Role of Some microRNA/ADAM Proteins Axes in Gastrointestinal Cancers as a Novel Biomarkers and Potential Therapeutic Targets-A Review.

Gastrointestinal (GI) cancers are some of the most common cancers in the world and their number is increasing. Their etiology and pathogenesis are still unclear. ADAM proteins are a family of transmembrane and secreted metalloproteinases that play a role in cancerogenesis, metastasis and neoangiogenesis. MicroRNAs are small single-stranded non-coding RNAs that take part in the post-transcriptional regulation of gene expression. Some ADAM proteins can be targets for microRNAs. In this review, we analyze the impact of microRNA/ADAM protein axes in GI cancers.

Cysteine is highly enriched in the canonical N-linked glycosylation motif of bovine spermatozoa N-Glycoproteome.

Glycosylation, one of the most important post-translational modifications of proteins, plays an irreplaceable role in the whole process of spermatogenesis, sperm-egg recognition, and fertilization. Herein, we mapped the first bovine sperm N-linked glycoproteome and a total of 1188 N-glycosylated sites on 626 proteins were identified. Bioinformatics analysis revealed that bovine sperm N-glycosylated proteins were classified into "extracellular region" and "lysosome" groups based on cellular component annotation and enrichment of glycoproteins with proteolytic and reproductive functions. Notably, cysteines were highly enriched in the canonical N-glycosylation motifs N-!P-[S/T/C] and the conservative motifs N-C-[S/T] were also significantly enriched, indicating these modifications play extraordinary roles in bovine spermatogenesis and maturation. The percentage of cysteine at the second position relative to modified asparagine was 7.5%, much higher than that of the previously reported N-linked glycoproteome. A total of 120 cysteine enriched N-glycoproteins were identified, which had significantly upregulated metalloendopeptidase activity and metal ion binding compared with the whole bovine sperm glycoproteome. Strikingly, 15 of 58 N-C-[S/T] motif-containing glycoproteins had a disintegrin and metalloproteinase (ADAM) protein domain. Thus, we hypothesized that ADAM-containing conserved free cysteine residues in N-linked glycoprotein motifs may be key cysteine-switches and may have extraordinary roles in bovine spermatozoa. In conclusion, almost all bovine sperm glycoproteins have enzyme activity, participate in proteolysis, and play indispensable roles in spermatogenesis, sperm-egg recognition, and eventual fertilization. The mapping of N-glycosylation on bovine sperm may provide a new means to explore potential biomarkers for improving sperm quality and fertility.

Antitumoral Potential of Lansbermin-I, a Novel Disintegrin from Porthidium lansbergii lansbergii Venom on Breast Cancer Cells.

BACKGROUND: Disintegrins from snake venoms bind with high specificity cell surface integrins, which are important pharmacological targets associated with cancer development and progression. OBJECTIVE: In this study, we isolated a disintegrin from the Porthidium lansbergii lansbergii venom and evaluated its antitumoral effects on breast cancer cells. METHODS: The isolation of the disintegrin was performed on RP-HPLC and the inhibition of platelet aggregation was evaluated on human platelet-rich plasma. The inhibition of cell adhesion was also evaluated in vitro on cultures of cell lines by the MTT method as well as the inhibition of breast cancer cell migration by the wound healing assay. The binding of the disintegrin to integrin subunits was verified by flow cytometry and confocal microscopy. Finally, inhibition of angiogenesis was assessed in vitro on HUVEC cells and the concentration of VEGF was measured in the cellular supernatants. RESULTS: The disintegrin, named Lansbermin-I, is a low molecular weight protein (< 10 kDa) that includes an RGD on its sequence identified previously. Lansbermin-I showed potent inhibition of ADP and collagen-induced platelet aggregation on human plasma and also displayed inhibitory effects on the adhesion and migration of breast cancer MCF7 and MDA-MB 231cell lines, without affecting nontumorigenic breast MCF-10A and lung BEAS cells. Additionally, Lansbermin-I prevented MCF7 cells to adhere to fibronectin and collagen, and also inhibited in vitro angiogenesis on human endothelial HUVEC cells. CONCLUSION: Our results display the first report on the antitumor and anti-metastatic effects of an RGDdisintegrin isolated from a Porthidium snake venom by possibly interfering with α2 and/or ß1-containing integrins. Thus, Lansbermin-I could be an attractive model to elucidate the role of disintegrins against breast cancer development.

ADAM9 Expression in Uterine Cervical Cancer and Its Associated Factors

Background: Cervical cancer is a preventable disease caused by human papillomaviruses. It is the third most common cancer to occur in women of reproductive age. The ADAM9 protein plays a role in basement membrane degradation and tumour metastasis in certain types of tumour. Thus, it has the potential to become a new targeted therapy. The objective of this study was to investigate ADAM9 expression in cervical cancer and to determine the factors associated with ADAM9-positive expression. Methods: This cross-sectional study was conducted in Hospital Universiti Sains Malaysia (HUSM) Kelantan, Malaysia from December 2010 to December 2012. Histological slides obtained from 95 cervical cancer cases diagnosed and/or treated in HUSM from 2000 to 2010 were analysed. The ADAM9 immunostain was then performed on the paraffin blocks. The statistical data entry and analysis were done using SPSS version 18.0. Multiple logistic regression analysis was performed to determine the factors associated with ADAM9-positive expression. Result: Of the 95 cervical cancer patients included in the study, 72 (75.8%) patients showed positive ADAM9 expression. The mean age of the patients was 53.89 (10.83) years old. Squamous cell carcinoma was the most common type of cervical cancer (n = 67, 70.5%). Factors that showed a statistically significant association with ADAM9-positive expression were tumour size (adjusted odds ratio [adj. OR]: 1.08; 95% confidence interval [CI]: 1.02, 1.13; p = 0.004), distant metastasis (adj. OR: 12.82; 95% CI: 1.91, 86.13; p = 0.009) and the histological type of cervical cancer (i.e. squamous cell carcinoma) (adj. OR: 7.39; 95% CI: 1.42, 38.51; p = 0.017). Conclusion: The ADAM9 immunostain was consistently positive in malignant cells. Thus, ADAM9 expression can be used as a prognostic/therapeutic indicator in aiding clinician decision-making regarding patient treatment (targeted therapy).

Signaling Pathways of Receptors Involved in Platelet Activation and Shedding of These Receptors in Stored Platelets.

All cells encounter various signals coming from the surrounding environment and they need to receive and respond to these signals in order to perform their functions. Cell surface receptors are responsible for signal transduction .Platelets are blood cells which perform several functions using diverse receptors. Platelet concentrate is one of the most consumed blood products. However, due to the short lifespan of the platelets and platelets damage during storage, we face shortage of platelet products. One of the damages that platelets undergo during storage is the loss of surface receptors. Since cell surface receptors are responsible for all cell functions, the loss of platelet receptors reduces the quality of platelet products. In this study, we reviewed the important receptors involved in platelet activation and their associated signaling pathways. We also looked at the platelet receptors that shed during storage and the causes of this incident. We found that GPIbα, P-selectin, CD40 and GPVI are platelet receptors that fall during platelet storage at room temperature. Considering that GPVI and GPIbα are the most important receptors which involved in platelet activation, their shedding can cause decrease in platelet activation after transfusion and decrease thrombus consistence. Shear stress and platelet contact with the container wall are among the mechanisms discussed in this process, but studies in this area have to be continued.

Relapse of congenital thrombotic thrombocytopenic purpura, after spontaneous remission, in a second-trimester primigravida: case report and review of the literature / Recidiva, após remissão espontânea, de púrpura trombocitopênica trombótica congênita em primigesta no segundo trimestre de gestação: relato de caso e revisão da literatura

ABSTRACT CONTEXT: Thrombotic microangiopathy syndrome or thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) describes distinct diseases sharing common pathological features: microangiopathic hemolytic anemia and thrombocytopenia, without any other apparent cause. CASE REPORT: An 18-year-old second-trimester primigravida presented with a history of fifteen days of intense weakness, followed by diarrhea over the past six days. She reported having had low platelets since childhood, but said that she had never had bleeding or menstrual abnormalities. Laboratory investigation showed anemia with schistocytes, thrombocytopenia and hypohaptoglobulinemia. Red blood cell concentrate and platelet transfusions were performed. The hypothesis of TTP or HUS was put forward and ADAMTS13 enzyme activity was investigated. The patient evolved with increasing platelet counts, even without specific treatment, and she was discharged. One month afterwards, she returned presenting weakness and swollen face and legs, which had developed one day earlier. The ADAMTS13 activity was less than 5%, without presence of autoantibodies. Regarding the two previous admissions (at 9 and 16 years of age), with similar clinical features, there was spontaneous remission on the first occasion and, on the second, the diagnosis of TTP was suspected and plasmapheresis was performed, but ADAMTS13 activity was not investigated. CONCLUSION: To date, this is the only report of congenital TTP with two spontaneous remissions in the literature This report reveals the importance of suspicion of this condition in the presence of microangiopathic hemolytic anemia and thrombocytopenia without any other apparent cause.

RESUMO CONTEXTO: A síndrome de microangiopatia trombótica, ou púrpura trombocitopênica trombótica-síndrome hemolítico urêmica (PTT-SHU), descreve doenças diversas com clínica e achados patológicos comuns: anemia hemolítica microangiopática e trombocitopenia, na ausência de outra causa aparente. RELATO DO CASO: Primigesta de 18 anos no segundo trimestre apresenta-se com quadro de 15 dias de fraqueza intensa seguida por diarreia há seis dias. Relata ter plaquetas baixas desde a infância e nega sangramentos e anormalidades menstruais. Investigação laboratorial identificou anemia com esquizócitos, plaquetopenia e hipo-haptoglobulinemia. Foi realizada transfusão de plaquetas e concentrado de hemácias. A hipótese de PTT ou SHU foi aventada e realizou-se pesquisa da atividade da enzima ADAMTS13. A paciente evoluiu com elevação das plaquetas, mesmo sem tratamento específico, tendo alta. Retornou após um mês da alta com queixa de fraqueza há um dia e inchaço de face e pernas. A atividade da ADAMTS13 foi menor que 5%, sem autoanticorpos. Nas duas internações anteriores (aos 9 e 16 anos), com quadros similares, houve remissão espontânea na primeira internação e, na segunda, o diagnóstico de PTT foi suspeitado e foi realizada plasmaférese, porém sem a pesquisa da atividade da ADAMTS13. CONCLUSÃO: Até esta data, este é único relato de TTP congênita com duas remissões espontâneas na literatura. Este relato revela a importância da suspeição desta patologia na presença de anemia hemolítica microangiopática e trombocitopenia sem outra causa aparente.

Association between polymorphism of S1, S2 locus allele in ADAM33 gene and chronic obstructive pulmonary disease in Xinjiang Uygur population / 天津医药

Objective To investigate the association between polymorphism of S1, S2 locus allele in ADAM 33 gene and chronic obstructive pulmonary disease (COPD) and lung function in Xinjiang Uygur population. Methods Blood sam?ples from 217 COPD patients and 218 healthy controls were collected. Samples of DNA was extracted, and S1, S2 single nu?cleotide polymorphism (ADAM 33) was detected by ABI SNaPshot SNP genotyping. Results There were no significant dif?ferences in the frequencies of S1 locus CC, CT, TT genotypes and C, T alleles between patient group and control group (P>0.05). There were no significant differences in the frequencies of S1 locus CC, CG, GG genotypes and C, G alleles between patient group and control group (P>0.05). In patient group, there were no significant differences in S1, S2 locus genotype and clinical indicators of lung function display, and in the FEV1%predicted and FEV1/FVC (P>0.05). Haplotype analysis showed that there were no significant differences in three kinds of haplotypes between patient group and control group ( P>0.05). Conclusion There is no significant difference in the polymorphism of S1, S2 locus allele in ADAM 33 gene and the susceptibility to COPD in Xinjiang Uygur population.

Association between ADAM33 gene polymorphism with chronic obstructive pulmonary disease incidence in Kazakh of Xinjiang / 天津医药

Objective To explore correlation of Xinjiang Kazakh population who suffered from COPD with polymor?phisms of F+1,S2,T1,ST+5 locus of ADAM33 gene. Methods Blood samples (n=193) from healthy controls (Control group, n=193) and COPD patients (Case group, n=197) were detected by SNP SNaP shot. Results Comparing case group with the control group, gene frequency and allele frequency of F+1 locus were of significant differences (P0.05). The gene frequencies and allele frequency of S2、T1 and ST+5 locus were not significantly differ?ent between case group and control group (P>0.05). F+1 and S2 locus were analyzed by haplotype analysis which showed that there was significant differences in Hap1 (CC) haplotype between case group and control group (P1 revealed that its haplotype may increase the risk of COPD . The distri?bution of Hap2 (TG) and Hap4 (CG) were not significantly different (P>0.05) between the 2 groups. T1 and ST+5 locus were analyzed by haplotype analysis which showed significant differences in haplotypes between case group and control group (P<0.05). Conclusion The occurrence of COPD may be related to the polymorphism of ADAM33 gene in F+1 locus in Xinjiang Kazakh.

γδ T Lymphocytes as a First Line of Immune Defense: Old and New Ways of Antigen Recognition and Implications for Cancer Immunotherapy.

Among γδT cells, the Vδ1 subset, resident in epithelial tissues, is implied in the defense against viruses, fungi, and certain hematological malignancies, while the circulating Vδ2 subpopulation mainly respond to mycobacteria and solid tumors. Both subsets can be activated by stress-induced molecules (MIC-A, MIC-B, ULBPs) to produce pro-inflammatory cytokines and lytic enzymes and destroy bacteria or damaged cells. γδT lymphocytes can also recognize lipids, as those associated to M. tuberculosis, presented by the CD1 molecule, or phosphoantigens (P-Ag), either autologous, which accumulates in virus-infected cells, or microbial produced by prokaryotes and parasites. In cancer cells, P-Ag accumulate due to alterations in the mevalonate pathway; recently, butyrophilin 3A1 has been shown to be the presenting molecule for P-Ag. Of interest, aminobisphosphonates indirectly activate Vδ2 T cells inducing the accumulation of P-Ag. Based on these data, γδT lymphocytes are attractive effectors for cancer immunotherapy. However, the results obtained in clinical trials so far have been disappointing: this review will focus on the possible reasons of this failure as well as on suggestions for implementation of the therapeutic strategies.

Specific inhibition of ectodomain shedding of glycoprotein Ibα by targeting its juxtamembrane shedding cleavage site.

BACKGROUND: Ectodomain shedding of glycoprotein Ibα (GPIbα), a proteolytic event in which metalloprotease ADAM17 cleaves the Gly464-Val465 bond and releases glycocalicin to the plasma, is considered a critical step in mediating clearance of stored platelets. Supporting evidence has largely come from studies using ADAM17 inhibitors. However, the definitive proof is lacking due to the broad substrate specificity of ADAM17. AIM: To achieve substrate-specific inhibition of GPIbα shedding. METHODS: Development of monoclonal antibodies that directly bind the sequence around the GPIbα shedding cleavage site and inhibit GPIbα shedding by blocking ADAM17 access to the cleavage site. RESULTS: Six anti-GPIbα monoclonal antibodies with varying binding affinities were obtained. The prototypic clone, designated 5G6, and its monomeric Fab fragment bind specifically purified GPIb-IX complex, human platelets, and transgenic murine platelets expressing human GPIbα. The clone 5G6 showed similar inhibitory potency as a widely used shedding inhibitor GM6001 in both constitutive and induced GPIbα shedding in human platelets. It does not recognize mouse GPIbα or inhibit shedding of other platelet receptors. Finally, 5G6 binding displays no detectable effect on platelet activation and aggregation. CONCLUSIONS: The clone 5G6 specifically inhibits GPIbα shedding with no detectable effect on platelet functions. The method of substrate-specific shedding inhibition by macromolecular binding of the shedding cleavage site can be applicable to many other transmembrane receptors undergoing ectodomain shedding.

ADAMTS13 deficiency and thrombotic thrombocytopenic purpura associated with trimethoprim-sulfamethoxazole.

Thrombotic thrombocytopenic purpura (TTP) is a hematological disease characterized by microangiopathic hemolytic anemia and thrombocytopenia. Although the link between ADAMTS13 deficiency and idiopathic TTP has been well-established, the role of trimethoprim-sulfamethoxazole (TMP-SMX) in the pathogenesis of TTP is not yet well elucidated. To the best of our knowledge, there have been only two previous reports linking this medication with the development of TTP. We present the case of a healthy woman, age 26 years, who developed TTP during TMP-SMX therapy for urinary tract infection. She was found to have ADAMTS13 deficiency with anti-ADAMTS13 antibodies. Her condition responded to discontinuation of the TMP-SMX, plasmapheresis, and rituximab therapy. We speculate that the acquired ADAMTS13 deficiency might have been triggered by the TMP-SMX therapy.

The value of anti-von Willebrand factor antibody in the mechanism of idiopathic thrombotic thrombocytopenic purpura / 中华检验医学杂志

Objective This study is aimed at determining whether anti-von Willebrand factor (VWF) autoantibodies are present in the plasma of idiopathic thrombotic thrombocytopenic purpura (TTP) patients with normal ADAMTS13 activity and undetectable anti-ADAMTS13 antibodies,and at examining whether murine monoclonal antibodies (mAbs) against human VWF decrease the susceptibility of VWF to ADAMTS13 in vitro.Methods Anti-VWF autoantibodies and ultralarge VWF (UL-VWF) multimers were measured in plasma samples of 53 adult patients with idiopathic TTP by enzyme-linked immunosorbent assay and sodium dodecylsulphate-agarose gel electrophoresis,respectively.Moreover,the effects of eight murine mAbs to different human VWF domains on VWF cleavage by ADAMTS13 were evaluated under fluid shear stress and static/denaturing conditions,respectively.Results Anti-VWF antibodies and UL-VWF multimers were detected in two TTP patients with normal ADAMTS13 activity and undetectable anti-ADAMTS13antibodies.The SZ34,an anti-VWF mAb,inhibited VWF proteolysis mediated by ADAMTS13 under flow,but not static conditions.Conclusion Anti-VWF antibody may be one of the causes of idiopathic TTP with normal ADAMTS13 activity and undetectable anti-ADAMTS13 antibodies.

Association between promoter polymorphisms of a disintegrin and metalloproteinase 10 gene and sporadic Alzheimer's disease / 中华神经科杂志

ObjectiveTo investigate the relationship between the polymorphisms of the promoter of a disintegrin and metalloproteinase 10(ADAM10) gene and sporadic Alzheimer's disease (SAD).Methods The promoter of ADAM10 gene in 10 controls and 10 SAD patients was sequenced.Three variations were found,then these variations in 298 SAD patients (SAD group) and 315 healthy controls (control group)were genotyped by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).ResultsThree polymorphisms were found in the promoter of ADAM10 gene: -279G/A (rs653765),- 630G/T( rs514049 ) and - 921GAGA/- ( rs33926666 ).For - 921GAGA/-,there were significant differences in genotype ( GAGA/GAGA:138 (46.3％ ),GAGA/-:155(52.0％),-/-:5(1.7％))and allele frequencies (GAGA:431 (73.6％),-:165 (27.7％) ) between SAD and control (genotype:x2 =34.130,P =0.000; allele:x2 =25.972,P =0.000). For - 279G/A,there were significant differences in genotype and allele frequencies between SAD and control in the subjects without ApoEε4 allele (genotype:x2 =8.734,P=0.013; allele:x2 =5.129,P=0.024). -279G and -921GAGA were relatively protective allele types for SAD,and they were not in linkage disequilibrium.ConclusionThe polymorphisms - 279G/A and - 921GAGA/- of ADAM10 are associated with SAD.Allele G or genotype G/G of -279G/A and the GAGA/GAGA genotype or the GAGA allele of -921GAGA/- might have a protective effect on SAD.

Family of ADAMs and gastric and colorectal cancer / 国际肿瘤学杂志

The ADAMs(a disintegrin and metalloproteinase) are a family of transmembrane or secreted proteins with important roles in cell fusion,adhesion,degradation of extracellular matrix,proteolysis,and signaling.The most important domains of ADAMs includes metalloprotease domain and disintegrin domain.Some ADAMs have been observed in gastric and colorectai cancer,and produced a marked effects during the tumor development and metastasis.The further research of ADAMs may provide more choices for tumor target therapy.

Effect of atorvastatin on ADAM10 in hippocampus of chronic cerebral hypoperfusion in rats / 国际脑血管病杂志

Objective To investigate the learning and memory functions,expression changes of disintegrin and metalloprotease 10 (ADAM10) mRNA in hippocampus in the aged rats with chronic cerebral hypoperfusion as well as the effect of atorvastatin on them.Methods A total of 72 rats were randomly divided into sham operation,cerebral hypoperfusion and atorvastatin treatment groups.A permanent bilateral common carotid artery occlusion (2VO)model was induced.Atorvastatin 10 mg/(kg · d) was administered orally after procedure in the atorvastatin treatment group.Real-time fluorescence quantitative polymerase chain reaction was used to detect the expression of ADAM10 mRNA in bilateral hippoocampus at 1,2,4,and 16 weeks after modeling,Results Two weeks after modeling,the learning and memory functions were decreased significantly in the cerebral hypoperfusion group compared to the sham operation group (P ＜ 0.05).At 4 and 16 weeks after modeling,they were further decreased (P ＜0.01); there were no significant differences in the learning and memory functions at 1,2,and 3 weeks after modeling between the atorvastatin treatment group and the cerebral hypoperfusion group,however,they were improved significantly at 16 weeks compared to the cerebral hypoperfusion group (P＜0.01).The expression of ADAM10 mRNA in hippocampus at different time points after modeling in the cerebral hypoperfusion group was down-regulated by 22％,43％,35％,and 50％,respectively compared to the sham operation group (all P ＜0.05).The expression of ADAM 10 mRNA in hippocampus at 2 weeks in the atorvastatin treatment group was higher than 22％ in the cerebral hypoperfusion group (P＜0.05).There were not significant differences at other time points.Conelusions Chronic cerebral hypoperfusion results in the down-regulation of the expression of ADAM10 mRNA in hippocampus in the aged rats,and atorvastatin may inhibit down-regulation of the expression of ADAM10 mRNA at early stage.

Correlation of a disintegrin and metalloprotease 12 level in maternal serum during the first trimester with pregnancy outcome / 中华妇产科杂志

05). Conclusion The maternal serum level of ADAM 12 in the first-trimester is a potential marker for aneupolyhaploid screening and early fetal loss prediction, and is suggested to be tested at 9-12 gestational weeks as part of prenatal screening.