Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Biologic pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 955 records · Page 53Linked to original sources
PubMed1996

Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase.

To understand the mechanism of Axl signaling, we have initiated studies to delineate downstream components in interleukin-3-dependent 32D cells by using a chimeric receptor containing the recombinant epidermal growth factor (EGF) receptor extracellular and transmembrane domains and the Axl kinase domain (EAK [for EGF receptor-Axl kinase]). We have previously shown that upon exogenous EGF stimulation, 32D-EAK cells are capable of proliferation in the absence of interleukin-3. With this system, we determined that EAK-induced cell survival and mitogenesis are dependent upon the Ras/extracellular-signal-regulated protein kinase (ERK) cascade. Although the phosphatidylinositol-3 kinase pathway is activated upon EAK signaling, it appears to be dispensable for the biological actions of the Axl kinase. Furthermore, we demonstrated that different threshold levels of Ras/ERK activation are needed to induce a block to apoptosis or proliferation in 32D cells. Recently, we have identified an Axl ligand, GAS6. Surprisingly, GAS6-stimulated 32D-Axl cells exhibited no blockage to apoptosis or mitogenic response which is correlated with the absence of Ras/ERK activation. Taken together, these data suggest that different extracellular domains dramatically alter the intracellular response of the Axl kinase. Furthermore, our data suggest that the GAS6-Axl interaction does not induce mitogenesis and that its exact role remains to be determined.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Quantification of 3-nitrotyrosine in biological tissues and fluids: generating valid results by eliminating artifactual formation.

Reactive nitrogen species such as peroxynitrite can nitrate specific amino acids, whether free or protein bound, and 3-nitrotyrosine is believed to be one marker of this reaction. To examine the significance of this pathway in biological systems we have developed an accurate, sensitive, and specific assay for 3-nitrotyrosine based on combined liquid chromatography tandem mass spectrometry. Our approach allowed simultaneous analysis of both tyrosine and 3-nitrotyrosine and employs isotopomer standards (i.e., [15N1, 13C9]-tyrosine and [13C6]-3nitrotyrosine). Calibration curves were linear (r2 = 0.999) across the range 0.5-100 pg/microL (i.e., 2.2-442 fmol/microL), and the detection limit for standard samples was 0.5 pg/microL (2.2 fmol/microL, or 10 fmol on column; S/N = 5) or 1 pg/microL (4.4 fmol/microL) for extracted (biological) samples. As a component of this study we have undertaken an extensive investigation of artifactual formation of 3-nitrotyrosine under conditions that exist during sample extraction and derivatization. Our studies show that under appropriate conditions (low pH, elevated temperatures, and in the presence of a vast excess of the two substrates, tyrosine and the nitrate anion), 3-nitrotyrosine can readily be formed as an artifact.

Animals↗
PubMed2002

Measuring end products of nitric oxide in vivo.

The methods we have presented are suitable for measuring end products of the NO pathway in biological fluids. In particular, the first part of this article demonstrated how standard methods could be improved to increase the sensitivity of NO measurements in biological methods. In addition, we showed two possibilities for the estimation of NO formation in higher species, as NO standard measurements in these species are often not reliable to detect changes of the NO pathway.

Breath Tests↗
PubMed2002

Expression of c-erbB2, p53, Bcl-2, Bax, c-myc and Ki-67 in apocrine metaplasia and apocrine change within sclerosing adenosis of the breast.

Molecular evidence has recently suggested a number of different pathways leading to the development of ductal carcinoma of the breast. The links between atypical ductal hyperplasia and low-grade ductal carcinoma in situ and lobular neoplasia and lobular carcinoma are well known pathologically, but high-grade in situ and invasive carcinomas appear to have a different biological oncogenetic pathway. Morphologically there is a similarity between apocrine cells and some cases of high-grade ductal carcinoma. In order to investigate this possibility a number of different biological markers known to occur in high-grade breast carcinomas were assessed in both apocrine metaplasia (APM) and a putative premalignant lesion called apocrine change within sclerosing adenosis (AA). In 64 cases of APM and 18 cases of AA we examined for expression of c-erbB2, p53, Bcl-2, Bax, c-myc and Ki-67 proteins using immunocytochemistry. c-erbB2 expression was seen in 55.6% of AA cases and in 10.9% of APM cases. p53 expression was detected in 27.8% of AA cases but only 1.6% of APM cases. All cases of AA and APM were negative for the anti-apoptotic protein Bcl-2, but all the APM and 33.3% of AA cases showed cytoplasmic positivity for Bax, a pro-apoptotic protein. All the cases of AA and APM were positive for c-myc oncoprotein, however, the mean percentage of nuclear positivity was 50% in AA and 37% in cases of APM cases. The mean percentage positivity for Ki-67, a proliferation associated antigen, was 3.6% in AA and 1.3% in APM. The results indicate that a subset of breast lesions containing APM epithelium show abnormal oncoprotein and apoptosis-related protein expression and have a higher proliferation rate.

Apocrine Glands↗
PubMed1978

Transport and transportation pathways of hazardous chemicals from solid waste disposal.

To evaluate the impact of hazardous chemicals in solid wastes on man and other organisms, it is necessary to have information about amounts of chemical present, extent of exposure, and chemical toxicity. This paper addresses the question of organism exposure by considering the major physical and biological transport pathways and the physicochemical and biochemical transformations that may occur in sediments, soils, and water. Disposal of solid wastes in both terrestrial and oceanic environments is considered. Atmospheric transport is considered for emissions from incineration of solid wastes and for wind resuspension of particulates from surface waste deposits. Solid wastes deposited in terrestrial environments are subject to leaching by surface and ground waters. Leachates may then be transported to other surface waters and drinking water aquifers through hydrologic transport. Leachates also interact with natural organic matter, clays, and microorganisms in soils and sediments. These interactions may render chemical constituents in leachates more or less mobile, possibly change chemical and physical forms, and alter their biological activity. Oceanic waste disposal practices result in migration through diffusion and ocean currents. Surface area-to-volume ratios play a major role in the initial distributions of chemicals in the aquatic environment. Sediments serve as major sources and sinks of chemical contaminants. Food chain transport in both aquatic and terrestrial environments results in the movement of hazardous chemicals from lower to higher positions in the food web. Bioconcentration is observed in both terrestrial and aquatic food chains with certain elements and synthetic organics. Bioconcentration factors tend to be higher for synthetic organics, and higher in aquatic than in terrestrial systems. Biodilution is not atypical in terrestrial environments. Synergistic and antagonistic actions are common occurrences among chemical contaminants and can be particularly important toxicity considerations in aquatic environments receiving runoff from several terrestrial sources.

Animals↗
PubMed2003

Gaining confidence in high-throughput protein interaction networks.

Although genome-scale technologies have benefited from statistical measures of data quality, extracting biologically relevant pathways from high-throughput proteomics data remains a challenge. Here we develop a quantitative method for evaluating proteomics data. We present a logistic regression approach that uses statistical and topological descriptors to predict the biological relevance of protein-protein interactions obtained from high-throughput screens for yeast. Other sources of information, including mRNA expression, genetic interactions and database annotations, are subsequently used to validate the model predictions without bias or cross-pollution. Novel topological statistics show hierarchical organization of the network of high-confidence interactions: protein complex interactions extend one to two links, and genetic interactions represent an even finer scale of organization. Knowledge of the maximum number of links that indicates a significant correlation between protein pairs (correlation distance) enables the integrated analysis of proteomics data with data from genetics and gene expression. The type of analysis presented will be essential for analyzing the growing amount of genomic and proteomics data in model organisms and humans.

Algorithms↗
PubMed1997

Interleukin-10: biology, role in inflammation and autoimmunity.

LEARNING OBJECTIVES: Reading this article will increase the readers' knowledge of the biology of interleukin-10 (IL-10) an important cytokine. The survival of an organism and its host defense mechanisms require, among other processes, a complex but target-oriented interaction and an interdependence between the immune and inflammatory pathways. The biologic role of interleukin-10 in these processes is presented as well as the possible involvement of IL-10 in the pathogenesis of various diseases. The influence of pharmacologic agents on IL-10 production and the possible pharmacologic role of IL-10 itself are discussed. DATA SOURCES: A detailed literature search was conducted. Studies considered relevant and important involving both humans and animals, in all languages were used. STUDY SELECTION: Material was taken only from peer reviewed journals. RESULTS: IL-10 is produced by CD4+, Tho, Th1, B lymphocytes, mast cells, eosinophils, monocytes, macrophages and keratinocytes. IL-10 has a diverse array of actions, which differ depending on cell type, nature of stimulus and the cellular microenvironment. Interleukin-10 has an important role in the inflammatory and immune systems. In addition, present studies suggest that IL-10 may well play a pivotal role in the pathogenesis of several diseases. It has the potential for therapeutic use. Most of the data on IL-10 have been obtained from in vitro studies or animal experiments. Studies on humans are few, but rapidly increasing. CONCLUSIONS: Interleukin-10 is an important molecule with a central role in maintaining health and in the pathogenesis of disease. Known pharmacologic agents and some under investigation can modify IL-10 production in vivo. Development of agents that can selectively affect a very specific biologic action of IL-10 may provide significant benefit in treating autoimmune and inflammatory diseases.

Animals↗
PubMed2005

Towards quantitative biology: integration of biological information to elucidate disease pathways and to guide drug discovery.

Developing a new drug is a tedious and expensive undertaking. The recently developed high-throughput experimental technologies, summarised by the terms genomics, transcriptomics, proteomics and metabolomics provide for the first time ever the means to comprehensively monitor the molecular level of disease processes. The "-omics" technologies facilitate the systematic characterisation of a drug target's physiology, thereby helping to reduce the typically high attrition rates in discovery projects, and improving the overall efficiency of pharmaceutical research processes. Currently, the bottleneck for taking full advantage of the new experimental technologies are the rapidly growing volumes of automatically produced biological data. A lack of scalable database systems and computational tools for target discovery has been recognised as a major hurdle. In this review, an overview will be given on recent progress in computational biology that has an impact on drug discovery applications. The focus will be on novel in silico methods to reconstruct regulatory networks, signalling cascades, and metabolic pathways, with an emphasis on comparative genomics and microarray-based approaches. Promising methods, such as the mathematical simulation of pathway dynamics are discussed in the context of applications in discovery projects. The review concludes by exemplifying concrete data-driven studies in pharmaceutical research that demonstrate the value of integrated computational systems for drug target identification and validation, screening assay development, as well as drug candidate efficacy and toxicity evaluations.

Animals↗
PubMedDate not supplied

Molecular biology of macrophage activation: a pathway whereby psychosocial factors can potentially affect health.

Over the past decade, numerous links between the mind, the immune system, and the nervous system have been clearly elucidated in regard to the lymphoid elements of the immune system. Recently, attention has been given to the suggestion that such links exist to mononuclear phagocytes. The fundamental biology and physiology of these cells are clearly consonant with such a role. Mononuclear phagocytes bear receptors on their surface for numerous ligands, including neuroendocrine peptides and hormones. Furthermore, macrophages can be modulated by a variety of life-style choices such as smoking, ingestion of alcohol, and dietary lipid. Mononuclear phagocytes are key cells in the development of atherosclerosis and play significant roles in host protection against neoplasia and in the development of certain autoimmune diseases. In regard to atherogenesis, stress can potentiate the effects of a high lipid diet in initiating formation of the macrophage-laden lesions of early atherosclerosis. We have been able to show that oxidized lipids, acting in concert with stress as modeled pharmacologically in terms of catecholamines, induces a macrophage phenotype which would likely promote the development of atherosclerosis but lower host resistance to neoplasia. We are currently testing this hypothesis critically. Over the coming decade, it will be important for numerous investigators to examine the broad hypothesis that mononuclear phagocytes are one key element in the induction of psychosocially produced diseases. A clear understanding of the biology and molecular biology of these cells will provide a potent tool for analyzing these problems.

Arteriosclerosis↗
PubMed2006

Novel platelet and vascular roles for immunoreceptor signaling.

The immunoreceptor signaling pathway has classically been defined by its role in mediating intracellular signals downstream of immune receptors on circulating cells, but recent studies have revealed new and unexpected roles for this pathway in vascular biology. In platelets the immunoreceptor signaling pathway is coupled to 2 structurally distinct platelet collagen receptors, glycoprotein VI and integrin alpha2beta1, and is required for the activation of platelets after exposure to vessel wall collagen during plaque rupture. During vascular development immunoreceptor signaling is required for proper formation of the lymphatic system, a role that has revealed the contribution of hematopoietic endothelial progenitors to that process. In conjunction with the identification of new biological roles in vascular cell types, new molecular mechanisms of activating this signaling pathway have been discovered, including activation by integrins and immunoreceptor tyrosine activation motifs (ITAMs) on receptors that do not function as part of the immune response. Here we discuss some of these recent findings and their implications for vascular biology and the treatment of human vascular diseases.

Animals↗
PubMed2003

Specific signaling pathways triggered by IL-2 in human V gamma 9V delta 2 T cells: an amalgamation of NK and alpha beta T cell signaling.

The global immune response can be simplified into two components: the innate and the acquired systems. The innate immune response comprises primarily macrophages and NK cells, while B and T cells orchestrate the acquired response. Human Vgamma9Vdelta2 T cells represent a minor T cell subpopulation in blood (1-5%) that is activated via the TCR by small nonpeptidic molecules. Their percentage dramatically increases during the early phase of infection by intracellular pathogens, and they display many characteristics of NK cells, which places them at a unique position within the immune system. Our aim was to explore the behavior of these cells when they are activated by a receptor that is common to NK and alphabeta T cells, and to determine signaling pathways and biological responses induced in these cells through this receptor. Thus, we investigated whether Vgamma9Vdelta2 T cells behave as NK cells or as alphabeta T cells. We demonstrated that IL-2 activates not only STAT3, STAT5, the phosphatidylinositol 3-kinase pathway, and extracellular signal-regulated kinase-2 pathway, but also STAT4 as in NK cells, and the p38 mitogen-activated protein kinase pathway as in alphabeta T cells. Moreover, IL-2 induces the production of IFN-gamma in Vgamma9Vdelta2 T cells as observed in NK cells. Due to their double profiles, Vgamma9Vdelta2 T cells are at the interface of the innate and the acquired immune response and may therefore not only modulate the activity of innate cells, but also influence Th1/Th2 differentiation.

Cells, Cultured↗
PubMed2001

Oxidative pathways in cardiovascular disease: roles, mechanisms, and therapeutic implications.

Despite some recent declines, cardiovascular disease (CVD) remains the major cause of death in the United States and worldwide. Most recent advances in the treatment of CVD states have been produced by inhibition of mechanisms involved in disease progress. Many studies conducted in the last decade have illustrated increased biological oxidative pathways during CVD in animals and humans. Thus, increased production of reactive oxygen species may be a unifying mechanism in CVD progression, and antioxidants may have therapeutic value in this setting. In this review we address the following questions: Do oxidative mechanisms play a role in CVD? Where do the oxidants come from? What are the relevant oxidative events? What are the therapeutic implications?

Animals↗
PubMed2006

Autonomic and cardiovascular responses to scent stimulation are altered in cry KO mice.

Previously, we observed that in rats, olfactory stimulation with scent of grapefruit oil (SGFO) elevates the activities of sympathetic nerves. SGFO also suppresses gastric vagal (parasympathetic) nerve activity (GVNA), increases the plasma glycerol concentration, blood pressure (BP) and body temperature, and reduces appetite. In contrast, olfactory stimulation with scent of lavender oil (SLVO) has opposite effects in rats. Here, we show that in mice, olfactory stimulation with SGFO elevated activities of sympathetic nerves innervating the kidney, adrenal gland and brown adipose tissue as well as increasing BP and suppressing GVNA, whereas olfactory stimulation with SLVO decreased these sympathetic nerve activities and BP, and elevated GVNA. Electrolytic lesions of the mouse hypothalamic suprachiasmatic nucleus (SCN) eliminated changes in renal sympathetic nerve activity (RSNA), BP and GVNA induced by either SGFO or SLVO. Furthermore, SGFO-induced elevations in RSNA and BP and the SLVO-induced GVNA increase were not observed in Cryptochrome (Cry)-deficient mice, which harbor mutations in both cry1 and cry2 and lack normal circadian rhythms. These findings suggest that SGFO and SLVO affect autonomic neurotransmission and BP via the SCN in mice. Moreover, the molecular clock mechanism in the SCN, which involves the cry1 and cry2 genes, is partially involved in mediating these autonomic and cardiovascular actions of SGFO and SLVO.

Adipose Tissue, Brown↗
PubMed2005

Chemistry and biology of wortmannin.

Recent synthetic and biological studies of the viridin class of steroidal furans have revealed multiple opportunities for fundamental discoveries as well as advanced drug design. Wortmannin is a potent enzyme inhibitor that binds to the ATP site of important regulatory kinases such as PI-3 kinase and Polo-like kinase. The natural product shares a unique mechanism-based biological activation pathway with other viridins. Furthermore, while there have been several encouraging approaches toward the total synthesis of these compounds, there is still ample room for improvements in synthetic strategies and tactics, and the development of structurally simplified analogs that exert more specific biological effects and are devoid of toxicity issues that have thwarted the clinical development of the parent compounds.

Adenosine Triphosphate↗
PubMed1989

The alternative pathway of T cell activation: biology, pathophysiology, and perspectives for immunopharmacology.

The application of monoclonal antibodies and recombinant mediators to studies of T cell activation has led to a new concept regarding the central mechanisms underlying specific immune responses in man. Stimulation of human T cells to express their functional programs with regard to immunoregulatory activities and effector functions can be mediated through several distinct mechanisms or pathways. We report on the recently discovered T3-Ti antigen receptor independent mode of human T cell activation, namely, the T11-mediated "alternative pathway." Recent evidence supports the notion that this pathway plays an important role in the immune response in man and that failure to activate T cells through T11 is associated with immunodeficiency. The characterization of functional epitopes of the T11 molecule along with functional investigations on patients suffering from etiologically different cases of immunodeficiency provides important perspectives for future pharmacological interventions into the human immune system. It seems likely that immunologic disorders such as autoimmune disease and immunodeficiencies result from overamplification or blockades of the "alternative pathway of T cell activation" and that the T11 epitope represents a potential site for selective inhibition of the "alternative pathway of T cell activation," e.g., by means of synthetic peptide analogues. Conversely, high affinity ligands to the T11 epitope might be suitable for immunostimulation immunodeficiencies that result from circulating blocking factors of the LFA-3/T11 interaction.

Animals↗
PubMed2006

Cholangiocyte biology.

PURPOSE OF REVIEW: Cholangiocytes are increasingly recognized as biologically important epithelia because of the diverse array of cellular processes in which they participate. Collectively, these processes define normal function and, when disturbed, account for abnormalities that cause disease. Advances in animal models and sophisticated technology in imaging and gene silencing have led to substantial progress in defining the roles that cholangiocytes play in signaling, transport of water, ions and solutes, and alterations that result in cholestasis. The pace of advances in technology justifies a yearly summary to identify trends, and inform the readership of the most significant developments in cholangiocyte biology. RECENT FINDINGS: The main areas of recent progress include insights into the molecular mechanisms of bile secretion and the development of new experimental models and technologies. Major advances have also included the identification of novel roles for receptors and better understanding of mechanistic pathways and biologic processes. SUMMARY: Understanding the key mechanistic and biologic processes in cholangiocytes is required to generate hypotheses and therapies relevant to disease. This compendium of current activities in cholangiocyte biology may promote collegial sharing and exchange of novel concepts, ideas, reagents and probes, thereby promoting positive advances in the field.

Animals↗
PubMed2004

A model for the role of the proline-linked pentose-phosphate pathway in phenolic phytochemical bio-synthesis and mechanism of action for human health and environmental applications.

The combination of immunodeficiency, inflammatory process and nutritional status that is characteristic of infective and food-borne illness is more evident in chronic diet- and environment-influenced chronic diseases such as diabetes, obesity, cardiovascular disease, cancer, arthritis and neuro-degeneration diseases. These chronic diseases tend to be oxidation-linked and may manifest in communities around the world, irrespective of income. In addressing the challenges of the above diseases, a significant role for dietary phytochemicals is emerging. Phytochemicals are required from a spectrum of food for at least their antioxidant role, if not for other properties, to protect tissues from activities that manifest themselves into what we call chronic disease. Among the diverse groups of phytochemicals, phenolic antioxidants and antimicrobials from food plants are being targeted for designed dietary intervention to manage major oxidation-linked diseases such as diabetes, cardiovascular diseases, arthritis, cognition diseases and cancer. Foods containing phenolic phytochemicals are also being targeted to manage bacterial infections associated with chronic diseases such as peptic ulcer, urinary tract infections, dental caries and food-borne bacterial infections. Plants produce phenolic metabolites as a part of growth, developmental and stress adaptation response. These stress and developmental responses are being harnessed to design consistent phytochemical profiles for safety and clinical relevancy using novel tissue culture and bioprocessing technologies. The biochemical strategy for harnessing phenolic phytochemicals for human health and wellness is based on the hypothesis that phenolic metabolites in plants are efficiently produced through an alternative mode of metabolism linking proline synthesis with pentose-phosphate pathway. In this model, stress-induced proline biosynthesis is coupled to pentose-phosphate pathway, driving the synthesis of NADPH(2) and sugar phosphates for anabolic pathways, including phenolic and antioxidant response pathways, while simultaneously providing reducing equivalents needed for mitochondrial oxidative phosphorylation in the form of proline as an alternative to NADH from Krebs/TCA cycle. Based on this model, tissue culture techniques and elicitation concepts have been used to stimulate phenolic metabolites with an antioxidant response in germinating seeds, sprouts and clonal lines of dietary plants. From our initial investigations, a model has been proposed in which the proline-linked pentose-phosphate pathway is suggested to be critical for modulating protective antioxidant response pathways in diverse biological systems, including biochemical and cellular pathways important for human health. The proposed proline-linked pentose-phosphate pathway model provides a mechanism for understanding the mode of action of phenolic phytochemicals in modulating antioxidant pathways and provides avenues by which dietary approaches may manage oxidation-linked chronic and infectious diseases. The model also has implications for the development of antimicrobial phenolic phytochemicals against bacterial pathogens in an era of increasing antibiotic resistance. Further, this model also has relevance for improving fungal and yeast-based food bioprocessing for designing functional foods and for environmental bioremediation using plant and microbial systems, as well as for improving agricultural and food systems in harsh environments.

Antioxidants↗