Vitamin A metabolism and adipose tissue biology

In recent years, the importance of vitamin A in adipose tissue biology, obesity and type II diabetes has become apparent. This review focuses on recent developments within the area of vitamin A and adipose tissue biology. Adipose tissue has an active vitamin A metabolism as it not only stores vitamin A but retinol is also converted to its active metabolite retinoic acid. Several mouse models point to a relationship between vitamin A metabolism and the development of adiposity. Similarly, in vitro studies provide new molecular mechanisms for the function of different forms of vitamin A and retinol- or retinoic acid-binding proteins in adipose tissue.     

Advances in methods to evaluate gastrointestinal transport function

Malnutrition is a serious problem, and malabsorption of nutrients is believed to be partially responsible for its prevalence. A wide variety of innovative methods have been developed to study gastrointestinal transport function. Some of the first research into gastrointestinal function was conducted in the 1700's with animal and human models. Methodological advancements continue to allow scientists to innovatively assess gastrointestinal function in animal models, cellular preparations and clinical settings. For this update, the methods are divided into in vivo, ex vivo, isolated cells and membranes, and molecular biology approaches. The in vivo methods discussed include animal and human models to measure nutrient disappearance, catheterized animal models, models with isolated intestinal segments, and a new procedure for sampling luminal fluid from patients. The ex vivo approaches discussed obtain measurements with intact tissue, such as the everted sleeves method and Ussing chambers. The utility of novel cellular preparations, membrane fractionation procedures and various molecular biology techniques is included. Various aspects of these methods are evaluated to provide a detailed overview of recent methodological developments.     

Diffuse large cell lymphoma: new molecular approaches

The term lymphoma comprises a group of neoplasias that develop within the lymphatic system and represent one of the most frequent types of cancer worldwide. During the last decade, significant advances on the molecular biology of lymphoma have been achieved, which have been important not only to understand the etiology of this disease, but also in the development of fast and accurate diagnostic and prognostic methods, which in turn, will allow us to develop appropriate treatments for individual patients. Current systems for the classification of lymphomas have also been influenced by new molecular tools, recently developed. The main goal of this article is to present a general view on the latest advances in the molecular biology of lymphoma. In order to do so, we have focused on Diffuse Large B-Cell Lymphoma (DLBCL), one of the most common, and most studied, types of lymphoma. It is noteworthly that most of what we know about DLBCL arises from studies on lymph nodes, and this is reflected in the present review; however, here we have also included recent information regarding cellular and molecular findings in bone marrow from DLBCL patients. These latter observations may be relevant in opening new lines of research in the near future.     

Guar gum and similar soluble fibers in the regulation of cholesterol metabolism: Current understandings and future research priorities

The hypocholesterolemic effects associated with soluble fiber consumption are clear from animal model and human clinical investigations. Moreover, the modulation of whole-body cholesterol metabolism in response to dietary fiber consumption, including intestinal cholesterol absorption and fecal sterol and bile acid loss, has been the subject of many published reports. However, our understanding of how dietary fibers regulate molecular events at the gene/protein level and alter cellular cholesterol metabolism is limited. The modern emphasis on molecular nutrition and rapid progress in ‘high-dimensional’ biological techniques will permit further explorations of the role of genetic polymorphisms in determining the variable interindividual responses to soluble fibers. Furthermore, with traditional molecular biology tools and the application of ‘omic’ technology, specific insight into how fibers modulate the expression of genes and proteins that regulate intestinal cholesterol absorption and alter hepatic sterol balance will be gained. Detailed knowledge of the molecular mechanisms by which soluble fibers reduce plasma cholesterol concentrations is paramount to developing novel fiber-based “cocktails” that target specific metabolic pathways to gain maximal cholesterol reductions.     

Arenavirus genetic diversity and its biological implications

The Arenaviridae family currently comprises 22 viral species, each of them associated with a rodent species. This viral family is important both as tractable experimental model systems to study acute and persistent infections and as clinically important human pathogens. Arenaviruses are enveloped viruses with a bi-segmented negative-strand RNA genome. The interaction with the cellular receptor and subsequent entry into the host cell differs between Old World and New World arenavirus that use α-dystoglycan or human transferring receptor 1, respectively, as main receptors. The recent development of reverse genetic systems for several arenaviruses has facilitated progress in understanding the molecular biology and cell biology of this viral family, as well as opening new approaches for the development of novel strategies to combat human pathogenic arenaviruses. On the other hand, increased availability of genetic data has allowed more detailed studies on the phylogeny and evolution of arenaviruses. As with other riboviruses, arenaviruses exist as viral quasispecies, which allow virus adaptation to rapidly changing environments. The large number of different arenavirus host reservoirs and great genetic diversity among virus species provide the bases for the emergence of new arenaviruses potentially pathogenic for humans.     

1987 McCollum award lecture. Kinetics of human amino acid metabolism: nutritional implications and some lessons

Clinical nutrition is an integrative science with the ultimate purpose of defining in quantitative terms the characteristics of an optimum nutritional intake in relation to a defined level of nutritional health. Thus, to achieve major progress in our field of clinical nutrition, data from the molecular, subcellular, cellular, and organ levels need to be exploited and considered in reference to the whole organism; this requires that we identify important unanswered questions for this latter and more complex, hierarchical level of biological organization and then pursue the answers with the aid of techniques and approaches used in and concepts emerging from all areas of modern biology. In relation to this, the present overview of some of the studies that my colleagues, my students, and I have conducted was meant to emphasize that there is considerable merit in attempting to explore the integrative aspects of the physiology and biochemistry of human nutrient metabolism, specifically of amino acids, with the aid of stable-isotope probes. Recognition of the importance of the phosphorylation and dephosphorylation of cellular proteins as a major regulatory process and of the regulation of leucine oxidation through changes in the activity of the branched-chain 2-Oxo acid dehydrogenase complex via a reversible phosphorylation catalyzed by a specific branched-chain dehydrogenase kinase and phosphatase is indeed exciting new knowledge. Following from this, Espinal et al state: "The activity of the complex determines the rate of degradation and the dietary requirement for branched-chain amino acids." However, the physiological situation cannot be appreciated simply in these terms because we showed that the rate of oxidation of leucine depends upon the tissue availability of the amino acid. Furthermore, our studies revealed that the regulation of leucine oxidation in the intact human appears to be achieved through biochemical mechanisms that are linked to the host's nutritional requirements. These observations and interpretations would not have emerged by considering only the enzymology of branched-chain amino acid metabolism; this underscores the value of exploring, through use of safe noninvasive tracer techniques, the communication of amino acid metabolism among different systems and how these systems might interplay to influence the nutritional needs of the individual. This recalls Fishman's advice: "Physiology has a special role to play here, for after probing the submicroscopic, life is left behind. It is physiology's responsibility to put together the lifeless pieces of the molecular biologist into living systems."(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification

Among the proteins known or suspected to be involved in bone and vascular biology are several members of the vitamin K-dependent or Gla protein family. This review focuses on the role of two of these: osteocalcin and matrix Gla protein. Osteocalcin metabolism has been implicated in the pathogenesis of osteoporosis through an unknown mechanism that may be linked to suboptimal vitamin K status resulting in its undercarboxylation and presumed dysfunction. Recent studies that have investigated this hypothesis are discussed, as are recent promising clinical studies of vitamin K supplementation in osteoporosis. A recently delineated function of matrix Gla protein is as a powerful inhibitor of calcification of arteries and cartilage. In the period covered by this review there have been several landmark studies using cell systems, whole animals and genetic techniques that have consolidated and extended our knowledge of the role of matrix Gla protein in the prevention of ectopic calcification.     

Applications of new technology in molecular epidemiology and their relevance to occupational medicine

Technological advances in molecular biology over the past 2 decades have offered more complex techniques that can be used to study the role of specific exogenous agents and host variables that cause ill health. Increasingly, studies in human populations use this new technology, combined with epidemiological methods, to shed light on the understanding of the biological processes associated with development of disease. This approach has many potential applications in occupational and environmental medicine (OEM), and some aspects of the work in this growing field are reviewed. An understanding of biochemistry and genetics at the molecular level, specific knowledge on metabolism and mechanisms of action, and epidemiology have become increasingly important for the OEM practitioner. This is necessary to consider the major question of validation and relevance of these molecular biomarkers. As end users, OEM practitioners should also consider the impact of these advances on their practices. For example, the availability of genetic tests to identify susceptible workers raises issues of ethics, individual privacy, right to work, and the relevance of such tests. Several studies have presented data on the association of environmental measurements and various biomarkers for internal and biologically effective dose, genetic polymorphisms, and early response markers. Given the limitations of individual molecular biomarkers in assessing risk to health, and the multifactorial nature of environmental disease, it is likely that such an approach will increase our understanding of the complex issue of mechanisms of disease and further refine the process of risk assessment.

 

     

代谢组学技术在电离辐射防护研究中的应用

代谢组学作为系统生物学研究的重要方法,不仅在生命科学研究中发挥重要作用,在辐射防护研究领域的应用也日益广泛。本文从啮齿类动物、灵长类动物模型的代谢组学和代谢组学方法的临床研究等方面,综述代谢组学方法和技术在辐射损伤中的诊断和机制研究,以及在辐射防护药物研究中的价值。     

The butyrate story: old wine in new bottles?

PURPOSE OF REVIEW: Short-chain fatty acids are important end products of bacterial carbohydrate fermentation in the colon. In particular, n-butyrate is thought to play a regulatory role in the maintenance of a physiological environment. Disturbances in the interplay between the microflora and the lining epithelium may lead to mucosal inflammation and promote carcinogenesis. The purpose of this article is to review the literature between March 2003 and February 2004 and to determine if recent studies have improved the understanding of butyrate effects in health and disease. RECENT FINDINGS: Preclinical studies (cell culture experiments, animal studies) using modern molecular biological tools (including cDNA arrays) have provided new insights into the action of butyrate on colonic epithelial, vascular endothelial and extracolonic cell types. The new information adds pieces of evidence to the assumption that butyrate may ameliorate colonic inflammation and may be chemopreventive in carcinogenesis. In contrast, new data from clinical studies have been limited in the review period. SUMMARY: In the era of molecular biology our understanding of subcellular processes that ultimately lead to inflammatory bowel disease or colorectal cancer has widened considerably. The new powerful technology of genomics and proteomics, however, raises new questions without easy answers. With this new information in mind, we will have to go back to human intervention trials to test the hypotheses generated in vitro. The preclinical data from the review period justify the need for carefully designed clinical trials to test the benefits derived from butyrate production.     

Genomics and proteomics: importance for the future of nutrition research

A huge number of genes within the human genome code for proteins that mediate and/or control nutritional processes. Although a large body of information on the number of genes, on chromosomal localisation, gene structure and function has been gathered, we are far from understanding the orchestrated way of how they make metabolism. Nevertheless, based on the genetic information emerging on a daily basis, we are offered fantastic new tools that allow us new insights into the molecular basis of human metabolism under normal as well as pathophysiological conditions. Recent technological advancements have made it possible to analyse simultaneously large sets of mRNA and/or proteins expressed in a biological sample or to define genetic heterogeneity that may be important for the individual response of an organism to changes in its nutritional environment. Applications of the new techniques of genome and proteome analysis are central for the development of nutritional sciences in the next decade and its integration into the rapidly developing era of functional genomics.     

Molecular biology in clinical cancer research: the example of digestive cancers

Cancer is a DNA disease characterized by uncontrolled cell proliferation due to the accumulation of genetic alterations. Recent progress in molecular biology allowed the identification of markers potentially usefull for patients management through the identification of these genetic alterations and a best understanding of chemotherapy molecular targets. Several examples in digestive oncology underline the relevance of molecular biology in clinical research. If almost all colorectal cancers (CRC) correspond to the same histopathological type (adenocarcinoma), molecular biology allowed the identification of two different molecular mechanisms of colorectal carcinogenesis: chromosomal instability characterized by recurrent allelic losses on chromosomes 17, 5, 18, 8 and 22 that contribute to the inactivation of tumor suppressor genes, and genetic instability characterized by the instability of microsatellite loci due to an alteration of DNA mismatch repair leading to the accumulation of mutations in genes involved in the control of cell cycle and apoptosis. These data are potentially interesting for the management of CRC patients. Indeed, microsatellite instability seems not only to be a good prognostic factor but also a molecular factor that can predict response to adjuvant 5-fluorouracil based chemotherapy. Therapeutic clinical trials taking into account these molecular parameters are still going on. DNA microarray-based gene expression profiling technology that allows the simultaneous analysis of thousand of tumor genes represents also an interesting approach in oncology with the recent identification of a "genetic signature" as a risk factor of tumor recurrence in stage II CRC, a setting in which the benefit of adjuvant chemotherapy remains on debate. At last, a best understanding of chemotherapy molecular targets allowed the identification of genetic markers that can predict the response and/or the toxicity of anti-cancer drugs used in gastrointestinal cancers, which could be helpful in the future to propose for each patient a personalized treatment. Mutations that can predict the response of new target therapies such as the inhibitors of the c-KIT tyrosine kinase activity in gastrointestinal stromal tumors have also been found and will allow the selection of patients who can have benefit from these new therapeutic drugs.     

New advances in radiation biology

Current understanding of risk associated with low-dose radiation exposure has for many years been embedded in the linear-no-threshold (LNT) approach, based on simple extrapolation from the Japanese atomic bomb survivors. Radiation biology research has supported the LNT approach although much of this has been limited to relatively high-dose studies. Recently, with new advances for studying effects of low-dose exposure in experimental models and advances in molecular and cellular biology, a range of new effects of biological responses to radiation has been observed. These include genomic instability, adaptive responses and bystander effects. Most have one feature in common in that they are observed at low doses and suggest significant non-linear responses. These new observations pose a significant challenge to our understanding of low-dose exposure and require further study to elucidate mechanisms and determine their relevance.     

镉对肾脏和骨骼的毒性研究进展

镉是一种广泛存在于水及土壤中的毒性物质。肾脏和骨骼是镉的重要靶器官，并且研究表明镉对肾脏和骨骼的毒性可能具有相关性，即骨骼损害继发于肾脏损害，但是也有研究表明镉可能具有直接的骨毒性，包括影响成骨细胞、破骨细胞活性、干扰胶原代谢以及抑制矿化等。本文从人群、动物及细胞分子生物学等多个方面就镉对肾脏和骨骼的损害进行综述，为探讨镉的毒效应提供参考。     

Role of biochemical mediators in clinical nutrition and surgical metabolism

Over the past several decades, research on the role of mediators in inflammation, immunity, repair processes, cell growth, and substrate metabolism have centered around the use of purified products of stimulated macrophages. With the current availability of recombinant mediators, the participation of individual monokines in cellular metabolism has been more clearly defined. Interactions among various mediators have been demonstrated, but their exact role in metabolism is currently under intense study. With the use of recombinant monokines, formal evidence for their participation in the acute phase response has been developed. Their use has also assisted in the reinterpretation of data gathered in older studies using purified preparations, which were almost certainly contaminated with several monokines. In this review we will try to give the reader insight into recent advances in the understanding of the role of cellular mediators in relation to nutrition and intermediary metabolism. With a clearer knowledge of the role of cellular mediators in the pathophysiology of disease, it may be possible to develop rationales for their therapeutic use as modulators of substrate metabolism during critical illness.     

Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics

Metabolic reprogramming and altered energetics have become an emerging hallmark of cancer and an active area of basic, translational, and clinical cancer research in the recent decade. Development of effective anticancer therapeutics may depend on improved understanding of the altered cancer metabolism compared to that of normal cells. Changes in glucose transport and glycolysis, which are drastically upregulated in most can-cers and termed the Warburg effect, are one of major focuses of this new research area. By taking advantage of the new knowledge and understanding of cancer's mechanisms, numerous therapeutic agents have been developed to target proteins and enzymes involved in glucose transport and metabolism, with promising results in cancer cells, animal tumor models and even clinical trials. It has also been hypothesized that targeting a pathway or a process, such as glucose transport or glucose metabolism, rather than a specific protein or enzyme in a signaling pathway may be more effective. This is based on the observation that cancer somehow can always bypass the inhibition of a target drug by switching to a redundant or compensatory pathway. In addition, cancer cells have higher dependence on glucose. This review will provide background information on glucose transport and metabolism in cancer, and summarize new therapeutic developments in basic and translational research in these areas, with a focus on glucose transporter inhibitors and glycolysis inhibitors. The daunting challenges facing both basic and clinical researchers of the field are also presented and discussed.     

S-Adenosyl-L-methionine (SAMe): from the bench to the bedside--molecular basis of a pleiotrophic molecule

S-Adenosyl-L-methionine (SAMe), a metabolite present in all living cells, plays a central role in cellular biochemistry as a precursor to methylation, aminopropylation, and transsulfuration pathways. As such, SAMe has been studied extensively since its chemical structure was first described in 1952. Decades of research on the biochemical and molecular roles of SAMe in cellular metabolism have provided an extensive foundation for its use in clinical studies, including those on depression, dementia, vacuolar myelopathy, liver disease, and osteoarthritis. This article provides an overview of the biochemical, molecular, and therapeutic effects of this pleiotrophic molecule.