4 mRNA in the kidneys of normal mice and diabetic mice. Results Compared to normal control mice, THEM4 expression decreased by 37.7％ followed by 3.66, 1.29 2.33, 1.99 and 2.82 times increased of phospho-Akt (Ser473), TGF-β1, a-SMA, Col Ш and FN in kidney of diabetes mellitus. Extracellular matrix accumulation was found in renal interstitial region of diabetic mice. Conclusion The decreased THEM4 might cause extracellular matrix deposit in kidney of diabetic mice by upregulating the phosphorylation of Akt and TGF-β1, α-SMA expression in diabetic mice.

Role of up-regulation of THEM4 on extracellular matrix accumulation in kidney of diabetic mice / 中国药理学通报

Aim To observe the effect of thioesterase superfamily member 4 ( THEM4 ) expression on extra-cellular matrix ( ECM ) accumulation in the kidney of diabetic mice .Methods For in vivo vector delivery experiment , male CD1 mice were randomly divided in-to four groups: normal control mice ( Control group ) , diabetic mice ( DM group ) , diabetic mice receiving pYr-ads-4-THEM4 vector ( DM+THEM4 vector ) and diabetic mice receiving pYr-adshuttle-4 vector ( DM+V vector ) .pYr-ads-4-THEM4 vector or pYr-adshuttle-4 vector ( 1 mg · kg -1 ) were mixed with TransIT-EE Hydrodynamic Delivery Solution from Mirus Co .and injected into tail vein once a week for four weeks after STZ injection.Four weeks later, mice were sacrificed and Western blot , immunohistochemistry and real-time PCR were used to detect the expression of phospho-Akt(Ser 473), THEM4, TGF-β1, α-SMA, Col Ⅲ, FN proteins and THEM4 mRNA in kidneys respectively . Results THEM4 decreased in kidney of diabetes mel-litus accompanied with increased phospho-Akt ( Ser 473), TGF-β1, α-SMA and ECM.The delivery of pYr-ads-4-THEM4 vector increased THEM4 expression and decreased phospho-Akt (Ser 473), TGF-β1, α-SMA and ECM deposit in kidneys of diabetic mice . Conclusion The up-regulation of THEM4 may pre-vent ECM deposit by inhibiting the phosphorylation of Akt and down-regulating the expression of TGF-β1 andα-SMA in kidneys of diabetic mice .

Papel de la superfamilia ABC en la resistencia farmacológica / Role of the superfamily of ABC transports in pharmacological resistance / Papel da superfamília ABC na resistência a drogas / Rôle de la superfamille ABC dans la résistance pharmacologique

Resumen Objetivo: Actualizar los conocimientos acerca de los transportadores de la superfamilia ABC vinculados con la resistencia farmacológica. Materiales y métodos: Se realizó un estudio donde se aplicó el método cualitativo, mediante una revisión bibliográfica y documental sobre el tema en fuentes de datos digitales. Se usaron los descriptores DeCs-MeSH: transportadores ABC, superfamilia ABC, resistencia farmacológica, ATP binding- cassette. Se revisaron artículos publicados sobre el tema, a través de los buscadores habituales (Google, PubMed, Cochrane, Future Medicine, Scielo, entre otros), teniendo en cuenta la calidad y la actualidad de ellos. Resultados: Se destaca la importancia clínica de estos transportadores que se relacionan con la aterosclerosis, enfermedades hepáticas, enfermedad de Alzheimer, entre otras. Esto los convierte en dianas atractivas para el diseño de nuevos medicamentos; pero al mismo tiempo, pueden expulsarlos de la célula, haciéndola resistente como a los antitumorales, antimicrobianos y antivirales. Conclusiones: Los transportadores ABC tienen una función central en los efectos adversos que diferentes sustancias, entre ellas los fármacos, tienen sobre la célula. Además, el polimorfismo genético en esta superfamilia se asocia con alteraciones farmacocinéticas que pueden desencadenar resistencia farmacológica; el impacto de estas modificaciones es el centro de recientes investigaciones que las sitúan como posible blanco terapéutico.

Abstract Objective: To update the knowledge about the ABC transporters superfamily linked to drug resistance. Materials and methods: A qualitative study where the method was applied, using a bibliographical and documentary review on the subject of digital data sources was conducted. ABC transporters, ABC superfamily, and drug resistance, binding- ATP cassette: the DECS-MeSH descriptors were using published articles on the subject through the usual search engines (Google, PubMed, Cochrane, Future Medicine, Scielo, among others), counting on the quality and timeliness of them were review. Results: The clinical significance of these transporters is stress as they relate to atherosclerosis, liver disease, Alzheimer's disease, among other conditions. This makes them attractive targets for new drug design; but at the same time, they can expel the cell making it resistant as antitumor, antimicrobial and antiviral. Conclusions: ABC transporters have central role in the adverse effects of different substances, including drugs, have on the cell. In addition, the genetic polymorphism in this superfamily is associated with pharmacokinetic changes that can trigger drug resistance; the impact of these changes is the focus of recent research that place them as a possible therapeutic target.

Resumo Objectivo: Atualizar o conhecimento sobre os transportadores de superfamilia ABC ligada a resistência a drogas. Materiais e métodos: Foi realizado um estudo qualitativo, através de uma revisão da literatura e documental sobre o tema em fontes de dados digitais. Foram utilizados os descritores DeCs-MeSH: transportadores ABC, superfamilia ABC, resistência farmacológica, ATP binding- cassette. Foram pesquisados artigos sobre o tema, através dos motores de busca (Google, PubMed, Cochrane, Future Medicine, Scielo, entre outros), tendo em conta a qualidade e a sua atualidade. Resultados: Destacou-se a importãncia clínica destes transportadores que se relacionam com a aterosclerose, doen9as hepáticas, de Alzheimer, entre outras. Isso os torna alvos atraentes para o design de novos fármacos, mas ao mesmo tempo, os fármacos podem ser expulsos da célula, tornando-a resistente aos antitumorais, antimicrobianos e antivirais. Conclusões: Os transportadores ABC têm uma função central nos efeitos adversos que diferentes substãncias, tais como os fármacos, possuem sobre a célula. Além disso, o polimorfismo genético desta superfamilia está associado as alterações farmacocinéticas que podem desencadear a resistência aos medicamentos; o impacto dessas mudanças é o centro de pesquisas recentes que os coloca como um possível alvo terapéutico.

Résumé Objectif: Actualiser les connaissances sur les transporteurs de la superfamille ABC liés a la résistance pharmacologique. Matériaux et méthodes: Une étude qualitative a été réalisée au moyen d'une recherche bibliographique et documentaire dans différentes sources de données numériques avec les moteurs de recherche habituels (Google, PubMed, Cochrane, Medicine Future, Scielo, entre autres). Les descripteurs DeCs-MeSH utilisés ont été: transporteurs ABC, superfamille ABC, résistance pharmacologique, ATP binding- cassette. Un certain nombre d'articles relatifs au sujet ont été sélectionnés en fonction de leur qualité et de leur actualité. Résultats: Les résultats mettent en avant l'importance clinique de ces transporteurs du fait de leur relation avec l'athérosclérose, certaines maladies hépatiques, la maladie d'Alzheimer, et d'autres affections. Cela en fait des cibles attrayantes pour la conception de nouveaux médicaments; mais en meme temps, ils peuvent expulser des médicaments de la cellule et la rendre résistante aux antitumoraux, antimicrobiens et antiviraux, par exemple. Conclusions: Les transporteurs ABC jouent un role central dans les conséquences néfastes de différentes substances, y compris les médicaments, sur la cellule. En outre, le polymorphisme génétique dans cette superfamille est associé a des modifications pharmacocinétiques qui peuvent déclencher une résistance aux médicaments; l'impact de ces modifications est l'objet de recherches récentes qui les placent comme cible thérapeutique possible.

FOXP in Tetrapoda: Intrinsically Disordered Regions, Short Linear Motifs and their evolutionary significance

Abstract The FOXP subfamily is probably the most extensively characterized subfamily of the forkhead superfamily, playing important roles in development and homeostasis in vertebrates. Intrinsically disorder protein regions (IDRs) are protein segments that exhibit multiple physical interactions and play critical roles in various biological processes, including regulation and signaling. IDRs in proteins may play an important role in the evolvability of genetic systems. In this study, we analyzed 77 orthologous FOXP genes/proteins from Tetrapoda, regarding protein disorder content and evolutionary rate. We also predicted the number and type of short linear motifs (SLIMs) in the IDRs. Similar levels of protein disorder (approximately 70%) were found for FOXP1, FOXP2, and FOXP4. However, for FOXP3, which is shorter in length and has a more specific function, the disordered content was lower (30%). Mammals showed higher protein disorders for FOXP1 and FOXP4 than non-mammals. Specific analyses related to linear motifs in the four genes showed also a clear differentiation between FOXPs in mammals and non-mammals. We predicted for the first time the role of IDRs and SLIMs in the FOXP gene family associated with possible adaptive novelties within Tetrapoda. For instance, we found gain and loss of important phosphorylation sites in the Homo sapiens FOXP2 IDR regions, with possible implication for the evolution of human speech.

Cloning and Expression Analysis of Nine Major Facilitator Superfamily Encoding Genes in Polyporus umbellatus / 中国药学杂志

OBJECTIVE: To clone and isolate the major facilitator superfamily(MFS)genes of Polyporus umbellatusand carry out bioinformatic analysis. METHODS: Nine major facilitator superfamily(MFS)genes were cloned fromPolyporus umbellatus sclerotia by RT-PCR and the expression analysis of the nine genes in different parts ofPolyporus umbellatus sclerotia was carried out using quantitative Real-time PCR.RESULTS: The full open reading frame cDNA sequence of these nine genes was between 1 321 and 1 860 bp, the putative encoding proteins were between 441 and 620 amino acids, the molecular weight was between 48.45×103 and 64.79×103 and the theoretical pI was between 6.59 and 9.56. The amino acids of these nine genes possessed 11 to 14 membrane-spanning domains. Phylogenetic tree analysis indicated that Comp34750, Comp34832, Comp29252, Comp42895, Comp32579 and Comp27555 had the highest similarity with MFS general substrate transporter, Comp28872 andComp26306 had the highest similarity with MFS monosaccharide transporter, and Comp33117 had the highest similarity with MFS sugar transporter. Quantitative real-time PCR showed that these nine genes were expressed in both the symbiotic part and non-symbiotic part. Meanwhile, the expressions of seven genes were significantly up-regulated in the symbiotic part except Comp34382 and Comp32579. CONCLUSION: The investigated nine genes might play an important role during the defense response and nutrient absorption of P.umbellatus.

Progress in gene CaMDR1 mediating multidrug resistance of Candida albicans / 中国人兽共患病学报

Gene CaMDR1 is a member of the major facilitator superfamily (MFS),mediating multidrug resistance of Candida albicans,and can confer resistance to benomyl,fluconazole and so forth.In this review,the progress in structure and function of the protein code by gene CaMDR1 and the transcriptional regulation mechanisms of CaMDR1 are summarized.

Progress in gene CaMDR1 mediating multidrug resistance of Candida albicans / 中国人兽共患病学报

Gene CaMDR1 is a member of the major facilitator superfamily (MFS),mediating multidrug resistance of Candida albicans,and can confer resistance to benomyl,fluconazole and so forth.In this review,the progress in structure and function of the protein code by gene CaMDR1 and the transcriptional regulation mechanisms of CaMDR1 are summarized.