Complexity Of Metabolic Pathways Research Articles

Selected Golgi-Localized Proteins and Carcinogenesis: What Do We Know?

The role of the Golgi apparatus in carcinogenesis still remains unclear. A number of structural and functional cis-, medial-, and trans-Golgi proteins as well as a complexity of metabolic pathways which they mediate may indicate a central role of the Golgi apparatus in the development and progression of cancer. Pleiotropy of cellular function of the Golgi apparatus makes it a "metabolic heart" or a relay station of a cell, which combines multiple signaling pathways involved in carcinogenesis. Therefore, any damage to or structural abnormality of the Golgi apparatus, causing its fragmentation and/or biochemical dysregulation, results in an up- or downregulation of signaling pathways and may in turn promote tumor progression, as well as local nodal and distant metastases. Three alternative or parallel models of spatial and functional Golgi organization within tumor cells were proposed: (1) compacted Golgi structure, (2) normal Golgi structure with its increased activity, and (3) the Golgi fragmentation with ministacks formation. Regardless of the assumed model, the increased activity of oncogenesis initiators and promoters with inhibition of suppressor proteins results in an increased cell motility and migration, increased angiogenesis, significantly activated trafficking kinetics, proliferation, EMT induction, decreased susceptibility to apoptosis-inducing factors, and modulating immune response to tumor cell antigens. Eventually, this will lead to the increased metastatic potential of cancer cells and an increased risk of lymph node and distant metastases. This chapter provided an overview of the current state of knowledge of selected Golgi proteins, their role in cytophysiology as well as potential involvement in tumorigenesis.

Application of Q-TOF and IT-TOF Mass Spectrometry Technology in Identifying the Natural Products and their Biological Metabolites

Most natural products undergo extensive metabolism in the biological conditions.Due to the diversity and complexity of metabolic pathways for natural products,the identification of metabolites is still a great technical challenge.The purpose of this review is to provide an overview on the state of art and applicability of mass spectrometry for the identification and structural elucidation of the trace level metabolites in the complex matrices.After comparing the pros and cons in compound identification with some mass spectrometry techniques widely used nowadays,as well as the recent developments in this field at home and abroad,the potential and future trends of applying Q-TOF and IT-TOF techniques combined with related strategies for identifying the metabolites of natural products are highlighted.

Gene-Environment Interactions in the Development of Complex Disease Phenotypes

The lack of knowledge about the earliest events in disease development is due to the multi-factorial nature of disease risk. This information gap is the consequence of the lack of appreciation for the fact that most diseases arise from the complex interactions between genes and the environment as a function of the age or stage of development of the individual. Whether an environmental exposure causes illness or not is dependent on the efficiency of the so-called "environmental response machinery" (i.e., the complex of metabolic pathways that can modulate response to environmental perturbations) that one has inherited. Thus, elucidating the causes of most chronic diseases will require an understanding of both the genetic and environmental contribution to their etiology. Unfortunately, the exploration of the relationship between genes and the environment has been hampered in the past by the limited knowledge of the human genome, and by the inclination of scientists to study disease development using experimental models that consider exposure to a single environmental agent. Rarely in the past were interactions between multiple genes or between genes and environmental agents considered in studies of human disease etiology. The most critical issue is how to relate exposure-disease association studies to pathways and mechanisms. To understand how genes and environmental factors interact to perturb biological pathways to cause injury or disease, scientists will need tools with the capacity to monitor the global expression of thousands of genes, proteins and metabolites simultaneously. The generation of such data in multiple species can be used to identify conserved and functionally significant genes and pathways involved in gene-environment interactions. Ultimately, it is this knowledge that will be used to guide agencies such as the U.S. Department of Health and Human Services in decisions regarding biomedical research funding and policy.

INVIVOMEASUREMENT OFFLUXES THROUGHMETABOLICPATHWAYS: The Missing Link in Functional Genomics and Pharmaceutical Research

In the postgenomic era of biology, much attention has been given to functional genomics, or the relation between genes and higher levels of organization in the cell. The latter are typically represented as mRNA, protein, or organic metabolite complements. The theme of this review is that the operational unit of function in complex biological systems is more properly seen as the fully assembled metabolic pathway in the whole organism. Due to the connectivity, interactions, and complexity of metabolic pathways, the measurement of components is an inadequate method for predicting phenotype. Measurement of the outputs of pathways (molecular fluxes) involves different tools than static measures of components, however. Here, we review recently developed stable isotope-mass spectrometric tools for measuring fluxes through metabolic pathways in vivo, focusing on the response to dietary macronutrients (carbohydrates and fats). Methods discussed include measurement of lipid dynamics, DNA replication, hepatic assembly of lipoproteins, and long-lived protein synthesis. Measuring fluxes through multiple pathways concurrently allows regulatory themes to emerge. Use of 2H2O-labeling is emerging as a particularly powerful approach for multiple concurrent biosynthetic flux measurements. Several examples demonstrate that pathway flux results are often unexpected and not predicted by classic biochemistry or the expression of genes and proteins.