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Results for “potential targets”

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PubMed1993

Carbohydrate antigens of pig tissues reacting with human natural antibodies as potential targets for hyperacute vascular rejection in pig-to-man organ xenotransplantation.

Pig tissues were screened by immunofluorescence with lectins, mAb, and human natural antibodies for the presence of carbohydrate antigens, which may be potential targets for hyperacute vascular rejection in pig to man xenotransplantation. The unfucosylated monomorph linear B-antigen was found at the surface of all porcine vascular endothelial cells. This pig linear-B antigen reacts strongly with the anti-alpha Gal isolectin B4 from Griffonia simplicifolia 1 and with human natural anti-alpha Gal antibodies specifically purified by affinity chromatography on synthetic oligosaccharides containing the terminal nonreducing alpha Gal1-->3 beta Gal-R disaccharide. This antigenic activity is destroyed by treatment of pig tissues with alpha-galactosidase. The localization of this linear-B epitope on vascular endothelium and its reactivity with natural human anti-alpha Gal antibodies suggest that it may play a major role in the hyperacute vascular rejection of pig to man organ xenografts. The lectin from Maackia amurensis reacting with alpha NeuAc2-->3 beta Gal1-->4GlcNAc/Glc was also positive on pig vascular endothelium, but we do not know yet whether there are human natural antibodies reacting with the carbohydrate recognized by this lectin. Epithelial cells of pig renal proximal convoluted tubules, respiratory epithelium, pancreatic ducts, and epidermis express the linear-B antigen, but they are less likely to trigger a hyperacute vascular rejection because they are not directly exposed to the blood. The genetically defined pig A+/A- system controls the expression of A and H antigens in pig epithelial cells from renal distal and collecting tubules, biliary ducts, pancreatic ducts, large bronchi, and digestive mucosa. The pig A antigen may trigger an immune response in human O or B recipients if they are transplanted with organs from A+ pigs, but the pig A antigen is probably not involved in the hyperacute vascular rejection of a xenograft because it is not expressed on vascular endothelium.

Acute Disease↗

PubMed2005

Genetic profiling of aortic allografts: prothymosin alpha as potential target?

Transplant arteriosclerosis is the result of intima proliferation in large vessels upon organ transplantation. Obliteration of the vascular lumen will ultimately lead to ischemia and late graft failure. Gene array analysis was performed to identify factors involved in the pathogenesis of transplant arteriosclerosis. Aortic transplants from Dark Agouti to Wistar Furth rats were performed to identify potential target genes. Hierarchical clustering of genes specifically upregulated in allogeneic but not in syngeneic aortas revealed 19 genes. A gene that fulfilled these criteria is prothymosin alpha (PTMA), a regulator of estrogen receptor transcriptional activity. PTMA gene and protein expression levels were confirmed by PCR and immunohistochemistry. Estrogen receptor staining was increased in allogeneic aortas. Furthermore, cyclin D1 a downstream target of PTMA, was also up regulated in allogeneic aortas. In conclusion, PTMA was identified as potential candidate gene involved in transplant arteriosclerosis.

Animals↗

PubMed2004

The RET proto-oncogene: a potential target for molecular cancer therapy.

The inhibition of activated receptor tyrosine kinases has defined a new era of selective cancer therapy. The value of these approaches has been demonstrated for a growing number of tyrosine kinases. Gain-of-function alterations within the RET proto-oncogene are responsible for the development of medullary, as well as papillary, thyroid carcinoma and make it a candidate for the design of targeted therapies. Recently, various strategies have been used to block the activity of RET in pre-clinical models, providing evidence that RET is a potential target for a selective cancer-therapy approach, especially when considering that the inhibition of RET activity is sufficient to revert neoplastic characteristics. Although the ideal clinically useful therapeutic option has yet to be developed, successes with other selective tyrosine kinase inhibitors encourages further effort.

Animals↗

PubMed1995

Fungal glycoproteins and their biosynthetic pathway as potential targets for antifungal agents.

The yeast cell wall as a good antifungal target is discussed in general. More specifically the reaction, catalyzed by Dol-P-Man: protein O-D-mannosyltransferase is proposed as a new potential target. Six genes responsible for this endoplasmic reticulum-localized reaction have been cloned and characterized so far. Triple disruptions of these genes are either lethal or the corresponding cells have to be osmotically stabilized to survive. No inhibitors of this reaction are as yet known.

Antifungal Agents↗

PubMed2002

Regulation of calcium homeostasis in activated human neutrophils--potential targets for anti-inflammatory therapeutic strategies.

OBJECTIVES: The objectives of the current study were to: (i) present an integrated model for the restoration of calcium homeostasis in activated human neutrophils based on current knowledge and recent research; and (ii) identify potential targets for the modulation of calcium fluxes in activated neutrophils based on this model and to investigate the effects of intracellular probes which target key processes involved in calcium homeostasis and pro-inflammatory activity in these cells. DESIGN AND SETTING: Laboratory-based experimental research using purified human neutrophils from healthy, adult human volunteers. OUTCOME MEASURES: Calcium metabolism and pro-inflammatory activity of neutrophils. RESULTS: Modulation of calcium fluxes in activated human neutrophils can be achieved by cAMP-dependent upregulation of the activity of the endomembrane Ca(2+)-ATPase which resequesters cytosolic Ca2+. Formoterol, a long-acting beta 2-agonist, elevates intracellular cAMP levels, accelerates Ca2+ restoration in activated neutrophils and downregulates the pro-inflammatory responses of these cells. Alterations in the membrane potential of activated neutrophils may play a role in regulating calcium reuptake into the cells as attenuation of the membrane depolarisation response is associated with accelerated calcium influx. CONCLUSIONS: Modulation of the activity of the endomembrane Ca(2+)-ATPase in human neutrophils represents an important target for anti-inflammatory

Adrenergic beta-Agonists↗

PubMed1995

Cutaneous and muscle afferents: interactions with potential targets in vitro.

Previous studies suggest that cutaneous and muscle afferents use different environmental cues in growing to their peripheral targets. As a first approach to learning whether these earlier observations reflect differences in the behavior of individual growth cones, trigeminal cutaneous and muscle afferents of embryonic day 10 chicks were cocultured with explants of epidermis or dermis or with myotubes, and interactions of their growth cones with these potential targets were followed with time lapse video microscopy. Cutaneous and muscle afferents differed in their response to all three targets. In birds, few cutaneous afferents innervate epidermis. Accordingly, most cutaneous neurites retracted within minutes of touching an epidermal cell. In contrast, most muscle afferents stopped growing but remained in contact with epidermis for as long as they were observed (> 1 hr). Further, most cutaneous afferents grew readily across explants of dermis, their normal target, at rates comparable to their growth on the substrate. In contrast, most muscle afferents advanced only poorly on dermis. Finally, most cutaneous afferents grew readily across myotubes, the normal targets of muscle afferents. In contrast, few muscle afferents grew across myotubes; most either retracted or changed course and grew along the myotube. Overall, muscle afferents stayed in contact with myotubes longer than cutaneous afferents. These cell-type-specific responses reflect in large part the patterns of cutaneous and muscle afferent growth in vivo. Further studies are required to determine whether these observed differences between the behavior of regenerating cutaneous and muscle afferent growth cones could potentially play a role in the selection of targets or pathways during embryonic development.

Afferent Pathways↗

PubMed1998

The small G-proteins Rap 1 as potential targets of vasoactive intestinal peptide effects in the human clonic cancer cells HT29.

We recently reported that the vasoactive intestinal peptide (VIP) potently inhibited proliferation and induced in parallel a strong cAMP rise, in the human colonic cancer cell line HT29. In this study, we investigated whether Rap 1 proteins could be potential targets of VIP effects in HT29 cells. These Ras-related proteins in which activity was demonstrated to be regulated by PKA phosphorylation, are considered as potential modulators of the Ras / Raf / MAP kinases cascade that governs cell growth control. Our data revealed that the Rap 1a isoform is highly expressed in HT29 cells and mainly localized in a late endosomal compartment. In these cells, VIP induces Rap 1 phosphorylation and a yet unidentified modification that leads to their acidification. This latter Rap 1 acidification seems to be, at least partially, cAMP-dependent. It is concluded that in HT29 cells, Rap 1 proteins may be part of a VIP-induced signaling cascade.

Antibodies↗

PubMed1997

In vitro mutational and inhibitory analysis of the cis-acting translational elements within the 5' untranslated region of coxsackievirus B3: potential targets for antiviral action of antisense oligomers.

The 5' untranslated region (5'UTR) of coxsackievirus B3 (CVB3) RNA forms a highly ordered secondary structure that has been implicated in controlling initiation of viral translation by internal ribosomal entry. To test this hypothesis, synthetic bicistronic RNAs, with all or part of the 5'UTR in the intercistronic space, were translated in rabbit reticulocyte lysates. In the presence of an upstream cistron, the chloramphenicol acetyltransferase gene, designed to block ribosomal scanning, the CVB3 5'UTR was capable of directing the internal initiation of translation of the downstream reporter gene (P1), confirming the presence of an internal ribosomal entry site (IRES). This finding was further supported by the data on predicted secondary structures within the 5'UTR. Of special note, analysis of various deletion mutants demonstrated that the IRES of CVB3 is located roughly at stem-loops G, H, and I spanning nucleotides (nt) 529 and 630. The region from nt 1 to 63 (stem-loop A) also appears important, and it may be an essential binding site for translation initiation factors. Based on these findings, in vitro translation inhibition assays using RNA fragments of the 5'UTR as inhibitor were performed. Both antisense and sense RNA segments transcribed from these two cis-acting regions and the surrounding sequence of the initiation codon AUG showed strong inhibition of viral protein synthesis. Antisense molecules may inhibit translation by blocking ribosome and initiation factor binding within the 5'UTR via specific hybridization to their viral RNA target sequences, while sense sequences may function by competing with viral RNA for ribosomes and/or translation initiation factors. These cis-acting translational elements may serve as potential targets for the antiviral action of oligomers.

Animals↗

PubMed2005

Polyamine transport in parasites: a potential target for new antiparasitic drug development.

The metabolism of the naturally occurring polyamines-putrescine, spermidine and spermine-is a highly integrated system involving biosynthesis, uptake, degradation and interconversion. Metabolic differences in polyamine metabolism have long been considered to be a potential target to arrest proliferative processes ranging from cancer to microbial and parasitic diseases. Despite the early success of polyamine inhibitors such as alpha-difluoromethylornithine (DFMO) in treating the latter stages of African sleeping sickness, in which the central nervous system is affected, they proved to be ineffective in checking other major diseases caused by parasitic protozoa, such as Chagas' disease, leishmaniasis or malaria. In the use and design of new polyamine-based inhibitors, account must be taken of the presence of up-regulated polyamine transporters in the plasma membrane of the infectious agent that are able to circumvent the effect of the drug by providing the parasite with polyamines from the host. This review contains information on the polyamine requirements and molecular, biochemical and genetic characterization of different transport mechanisms in the parasitic agents responsible for a number of the deadly diseases that afflict underdeveloped and developing countries.

Animals↗

PubMed2003

[Renin-angiotensin system as a potential target for the treatment with heart failure: ACE inhibitors, angiotensin-II receptor blockers and aldosterone antagonists].

Recent experimental studies and clinical trials have revealed that the modulation of either systemic or regional(cardiovascular) renin-angiotensin systems(RAS) is one of the potential targets to prevent the progression of heart failure. Either ACE inhibitor, angiotensin-II receptor blocker or aldosterone antagonist differently block RAS. Many clinical trials told us that each of them improves heart failure and might promise the better prognosis. Now, some experimental studies are encouraging us to test the comparative effects or the effects in combination of them. Here we will summarize the current outcomes from the experimental and clinical studies, and discuss the future direction.

Angiotensin II↗

PubMed2000

Potential targets for HSF1 within the preinitiation complex.

Protein-protein interactions between human heat shock transcription factor 1 (hHSF1) and general transcription factors TFIIA-gamma, TFIIB, TBP, TAF(II)32, and TAF(II)55 and positive coactivator PC4 were characterized in order to identify potential targets of contact in the transcriptional preinitiation complex. These contacts represent one of the final steps in the signal transfer of heat stress to the transcriptional apparatus. TATA-binding protein (TBP) and transcription factor IIB (TFIIB) were identified as major targets for HSF1 transcriptional activation domains AD1 and AD2 based on in vitro interaction assays. TBP showed affinity for AD2 and a fragment containing AD1, while the core domain of TFIIB interacted primarily with the AD1 fragment. Interactions were also detected between full-length HSF1 and the small subunit (gamma) of TFIIA. PC4 interacted weakly with HSF2 and showed even less affinity for HSF1. Coimmunoprecipitation of transiently expressed TBP in HeLa cells demonstrated that HSF1 AD2 and AD1+AD2 are able to bind TBP in vivo. Assays based on transcriptional interference confirmed predictions that both TBP and TFIIB can interact with HSF1 activation domains in HeLa cells. The negative regulatory region (NR) of HSF1 did not interact with any general factors tested in vitro but did bind TFIID in nuclear extracts through contacts that probably involve TATA associated proteins (TAFs). These results suggest a model for transcriptional regulation by HSF1 that involves a shift between formation of dysfunctional TFIID complexes with the NR and transcriptionally competent complexes with the C-terminal activation domains.

Blotting, Western↗

PubMed2004

Presynaptic excitability as a potential target for the treatment of the traumatic cerebellum.

Using an extracellular recording method, we have previously shown a hyperexcitability of the presynaptic response in fluid percussion injury (FPI) in rats. In this study, we demonstrated that treatment with cis-ACBD, a glutamate reuptake inhibitor, depressed the presynaptic potential (PSP) in naive/sham controls, while it potentiated the PSP in FPI rats. On the contrary, (RS)-APICA, a selective group II metabotropic glutamate receptor antagonist, potentiated PSP in controls, but depressed PSP in FPI rats. These results indicate that an alteration of the normal function of metabotropic glutamate receptors and glutamate reuptake system or an altered reactivity of presynaptic fibers was induced by FPI. This alteration may contribute to the reported loss of Purkinje cells after FPI. PSP may be used as a potential tool for evaluating treatments of FPI or as a potential target for the prevention of Purkinje cell death.

Animals↗

PubMed1999

Muscarinic cholinergic receptor signal transduction as a potential target for the developmental neurotoxicity of ethanol.

Central nervous system dysfunctions (most notably mental retardation and microcephaly) are among the most significant effects of in utero exposure to ethanol. Ethanol has been shown to cause alterations of both neuronal and glial cells, including cell loss, and changes in their migration and maturation. Here, we propose that one of the potential targets for the developmental neurotoxicity of ethanol may be represented by the signal transduction systems activated by cholinergic muscarinic receptors. Ethanol has been shown to inhibit second messenger systems activated by various G-protein-coupled receptors, including certain subtypes of muscarinic receptors. Although the roles of muscarinic receptors in brain development have not been fully elucidated, two potentially relevant effects have been discovered in the past few years. By activating muscarinic receptors coupled to phospholipid metabolism, acetylcholine can induce proliferation of glial cells, and act as a trophic factor in developing neurons by preventing apoptotic cell death. Ethanol has been shown to inhibit both actions of acetylcholine in vitro. These effects of ethanol may lead to a decreased number of glial cells and to a loss of neurons, which have been observed following in vivo alcohol exposure. In turn, these may be the basis of microencephaly and cognitive disturbances in children diagnosed with Fetal Alcohol Syndrome.

Animals↗

PubMed2001

The HCMV chemokine receptor US28 is a potential target in vascular disease.

The human cytomegalovirus (HCMV) has been implicated in the acceleration of vascular disease for some time. The development of vascular disease involves a chronic inflammatory process with many contributing factors, and of these, chemokines and their receptors have recently been identified as key mediators. Interestingly, HCMV encodes four potential chemokine receptors (US27, US28, UL33 and UL78). Of these virally-encoded chemokine receptors, US28 has been the most widely characterized. US28 binds many of the CC-chemokines, and this class of chemokines contributes to the development of vascular disease. Importantly, HCMV infection mediates in vitro SMC migration, which is dependent upon expression of US28 and CC-chemokine binding. US28 and the US28 functional homologues that are capable of inducing the migration of SMC represent potential targets in the treatment of CMV-accelerated vascular disease such as atherosclerosis, restenosis, and transplant vascular sclerosis.

Animals↗

PubMed2002

Comparison of epidermal keratinocytes and dermal fibroblasts as potential target cells for somatic gene therapy of phenylketonuria.

Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase (PAH) and increased levels of phenylalanine. PAH requires the cofactor BH(4) to function and the rate-limiting step in the synthesis of BH(4) is GTP cyclohydrolase I (GTP-CH). The skin is a potential target tissue for PKU gene therapy. We have previously shown that overexpression of PAH and GTP-CH in primary human keratinocytes leads to high levels of phenylalanine clearance without BH(4) supplementation [Gene Ther. 7 (2000) 1971]. Here, we investigate the capacity of fibroblasts, another cell type from the skin, to metabolize phenylalanine. After retroviral gene transfer of PAH and GTP-CH both normal and PKU patient fibroblasts were able to metabolize phenylalanine, however, in lower amounts compared to genetically modified keratinocytes. Further comparative analyses between keratinocytes and fibroblasts revealed a higher copy number of transgenes in keratinocytes and also a higher metabolic capacity.

Blotting, Southern↗

PubMed1997

Evaluation of cell surface antigens as potential targets for recombinant tumor toxins.

Tumor toxins are recombinant polypeptides derived from the fusion of a single-chain antibody domain or a ligand specific for a cell surface receptor with the enzymatic domain of a bacterial or plant toxin. If these receptors are preferentially expressed on the surface of tumor cells, the tumor toxins can serve as efficient therapeutics. Examples in which growth factors, cytokines, hormones or antibody domains have been fused to toxins have been described and the bacterially expressed molecules have shown anti-tumor effects in vitro and in vivo. Since many tumors are not sensitive to the existing tumor toxins, the search continues for new antigens with tumor specific or tumor enhanced expression. We explored three antigenic structures for their possible use as targets for tumor toxins, i.e. (a) a glycosphingolipid with an Le(a) antigenic structure which is overexpressed in gastrointestinal carcinomas, e.g. colon carcinoma, (b) the epithelial glycoprotein episialin which shows altered expression in various tumor tissues such as breast, ovary and pancreas and (c) the neurotensin receptor which is found on NSLC, pancreatic and colonic cancer cells. For targeting the tumor toxin to the carbohydrate structures, we constructed recombinant single-chain antibody domains (scFv) fused to a truncated form of the exotoxin A from Pseudomonas aeruginosa (ETA). In the case of the neurotensin receptor, the ligand neurotensin was exploited to construct a recombinant fusion protein with exotoxin A as the effector domain. Binding experiments showed that the recombinant proteins are able to specifically recognize their respective target structures. In vitro cytotoxicity assays with neurotensin-ETA showed specific killing activity for receptor positive tumor cell lines. For the scFv-ETA constructs we could not observe in vitro tumor toxicity. We conclude that the antigenic targets for tumor toxins have to be carefully chosen and that specific cell binding activity is not a sufficient criterion for tumor cell killing. The neurotensin-ETA, a new anti-tumor agent, shows that seven transmembrane spanning receptors are potential targets which allow toxin binding and promote cell killing through the appropriate internalization.

ADP Ribose Transferases↗

PubMed2006

Identification of potential target genes for RFX4_v3, a transcription factor critical for brain development.

Regulatory factor X4 variant transcript 3 (Rfx4_v3) gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/-) prevented formation of the subcommissural organ, resulting in congenital hydrocephalus, while interruption of two alleles (homozygous, -/-) caused fatal failure of dorsal midline brain structure formation. To identify potential target genes for RFX4_v3, we used microarray analysis to identify differentially expressed genes in Rfx4_v3-deficient mouse brains at embryonic day 10.5, before gross structural changes were apparent. Of 109 differentially expressed transcripts, 24 were chosen for validation and 22 were confirmed by real-time PCR. Many validated genes encoded critical proteins involved in brain morphogenesis, such as the signaling components in the Wnt, bone morphogenetic protein (BMP) and retinoic acid (RA) pathways. Cx3cl1, a CX3C-type chemokine gene that is highly expressed in brain, was down-regulated in the Rfx4_v3-null mice. Both human and mouse Cx3cl1 proximal promoters contained highly conserved X-boxes, known cis-acting elements for RFX protein binding. Using the Cx3cl1 promoter as an example of a target gene, we demonstrated direct binding of RFX4_v3 to the Cx3cl1 promoter, and trans-acting activity of RFX4_v3 protein to stimulate gene expression. These data suggest that RFX4_v3 may act upstream of critical signaling pathways in the process of brain development.

Animals↗

PubMed2002

Plasmin-induced migration of endothelial cells. A potential target for the anti-angiogenic action of angiostatin.

Angiostatin, a plasminogen fragment containing 3-4 N-terminal kringle domains, is a potent inhibitor of tumor-induced angiogenesis, but its mechanism of action is unclear. Angiostatin is a ligand for integrin alphavbeta(3) but does not induce stress fiber formation upon integrin binding, suggesting that angiostatin is a potential integrin antagonist. Plasmin, the parent molecule of angiostatin and a major extracellular protease, induces platelet aggregation, migration of peripheral blood monocytes, and release of arachidonate and leukotriene from several cell types. In the current study, we found that plasmin specifically bound to alphavbeta(3) through the kringle domains and induced migration of endothelial cells. In contrast, angiostatin did not induce cell migration. Notably, angiostatin, anti-alphavbeta(3) antibodies, RGD-peptide, and a serine protease inhibitor effectively blocked plasmin-induced cell migration. These results suggest that plasmin-induced migration of endothelial cells requires alphavbeta(3) and the catalytic activity of plasmin and that this process is a potential target for the inhibitory activity of angiostatin.

Angiogenesis Inhibitors↗