A systems biology view of cancer

In order to understand how a cancer cell is functionally different from a normal cell it is necessary to assess the complex network of pathways involving gene regulation, signaling, and cell metabolism, and the alterations in its dynamics caused by the several different types of mutations leading to malignancy. Since the network is typically complex, with multiple connections between pathways and important feedback loops, it is crucial to represent it in the form of a computational model that can be used for a rigorous analysis. This is the approach of systems biology, made possible by new -omics data generation technologies. The goal of this review is to illustrate this approach and its utility for our understanding of cancer. After a discussion of recent progress using a network-centric approach, three case studies related to diagnostics, therapy, and drug development are presented in detail. They focus on breast cancer, B-cell lymphomas, and colorectal cancer. The discussion is centered on key mathematical and computational tools common to a systems biology approach.     

Oxidative stress and gene regulation

Reactive oxygen species are produced by all aerobic cells and are widely believed to play a pivotal role in aging as well as a number of degenerative diseases. The consequences of the generation of oxidants in cells does not appear to be limited to promotion of deleterious effects. Alterations in oxidative metabolism have long been known to occur during differentiation and development. Experimental perturbations in cellular redox state have been shown to exert a strong impact on these processes. The discovery of specific genes and pathways affected by oxidants led to the hypothesis that reactive oxygen species serve as subcellular messengers in gene regulatory and signal transduction pathways. Additionally, antioxidants can activate numerous genes and pathways. The burgeoning growth in the number of pathways shown to be dependent on oxidation or antioxidation has accelerated during the last decade. In the discussion presented here, we provide a tabular summary of many of the redox effects on gene expression and signaling pathways that are currently known to exist.     

Proteomics and metabolomics in cancer drug development

In this review article, the main recent advancements in the field of proteomics and metabolomics and their application in cancer research are described. In the second part of the review the main metabolic alterations observed in cancer cells are thoroughly dissected, especially those involving anabolic pathways and NADPH-generating pathways, which indirectly affect anabolic reactions, other than the maintenance of the redox poise. Alterations to mitochondrial pathways and thereby deriving oncometabolites are also detailed. The third section of the review is a discussion of how and to what extent (mutations to) tumor suppressors and oncogenes end up influencing cancer cell metabolism and cell fate, either promoting survival and proliferation or autophagy and apoptosis. In the last section of the review, an overview is provided of therapeutic strategies that make use of metabolic reprogramming approaches.     

Quantitative approaches for analysing fluxes through plant metabolic networks using NMR and stable isotope labelling

The quantitative analysis of metabolic networks is a prerequisite for understanding the integration and regulation of plant metabolism and for devising rational approaches for manipulating resource allocation in plants. The analysis of steady state stable isotope labelling experiments using nuclear magnetic resonance (NMR) spectroscopy has developed into a powerful method for determining these fluxes in micro-organisms and its application to heterotrophic plant metabolism is increasing. After an introductory discussion of the well known role of stable isotopes in pathway delineation, the review considers their application to metabolic flux analysis in plants. These applications are divided into two groups – small scale analyses of fluxes through particular pathways and large scale analyses of multiple fluxes through metabolic networks – and the problems caused by the complexity of intermediary metabolism in plants are discussed. It is concluded that metabolic flux analysis provides a powerful method for defining the metabolic phenotype of wild type, mutant and transgenic plants and that its development should be pursued.     

Bioenergetic challenges of microbial iron metabolisms

Before cyanobacteria invented oxygenic photosynthesis and O(2) and H(2)O began to cycle between respiration and photosynthesis, redox cycles between other elements were used to sustain microbial metabolism on a global scale. Today these cycles continue to occur in more specialized niches. In this review we focus on the bioenergetic aspects of one of these cycles - the iron cycle - because iron presents unique and fascinating challenges for cells that use it for energy. Although iron is an important nutrient for nearly all life forms, we restrict our discussion to energy-yielding pathways that use ferrous iron [Fe(II)] as an electron donor or ferric iron [Fe(III)] as an electron acceptor. We briefly review general concepts in bioenergetics, focusing on what is known about the mechanisms of electron transfer in Fe(II)-oxidizing and Fe(III)-reducing bacteria, and highlight aspects of their bioenergetic pathways that are poorly understood.     

A framework integrating plant growth with hormones and nutrients

It is well known that nutrient availability controls plant development. Moreover, plant development is finely tuned by a myriad of hormonal signals. Thus, it is not surprising to see increasing evidence of coordination between nutritional and hormonal signaling. In this opinion article, we discuss how nitrogen signals control the hormonal status of plants and how hormonal signals interplay with nitrogen nutrition. We further expand the discussion to include other nutrient-hormone pairs. We propose that nutrition and growth are linked by a multi-level, feed-forward cycle that regulates plant growth, development and metabolism via dedicated signaling pathways that mediate nutrient and hormonal regulation. We believe this model will provide a useful concept for past and future research in this field.     

Outstanding questions in flower metabolism

The great diversity of flowers, their color, odor, taste, and shape, is mostly a result of the metabolic processes that occur in this reproductive organ when the flower and its tissues develop, grow, and finally die. Some of these metabolites serve to advertise flowers to animal pollinators, other confer protection towards abiotic stresses, and a large proportion of the molecules of the central metabolic pathways have bioenergetic and signaling functions that support growth and the transition to fruits and seeds. Although recent studies have advanced our general understanding of flower metabolism, several questions still await an answer. Here, we have compiled a list of open questions on flower metabolism encompassing molecular aspects, as well as topics of relevance for agriculture and the ecosystem. These questions include the study of flower metabolism through development, the biochemistry of nectar and its relevance to promoting plant‐pollinator interaction, recycling of metabolic resources after flowers whiter and die, as well as the manipulation of flower metabolism by pathogens. We hope with this review to stimulate discussion on the topic of flower metabolism and set a reference point to return to in the future when assessing progress in the field.     

Selective anticancer strategies via intervention of the death pathways relevant to cell transformation

Apoptosis is an important physiological process that promotes tissue homeostasis by eliminating unnecessary or malfunctioning cells. Abnormality in this process contributes to tumorigenesis, as well as the resistance to cancer treatment by radiation and chemotherapy. Restoration of normal apoptosis would not only promote cancer cell death and halt tumor progression, but also increase the response to many current cancer therapies. Although apoptosis induction is an important principle of currently used radiation and chemotherapy treatment, uncovering the mechanisms that govern this process, and which are lost during transformation, represents an important direction for realizing improved therapies for the future. This article first briefly reviews aspects of current discovery strategies for new anticancer therapeutics based on intervening in cell death pathways, and then discusses in more detail several cancer-relevant death pathways, which are disabled during transformation and which can be targeted therapeutically. These include anoikis/cell adhesion; energy metabolism and the unfolded protein response. Finally, we introduce a new concept, which utilizes cancer-specific apoptosis induced by oncolytic viruses. The discussion of these topics involves novel targets, compounds and virotherapy.     

Compartmentation in plant metabolism

Cell fractionation and immunohistochemical studies in the last 40 years have revealed the extensive compartmentation of plant metabolism. In recent years, new protein mass spectrometry and fluorescent-protein tagging technologies have accelerated the flow of information, especially for Arabidopsis thaliana, but the intracellular locations of the majority of proteins in the plant proteome are still not known. Prediction programs that search for targeting information within protein sequences can be applied to whole proteomes, but predictions from different programs often do not agree with each other or, indeed, with experimentally determined results. The compartmentation of most pathways of primary metabolism is generally covered in plant physiology textbooks, so the focus here is mainly on newly discovered metabolic pathways in plants or pathways that have recently been revised. Ultimately, all of the pathways of plant metabolism are interconnected, and a major challenge facing plant biochemists is to understand the regulation and control of metabolic networks. One of the best-characterized networks links sucrose synthesis in the cytosol with photosynthetic CO(2) fixation and starch synthesis in the chloroplasts. One of the key features of this network is how the transport of pathway intermediates and signal metabolites across the chloroplast envelope conveys information between the two compartments, influencing the regulation of several enzymes to co-ordinate fluxes through the different pathways. It is widely accepted that chloroplasts and mitochondria originated from prokaryotic endosymbionts, and that new transporters and regulatory networks evolved to integrate metabolism in these organelles with the rest of the cell. Curiously, the present-day locations of many metabolic pathways within the cell often do not reflect their evolutionary origin, and there is evidence of extensive shuffling of enzymes and whole pathways between compartments during the evolution of plants.     

Tools and techniques to measure mitophagy using fluorescence microscopy

Mitophagy is a specialized form of autophagy that removes damaged mitochondria, thereby maintaining efficient cellular metabolism and reducing cellular stress caused by aberrant oxidative bursts. Deficits in mitophagy underlie several diseases, and a substantial body of research has elucidated key steps in the pathways that lead to and execute autophagic clearance of mitochondria. Many of these studies employ fluorescence microscopy to visualize mitochondrial morphology, mass, and functional state. Studies in this area also examine colocalization/recruitment of accessory factors, components of the autophagic machinery and signaling molecules to mitochondria. In this review, we provide a brief summary of the current understanding about the processes involved in mitophagy followed by a discussion of probes commonly employed and important considerations of the methodologies to study and analyze mitophagy using fluorescence microscopy. Representative data, where appropriate, are provided to highlight the use of key probes to monitor mitophagy. The review will conclude with a consideration of new possibilities for mitophagy research and a discussion of recently developed technologies for this emerging area of cell biology.     

Exploring poly-beta-hydroxy-butyrate metabolism through network-based extreme pathway analysis

The objective of this article is to obtain a more detailed insight into poly-beta-hydroxybutyrate (PHB) metabolism through network-based metabolic pathway analysis. We employ extreme pathways to perform this study, because calculating and interpreting extreme pathways is a promising way for pathway analysis and metabolic engineering. After giving an in silico model of butanoate metabolism of Bacillus thuringiensis 97-27 (btk), extreme pathways were calculated and classified. Furthermore, the type I and II extreme pathways were further classified and analyzed in detail based on their structure and functional capabilities. Besides "historical" biochemical pathways, the results also suggest that there are some novel pathways.     

腺苷-磷酸激活的蛋白激酶在脂类营养代谢中的研究及应用

腺苷-磷酸激活的蛋白激酶（AMP-activated protein kinase,AMPK）是公认的重要能量感受酶。其作用与多个代谢途径有关,尤其在脂类营养代谢过程中发挥着关键的调控作用。AMPK对脂质代谢的调控通过多个信号通路进行,涉及到骨骼肌、肝脏、乳腺等多个组织。对AMPK调控脂类营养代谢机理的研究为2型糖尿病、脂肪肝、肥胖症、癌症等多种疾病的治疗提供了靶点,但AMPK在奶牛乳腺组织的研究较少,其在提高奶牛生产性能方面潜能巨大。     

Prospects of yeast systems biology for human health: integrating lipid, protein and energy metabolism

The yeast Saccharomyces cerevisiae is a widely used model organism for studying cell biology, metabolism, cell cycle and signal transduction. Many regulatory pathways are conserved between this yeast and humans, and it is therefore possible to study pathways that are involved in disease development in a model organism that is easy to manipulate and that allows for detailed molecular studies. Here, we briefly review pathways involved in lipid metabolism and its regulation, the regulatory network of general metabolic regulator Snf1 (and its human homologue AMPK) and the proteostasis network with its link to stress and cell death. All the mentioned pathways can be used as model systems for the study of homologous pathways in human cells and a failure in these pathways is directly linked to several human diseases such as the metabolic syndrome and neurodegeneration. We demonstrate how different yeast pathways are conserved in humans, and we discuss the possibilities of using the systems biology approach to study and compare the pathways of relevance with the objective to generate hypotheses and gain new insights.     

Carbon metabolism in Bradyrhizobium japonicum bacteroids

Abstract Carbon metabolism in Bradyrhizobium japonicum bacteroids is reviewed. Additionally, the bacteroid tricarboxylic acid (TCA) cycle and its regulation under oxygen-limited conditions is considered, with emphasis on possible sites of TCA cycle rate-limiting reactions. Furthermore, we consider other adaptive pathways that may be employed by these organisms while in symbiosis. These pathways include: (1) a poly-β-hydroxy-butyrate shunt, (2) a malate-aspartate shuttle, (3) an α-ketoglutarate-glutamate shunt, (4) a modified dicarboxylic acid cycle, and (5) fermentation pathways leading to lactate, acetaldehyde and ethanol. The effects of oxygen limitation on host carbon metabolism are also considered briefly.