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At least 199 records · Page 11Linked to original sources
PubMed2002

Differential gene expression in a cell culture model of SOD1-related familial motor neurone disease.

Motor neurone disease is caused by mutations in Cu/Zn superoxide dismutase (SOD1) in 15-20% of familial cases, due to a toxic gain of function by the mutant enzyme. However, the underlying mechanism of SOD1-mediated neurodegeneration remains uncertain. By investigating alterations in gene expression in the presence of mutant Cu/Zn SOD, we aimed to identify pathways that contribute to motor neurone injury and cell death. Using a cellular model of familial motor neurone disease, the motor neuronal cell line NSC34 was stably transfected with either normal or mutant (G37R, G93A, I113T) SOD1 cDNAs, and the effect of the presence of these proteins on gene expression was analysed. This model allowed gene expression changes to be studied specifically in cells with a motor neurone phenotype, without interference from genes expressed by glia, astrocytes and other cell types located in the central nervous system. Using a commercially available cDNA membrane array, we investigated the expression levels of 588 genes from key biological pathways. Gene expression was studied in the cells under both basal culture conditions and following oxidative stress induced by serum withdrawal. Twenty-nine differentially expressed genes were identified, 7 of which were specifically downregulated in the presence of the mutant Cu/Zn SOD protein, and whose expression was further studied by real-time PCR. Presence of the mutant Cu/Zn SOD was confirmed to lead to a decrease in expression of KIF3B, a kinesin-like protein, which forms part of the KIF3 molecular motor. c-Fes, thought to be involved in intracellular vesicle transport was also decreased, further implicating the involvement of vesicular trafficking as a mode of action for mutant Cu/Zn SOD. In addition, a decrease was confirmed in ICAM1, a response in part due to the increased expression of SOD1, and decreased Bag1 expression was confirmed in two of the three mutant cell lines, providing further support for the involvement of apoptosis in SOD1-associated motor neurone death.

Animals↗
PubMed1992

Physiological relevance of protein glycosylation.

The glycosylation of proteins is a complex biological pathway which is ordered and non-random. It is also a deterministic pathway dependent upon protein sequence, cellular phenotype, and the physiological environment. Two principal physiological roles have emerged within the past decade for protein-linked glycans: as recognition determinants and as modulators of various protein attributes such as bioactivity, pharmacokinetics, folding, and immunogenicity. All these attributes are crucial to development and application of protein-based pharmaceuticals. However, protein glycosylation represents a difficult structure/function problem since most glycoproteins exhibit microheterogeneity and oligosaccharides frequently contribute to this heterogeneity. Nevertheless, recent data suggest that different members of the heterogeneous ensemble exhibit distinguishable intrinsic properties, suggesting that the microheterogeneity of protein glycosylation represents a sophisticated mechanism of biological control.

Animals↗
PubMed2001

The protein-protein interaction map of Helicobacter pylori.

With the availability of complete DNA sequences for many prokaryotic and eukaryotic genomes, and soon for the human genome itself, it is important to develop reliable proteome-wide approaches for a better understanding of protein function. As elementary constituents of cellular protein complexes and pathways, protein-protein interactions are key determinants of protein function. Here we have built a large-scale protein-protein interaction map of the human gastric pathogen Helicobacter pylori. We have used a high-throughput strategy of the yeast two-hybrid assay to screen 261 H. pylori proteins against a highly complex library of genome-encoded polypeptides. Over 1,200 interactions were identified between H. pylori proteins, connecting 46.6% of the proteome. The determination of a reliability score for every single protein-protein interaction and the identification of the actual interacting domains permitted the assignment of unannotated proteins to biological pathways.

Amino Acid Sequence↗
PubMed2026

Genome-wide discovery reveals 30 loci for choroidal thickness and uncovers potential causal links with angle-closure glaucoma.

The choroid is critical for maintaining vision and implicated in several ocular diseases, being the sole source of nutrients and waste removal for the outer retina. Genetic discovery can help elucidate the pathways through which choroidal features influence disease risk. Our meta-analysis of genome-wide association studies (n= 78,682 participants) identified 30 genomic regions, including 20 novel loci, associated with choroidal thickness. Findings suggest inflammatory and vascular processes drive choroidal thickness, with overlapping mechanisms shared with refractive error. Genome-wide independently significant SNPs accounted for 18.7% of the genetic variance in choroidal thickness. Mendelian randomisation analyses showed a causal effect of age-related macular degeneration on choroidal thickness, and suggest a bidirectional causal effect between choroidal thickness and primary angle-closure glaucoma. These findings provide insight into the shared genetic architecture and biological pathways linking choroidal thickness and related diseases.

Canadian Longitudinal Study on Aging↗
PubMed2003

Systematic discovery of multicomponent therapeutics.

Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of approximately 120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans, yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-alpha in human primary peripheral blood mononu-clear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.

Animals↗
PubMed1999

CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.

Amino Acid Sequence↗
PubMed2000

Roles of BRCA1 and its interacting proteins.

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. BRCA1 contains several functional domains that interact directly or indirectly with a variety of molecules, including tumor suppressors (p53, RB, BRCA2 and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell-cycle regulators (cyclins and cyclin-dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtIP) and others. Mounting evidence indicates that these physical associations are not artifacts; rather, BRCA1 is likely to serve as an important central component in multiple biological pathways that regulate cell-cycle progression, centrosome duplication, DNA damage repair, cell growth and apoptosis, and transcriptional activation and repression. This review examines our understanding of the significance of the interactions between BRCA1 and other proteins, through which BRCA1 maintains genome integrity and represses tumor formation. Published 2000 John Wiley & Sons, Inc.

BRCA1 Protein↗
PubMed2002

Energy imbalance and prostate cancer.

In this review, the emerging evidence that excessive energy intake relative to energy expenditure increases the risk of prostate cancer is discussed. The adverse effects of energy imbalance can be inferred from an experimental study demonstrating reduced prostate tumor growth, lower circulating concentrations of insulin-like growth factor-I and decreased expression of vascular endothelial growth factor with energy restriction in transplantable tumor models. The effects of energy restriction on factors mediating greater proliferation relative to apoptosis and angiogenesis suggest that energy imbalance may act late in the carcinogenic pathway. Energy intake also has been evaluated in relation to prostate cancer risk in 23 analytic epidemiologic studies. Among studies reporting effect estimates, 8 of 14 case-control studies support a direct association [top versus bottom quantile, OR(summary) = 1.3; 95% confidence interval (CI), 1.1-1.4], but none of four cohort studies do (RR(summary) = 1.0; 95% CI, 0.8-1.2). The four case-control studies that evaluated advanced disease suggest a higher risk with higher energy intake (OR(summary) = 1.6; 95% CI, 1.2-2.0). However, none of these studies considered the balance of energy intake with body size and physical activity, the major determinants of variability in energy demand. Numerous research questions remain to be addressed, including, Which biological pathways are adversely affected by energy imbalance? Does energy imbalance act early or late in prostate carcinogenesis? What is the optimal energy balance for minimizing risk of clinically important prostate cancer? Evidence is beginning to show that energy intake in excess of expenditure may affect prostate carcinogenesis and, in particular, risk of advanced disease.

Animals↗
PubMed2002

Targeted therapy in non-small-cell lung cancer.

Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes, topoisomerase inhibitors, vinorelbine (Navelbine), and gemcitabine (Gemzar), platinum-based combination therapy has appeared to reach a threshold of therapeutic effectiveness. A paradigm shift in approach to non-small-cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development. Such new agents include antibody epithelial growth factor receptor (EGFR) inhibitors (eg, the monoclonal antibodies trastuzumab [Herceptin] and cetuximab [IMC-C225, Erbitux]) and EGFR tyrosine kinase inhibitors (eg, ZD1839 [Iressa] and OSI-774), angiogenesis inhibitors (eg, matrix metalloproteinase inhibitors), vascular endothelial growth factor (VEGF) inhibitors (eg, monoclonal antibody to VEGF ligand and small-molecule tyrosine kinase), and signal transduction inhibitors (eg, ISIS-3521, an antisense oligonucleotide to protein kinase C-alpha). A number of these agents have entered advanced-phase clinical investigation. It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment, including maintenance therapy. It is even possible that these new biologic therapies will be used together as rational combinations (based on pathologic diagnosis) for advanced non-small-cell lung cancer.

Angiogenesis Inhibitors↗
PubMed2003

PreBIND and Textomy--mining the biomedical literature for protein-protein interactions using a support vector machine.

BACKGROUND: The majority of experimentally verified molecular interaction and biological pathway data are present in the unstructured text of biomedical journal articles where they are inaccessible to computational methods. The Biomolecular interaction network database (BIND) seeks to capture these data in a machine-readable format. We hypothesized that the formidable task-size of backfilling the database could be reduced by using Support Vector Machine technology to first locate interaction information in the literature. We present an information extraction system that was designed to locate protein-protein interaction data in the literature and present these data to curators and the public for review and entry into BIND. RESULTS: Cross-validation estimated the support vector machine's test-set precision, accuracy and recall for classifying abstracts describing interaction information was 92%, 90% and 92% respectively. We estimated that the system would be able to recall up to 60% of all non-high throughput interactions present in another yeast-protein interaction database. Finally, this system was applied to a real-world curation problem and its use was found to reduce the task duration by 70% thus saving 176 days. CONCLUSIONS: Machine learning methods are useful as tools to direct interaction and pathway database back-filling; however, this potential can only be realized if these techniques are coupled with human review and entry into a factual database such as BIND. The PreBIND system described here is available to the public at http://bind.ca. Current capabilities allow searching for human, mouse and yeast protein-interaction information.

Algorithms↗
PubMed2001

New technologies for chemical genetics.

Chemical genetics, in which small molecules are used in lieu of mutations to study biological processes, requires large and diverse chemical libraries to specifically perturb different biological pathways. Here we describe a suite of technologies that enable chemical libraries prepared by split-pool solid phase synthesis to be screened in a diverse range of chemical genetic assays. Compounds are synthesized on 500 micron high-capacity polystyrene beads, and arrayed into individual wells of 384-well plates using a hand-held bead arrayer. Compounds are cleaved from synthesis beads using a chemically-resistant ceramic dispensing system, producing individual stock solutions of single compounds. Nanoliter volumes of these solutions are then transferred into assay plates using an array of stainless steel pins mounted on a robotic arm. We have designed reusable 1536- and 6144-well assay plates made of silicone rubber that can be cast in the laboratory and filled by hand. This integrated technology platform enables hundreds of biological assays to be performed from the product of a single synthesis bead, enabling the results of different chemical genetic experiments to be directly compared.

Cell Extracts↗
PubMed1996

Endothelial cell function: biologic and physiologic functions in health and disease.

Endothelial cells (EC) form a monolayer with a strategic role in the control of many physiologic and biologic pathways. Although the endothelium initially was thought to be an inert and passive barrier of the vasculature, the diverse functions of EC have been better defined in the past decade. EC play an important role in the control of coagulation, vasomotor tone, growth of vascular smooth muscle cells, white cell trafficking, ischemic and reperfusion injuries, and the development of arteriosclerosis. Owing to their location in the arterial tree, EC also are considered a potential target for gene therapy. The introduction of foreign DNA into EC by in vitro transfection with viral vectors has produced encouraging results when using genes that encode for proteins such as insulin and urokinase. The seeding of EC onto vascular grafts appears to convey the thromboresistant properties of saphenous vein to an artificial surface. This review focuses on the important biologic and physiologic functions of EC in health and disease.

Animals↗
PubMed2026

KLHL17 as a Prognostic Indicator and Therapeutic Target in Cervical Cancer: A Comprehensive Analysis.

INTRODUCTION: This study aims to clarify the role of kelch like family member 17 (KLHL17) in cervical cancer (CESC) is unclear. OBJECTIVE: To clarify this uncertainty, our research employed bioinformatics analysis coupled with experimental corroboration. METHODS: We utilized the Cancer Genome Atlas (TCGA) database to assess the expression of KLHL17 in various cancers, specifically CESC, and to explore its association with clinical characteristics, diagnostic utility, and prognostic significance in CESC. The current investigation delved into the potential regulatory pathways related to KLHL17, examining its connection with the infiltration of immune cells, the expression of immune checkpoint genes, the status of microsatellite instability (MSI), and the efficacy of diverse therapeutic agents in CESC. The research analyzed KLHL17 expression patterns using single-cell sequencing data from CESC samples and investigated the genetic variations of KLHL17 within this context. KLHL17 expression was validated using GSE145372. The presence and levels of KLHL17 in different cell lines were validated through quantitative real-time PCR (qRT-PCR) assays. RESULTS: KLHL17 exhibited irregular expression profiles across various cancer types, including CESC. Furthermore, increased KLHL17 levels in CESC patients were significantly associated with a lower progression-free survival (PFS) rate (hazard ratio: 1.62; 95% confidence interval: 1.01-2.60, p = 0.044). Moreover, KLHL17 expression emerged as a distinct prognostic indicator for CESC patients (p = 0.031). It has been associated with various biological pathways, such as cytokine-cytokine receptor interaction, primary immunodeficiency, cell adhesion molecules (CAMs), chemokine signaling pathway, steroid hormone biosynthesis, and others. The expression levels of KLHL17 were found to correlate with the presence of immune cells, the expression of immune checkpoint genes, and the status of MSI within CESC. Furthermore, KLHL17 expression exhibited a significant and inverse correlation with XMD15-27, rTRAIL, Paclitaxel, tp4ek, and tp4ek-k6. Furthermore, KLHL17 was found to be significantly positively regulated in CESC cell lines. DISCUSSION: The findings suggest that KLHL17 is involved in the progression of CESC and may serve as a potential prognostic marker and therapeutic target. KLHL17's association with immune cell infiltration and immune checkpoint genes indicates a role in immuneevasion. Future research should focus on validating these findings through independent datasets and experimental studies to elucidate the molecular mechanisms underlying KLHL17's role in CESC progression and immune regulation. CONCLUSION: KLHL17 is a promising prognostic marker and potential therapeutic target in CESC.

Humans↗
PubMed1976

[Genetics of psychoses under a new aspect].

To analyze the biological pathways of the genetical activity in psychoses is growing more and more to an important goal. The research in this field should be started on the assumption of a multifactorial hereditary system controlling the somatic base of mental illness in a specific way as can be argued from twin and family studies. Screening the present data, there is strong evidence that the metabolism of affective psychoses is characterized by quantitative deviations only concerning the 5-hydroxytryptamine and norepinephrine turnover particularly. The biochemical findings in schizophrenic psychoses are suspicious for qualitative abnormities too. There are some indications of toxic products in the catecholamine metabolism and of antibodies against brain substances. All these disturbances could be caused by structural gene mutants or by mutations of the genetical regulatory system changing the sensitivity for the environmental stimulus. The simultaneous investigation of simple inherited serum groups is described as a useful tool for biological marking of the responsible genotypes.

Environmental Exposure↗
PubMed2025

ProteoformDB: A Built-In Application to Generate Proteoform Database.

Proteins play essential functions through their complex regulations on cell-type-specific expression, localization, and molecular complexes. Protein complexity is further enhanced by proteoforms, which are the diverse molecular forms that each gene can produce through genomic alterations, transcriptional variations, translational regulations, and protein modifications. Profiling of proteoforms is a promising method for gaining a deeper understanding of the role of proteins in biological pathways and disease mechanisms. Here, we developed ProteoformDB, an application tool for generating proteoform databases, and we cataloged a total of over one million unique single-site human proteoforms. We showed that ProteoformDB can serve as a valuable resource to document the experimentally identified proteoforms in a database, supporting protein characterization in quantitative proteomics for both total protein abundances and modified protein forms.

Humans↗
PubMed2001

Recent developments in computational proteomics.

The mapping of the human genome was completed earlier this year and efforts are underway to understand the role of gene products (i.e. proteins) in biological pathways and human disease and to exploit their functional roles to derive protein therapeutics and protein-based drugs. A key component to the next revolution in the 'post-genomic' era will be the increasingly widespread use of protein structure in rational experimental design. Improvements in quality, availability and utility of large-scale 3D and 4D protein structural information are enabling a revolution in rational design, having particular impact on drug discovery and optimization. New computational methodologies now yield modeled structures that are, in many cases, quantitatively comparable with crystal structures, at a fraction of the cost.

Animals↗
PubMed2000

Strength of evidence linking oral conditions and systemic disease.

Associations between dental diseases and systemic outcomes are potentially important because of the high occurrence of dental diseases. If this extremely common source of chronic infection (dental disease) leads to an increased morbidity and mortality rate, the public health impact of oral disease on millions of Americans would be substantial. Recent studies demonstrate an association between dental and systemic diseases, including systemic infections, cardiovascular disease, pregnancy outcomes, respiratory diseases, and increased all-cause mortality rate. Because there are several common risk factors for oral and systemic diseases, and limitations in published studies, a careful interpretation is needed. Confounding (shared risk factors for both systemic and dental disease) may explain part of the reported associations. It is also plausible that there may be a causal link. It is likely that if there is a causal link, several pathways and mediators coexist, linking oral and systemic disease. Bacteremia, bacterial endotoxins, cytokines, and other inflammatory mediators could conceivably be playing a direct or indirect role. Missing teeth are a surrogate marker for previous dental infection, and may also lead to altered dietary intake. Hence, diet may be an additional mediator for several of these outcomes. We caution clinicians not to recommend extracting infected teeth, based on the periodontal-systemic disease associations, if the teeth do not warrant extraction otherwise, because loss of teeth and edentulousness are associated with increased risk of systemic diseases. When assessed against causal-defined criteria, the evidence suggests possible causal associations between chronic periodontal disease and tooth loss with cardiovascular disease, bacterial endocarditis, pregnancy outcomes, and all-cause overall mortality. Further studies are needed to show consistency, to corroborate that the associations are independent of common risk factors for both systemic and dental disease, including healthy lifestyle factors, and to evaluate different biological pathways.

Bacterial Infections↗
PubMed2003

Automated detection of informative combined effects in genetic association studies of complex traits.

There is a growing body of evidence suggesting that the relationships between gene variability and common disease are more complex than initially thought and require the exploration of the whole polymorphism of candidate genes as well as several genes belonging to biological pathways. When the number of polymorphisms is relatively large and the structure of the relationships among them complex, the use of data mining tools to extract the relevant information is a necessity. Here, we propose an automated method for the detection of informative combined effects (DICE) among several polymorphisms (and nongenetic covariates) within the framework of association studies. The algorithm combines the advantages of the regressive approaches with those of data exploration tools. Importantly, DICE considers the problem of interaction between polymorphisms as an effect of interest and not as a nuisance effect. We illustrate the method with three applications on the relationship between (1). the P-selectin gene and myocardial infarction, (2). the cholesteryl ester transfer protein gene and plasma high-density-lipoprotein cholesterol concentration, and (3). genes of the renin-angiotensin-aldosterone system and myocardial infarction. The applications demonstrated that the method was able to recover results already found using other approaches, but in addition detected biologically sensible effects not previously described.

Algorithms↗