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  • Integrating circulating miRNA analysis in the clinical management of lung cancer: Present or future?
    Mol. Aspects Med. (IF 8.313) Pub Date : 2020-01-17
    Rita Lampignano; Vera Kloten; Thomas Krahn; Thomas Schlange

    Liquid biopsy holds great promise to complement traditional analysis on cancerous tissue during clinical management of cancer: screening of patients, (early) disease diagnosis, prognosis, therapy selection as well as early response to treatment and disease monitoring. Among emerging circulating biomarkers, cell-free miRNA (cfmiRNA) may have potential in detecting lung cancer and following the course of the disease. Furthermore, several studies highlighted the possibility to utilize these regulatory RNAs to obtain prognostic information as well as to verify patient's response towards treatment. However, despite these findings, cfmiRNA is not used in the clinical practice as biomarkers to date, since their clinical utility and validity has not been confirmed in prospective clinical studies yet. In addition, there is no consensus on standardized (pre)analytical procedures. In this review, we present an overview of cfmiRNA biomarker candidates for clinical management of lung cancer and we discuss the issue of assay standardization.

  • Macrophage activation as an archetype of mitochondrial repurposing
    Mol. Aspects Med. (IF 8.313) Pub Date : 2020-01-16
    Anthony E. Jones; Ajit S. Divakaruni

    Mitochondria are metabolic organelles essential not only for energy transduction, but also a range of other functions such as biosynthesis, ion and metal homeostasis, maintenance of redox balance, and cell signaling. A hallmark example of how mitochondria can rebalance these processes to adjust cell function is observed in macrophages. These innate immune cells are responsible for a remarkable breadth of processes including pathogen elimination, antigen presentation, debris clearance, and wound healing. These diverse, polarized functions often include similarly disparate alterations in the metabolic phenotype associated with their execution. In this chapter, mitochondrial bioenergetics and signaling are viewed through the lens of macrophage polarization: both classical, pro-inflammatory activation and alternative, anti-inflammatory activation are associated with substantive changes to mitochondrial metabolism. Emphasis is placed on recent evidence that aims to clarify the essential – rather than associative – mitochondrial alterations, as well as accumulating data suggesting a degree of plasticity within the metabolic phenotypes that can support pro- and anti-inflammatory functions.

  • Circulating cell-free DNA: Translating prostate cancer genomics into clinical care
    Mol. Aspects Med. (IF 8.313) Pub Date : 2020-01-16
    Delila Gasi Tandefelt; Johann de Bono

    Only in the past decade tremendous advances have been made in understanding prostate cancer genomics and consequently in applying new treatment strategies. As options regarding treatments are increasing so are the challenges in selecting the right treatment option for each patient and not the least, understanding the optimal time-point and sequence of applying available treatments. Critically, without reliable methods that enable sequential monitoring of evolving genotypes in individual patients, we will never reach effective personalised driven treatment approaches. This review focuses on the clinical implications of prostate cancer genomics and the potential of cfDNA in facilitating treatment management.

  • Emerging roles of β-cell mitochondria in type-2-diabetes
    Mol. Aspects Med. (IF 8.313) Pub Date : 2020-01-07
    Guy Las; Marcus F. Oliveira; Orian S. Shirihai

    Type-2-Diabetes (T2D) is the most common metabolic disease in the world today. It erupts as a result of peripheral insulin resistance combined with hyperinsulinemia followed by suppression of insulin secretion from pancreatic β-cells. Mitochondria play a central role in β-cells by sensing glucose and also by mediating the suppression of insulin secretion in T2D. Here, we will summarize the evidence accumulated for the roles of β-cells mitochondria in T2D. We will present an updated view on how mitochondria in β-cells have been associated with T2D, from the genetic, bioenergetic, redox and structural points of view. The emerging picture is that mitochondrial structure and dysfunction directly contribute to β-cell function and in the pathogenesis of T2D.

  • Mitochondrial bioenergetics and redox dysfunctions in hypercholesterolemia and atherosclerosis
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-12-25
    Helena C.F. Oliveira; Anibal E. Vercesi

    In the first part of this review, we summarize basic mitochondrial bioenergetics concepts showing that mitochondria are critical regulators of cell life and death. Until a few decades ago, mitochondria were considered to play essential roles only in respiration, ATP formation, non-shivering thermogenesis and a variety of metabolic pathways. However, the concept presented by Peter Mitchell regarding coupling between electron flow and ATP synthesis through the intermediary of a H+ electrochemical potential leads to the recognition that the proton-motive force also regulates a series of relevant cell signalling processes, such as superoxide generation, redox balance and Ca2+ handling. Alterations in these processes lead to cell death and disease states. In the second part of this review, we discuss the role of mitochondrial dysfunctions in the specific context of hypercholesterolemia-induced atherosclerosis. We provide a literature analysis that indicates a decisive role of mitochondrial redox dysfunction in the development of atherosclerosis and discuss the underlying molecular mechanisms. Finally, we highlight the potential mitochondrial-targeted therapeutic strategies that are relevant for atherosclerosis.

  • Mitochondrially-targeted treatment strategies
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-12-19
    Luiz H.M. Bozi; Juliane C. Campos; Vanessa O. Zambelli; Nikolas D. Ferreira; Julio C.B. Ferreira

    Disruption of mitochondrial function is a common feature of inherited mitochondrial diseases (mitochondriopathies) and many other infectious and non-infectious diseases including viral, bacterial and protozoan infections, inflammatory and chronic pain, neurodegeneration, diabetes, obesity and cardiovascular diseases. Mitochondria therefore become an attractive target for developing new therapies. In this review we describe critical mechanisms involved in the maintenance of mitochondrial functionality and discuss strategies used to identify and validate mitochondrial targets in different diseases. We also highlight the most recent preclinical and clinical findings using molecules targeting mitochondrial bioenergetics, morphology, number, content and detoxification systems in common pathologies.

  • Blood-based bioenergetics: An emerging translational and clinical tool
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-12-18
    Andrea Braganza; Gowtham K. Annarapu; Sruti Shiva

    Accumulating studies demonstrate that mitochondrial genetics and function are central to determining the susceptibility to, and prognosis of numerous diseases across all organ systems. Despite this recognition, mitochondrial function remains poorly characterized in humans primarily due to the invasiveness of obtaining viable tissue for mitochondrial studies. Recent studies have begun to test the hypothesis that circulating blood cells, which can be obtained by minimally invasive methodology, can be utilized as a biomarker of systemic bioenergetic function in human populations. Here we present the available methodologies for assessing blood cell bioenergetics and review studies that have applied these techniques to healthy and disease populations. We focus on the validation of this methodology in healthy subjects, as well as studies testing whether blood cell bioenergetics are altered in disease, correlate with clinical parameters, and compare with other methodology for assessing human mitochondrial function. Finally, we present the challenges and goals for the development of this emerging approach into a tool for translational research and personalized medicine.

  • Nanoparticle-aided glycovariant assays to bridge biomarker performance and ctDNA results
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-11-29
    Kamlesh Gidwani, Henna Kekki, Joonas Terävä, Tero Soukka, Karin Sundfeldt, Kim Pettersson

    Numerous immunoassay based cancer biomarkers established in the 1970 and 1980′ies are widely used in clinical routine. Initial expectations of biomarkers such as CEA, CA125, CA19-9, AFP to provide decisive help in the diagnosis of early stage, pre-symptomatic cancers have not been realized. Thus, they are primarily used for monitoring disease progression and occasionally being useful as prognostic indicators. This limitation is due to the marker also being measurable in healthy individuals and frequently at elevated concentrations in common benign conditions. Most conventional tumor markers are glycosylated and interestingly specific alterations of the glycostructure part can often be seen early in the cancerous process. Conventional double monoclonal immunoassays are however blind to such changes as they are based on peptide epitope recognition. Wide selections of carbohydrate recognizing macromolecules, lectins, but also glycan structure recognizing antibodies are potentially useful for detecting such changes. Despite numerous attempts generating proof-of-principle evidence for this, such assays have generally not been successfully introduced into clinical routine. The affinity constants of lectin and glycan specific antibodies for their corresponding carbohydrate structures may be up to several orders too low to provide the detection limits and robustness expected from routine tumor markers. In this review, we describe an approach based on the use of highly fluorescent Eu3+--chelate dyed nanoparticles onto which lectins or glycan specific antibodies are coated to provide the necessary binding strength and signal amplification to provide low detection limits, while maintaining the original glycan-structure specificity. This concept applied to three markers, PSA, CA125 and CA15-3 provide glycoform assays of greatly enhanced cancer specificity using sample volumes similar or lower than corresponding traditional ELISAs. For ovarian cancer, we show that this new approach when applied to ovarian cyst fluid samples provide results similar to the performance obtained with ctDNA determinations of a set of 17 driver mutations and greatly superior compared to corresponding conventional immunoassays. Based on our results, we predict that the nanoparticle-lectin concept will enable a new generation of simple, low-cost biomarker assays of highly improved cancer specificity. Such tools should ideally be evaluated together with determination of ctDNA to establish early detection schemes for cancers e.g. ovarian, pancreas, lung where the detection rate of early stage disease is presently unacceptably low.

  • Emerging isothermal amplification technologies for microRNA biosensing: Applications to liquid biopsies
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-11-23
    Guillaume Gines, Roberta Menezes, Wenjin Xiao, Yannick Rondelez, Valerie Taly

    The potential of microRNAs (miRNAs) as biomarker candidates in clinical practice for diagnosis, prognosis and treatment response prediction, especially in liquid biopsies, has led to a tremendous demand for techniques that can detect these molecules rapidly and accurately. Hence, numerous achievements have been reported recently in miRNA research. In this review, we discuss the challenges associated with the emerging field of miRNA detection, which are linked to the intrinsic properties of miRNAs, advantages and drawbacks of the currently available technologies and their potential applications in clinical research. We summarize the most promising nucleic acid amplification techniques applied to the in vitro detection of miRNAs, with a particular emphasis on the state of the art for isothermal alternatives to RT-qPCR. We detail the sensitivity, specificity and quantitativity of these approaches, as well as their potential for multiplexing. We also review the different detection formats to which these chemistries have been adapted, including analog readouts such as real-time monitoring, digital counting based on single-molecule amplification in compartments, and surface-based strategies.

  • Lifestyle and dietary environmental factors in colorectal cancer susceptibility
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-06-28
    Neil Murphy, Victor Moreno, David J. Hughes, Ludmila Vodicka, Pavel Vodicka, Elom K. Aglago, Marc J. Gunter, Mazda Jenab

    Colorectal cancer (CRC) incidence changes with time and by variations in diet and lifestyle, as evidenced historically by migrant studies and recently by extensive epidemiologic evidence. The worldwide heterogeneity in CRC incidence is strongly suggestive of etiological involvement of environmental exposures, particularly lifestyle and diet. It is established that physical inactivity, obesity and some dietary factors (red/processed meats, alcohol) are positively associated with CRC, while healthy lifestyle habits show inverse associations. Mechanistic evidence shows that lifestyle and dietary components that contribute to energy excess are linked with increased CRC via metabolic dysfunction, inflammation, oxidative stress, bacterial dysbiosis and breakdown of gut barrier integrity while the reverse is apparent for components associated with decreased risk. This chapter will review the available evidence on lifestyle and dietary factors in CRC etiology and their underlying mechanisms in CRC development. This short review will also touch upon available information on potential gene-environment interactions, molecular sub-types of CRC and anatomical sub-sites within the colorectum.

  • Update on genetic predisposition to colorectal cancer and polyposis
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-03-18
    Laura Valle, Richarda M. de Voer, Yael Goldberg, Wenche Sjursen, Asta Försti, Clara Ruiz-Ponte, Trinidad Caldés, Pilar Garré, Maren F. Olsen, Margareta Nordling, Sergi Castellvi-Bel, Kari Hemminki

    The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.

  • Approaches to functionally validate candidate genetic variants involved in colorectal cancer predisposition
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-04-01
    Laia Bonjoch, Pilar Mur, Coral Arnau-Collell, Gardenia Vargas-Parra, Bahar Shamloo, Sebastià Franch-Expósito, Marta Pineda, Gabriel Capellà, Batu Erman, Sergi Castellví-Bel

    Most next generation sequencing (NGS) studies identified candidate genetic variants predisposing to colorectal cancer (CRC) but do not tackle its functional interpretation to unequivocally recognize a new hereditary CRC gene. Besides, germline variants in already established hereditary CRC-predisposing genes or somatic variants share the same need when trying to categorize those with relevant significance. Functional genomics approaches have an important role in identifying the causal links between genetic architecture and phenotypes, in order to decipher cellular function in health and disease. Therefore, functional interpretation of identified genetic variants by NGS platforms is now essential. Available approaches nowadays include bioinformatics, cell and molecular biology and animal models. Recent advances, such as the CRISPR-Cas9, ZFN and TALEN systems, have been already used as a powerful tool with this objective. However, the use of cell lines is of limited value due to the CRC heterogeneity and its close interaction with microenvironment. Access to tridimensional cultures or organoids and xenograft models that mimic the in vivo tissue architecture could revolutionize functional analysis. This review will focus on the application of state-of-the-art functional studies to better tackle new genes involved in germline predisposition to this neoplasm.

  • Mendelian randomisation: A powerful and inexpensive method for identifying and excluding non-genetic risk factors for colorectal cancer
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-02-04
    Alex J. Cornish, Ian P.M. Tomlinson, Richard S. Houlston

    Colorectal cancer (CRC) is the third most common cancer in economically developed countries and a major cause of cancer-related mortality. The importance of lifestyle and diet as major determinants of CRC risk is suggested by differences in CRC incidence between countries and in migration studies. Previous observational epidemiological studies have identified associations between modifiable environmental risk factors and CRC, but these studies can be susceptible to reverse causation and confounding, and their results can therefore conflict. Mendelian randomisation (MR) analysis represents an approach complementary to conventional observational studies examining associations between exposures and disease. The MR strategy employs allelic variants as instrumental variables (IVs), which act as proxies for non-genetic exposures. These allelic variants are randomly assigned during meiosis and can therefore inform on life-long exposure, whilst not being subject to reverse causation. In previous studies MR frameworks have associated several modifiable factors with CRC risk, including adiposity, hyperlipidaemia, fatty acid profile and alcohol consumption. In this review we detail the use of MR to investigate and discover CRC risk factors, and its future applications.

  • Somatic mutational signatures in polyposis and colorectal cancer
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-05-23
    Judith E. Grolleman, Marcos Díaz-Gay, Sebastià Franch-Expósito, Sergi Castellví-Bel, Richarda M. de Voer

    The somatic mutation spectrum imprinted in the genome of a tumor represents the mutational processes that have been active in that tumor. Large sequencing efforts in various cancer types have resulted in the identification of multiple mutational signatures, of which several have been linked to specific biological mechanisms. Several pan-cancer mutational signatures have been identified, while other signatures are only found in specific tissue types. Research on tumors from individuals with specific DNA repair defects has led to links between specific mutational signatures and mutational processes. Studying mutational signatures in cancers that are likely the result of a genetic predisposition may represent an interesting strategy to identify constitutional DNA repair defects, including those underlying polyposis and colorectal cancer.

  • Microbiome and colorectal cancer: Roles in carcinogenesis and clinical potential
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-05-24
    Ester Saus, Susana Iraola-Guzmán, Jesse R. Willis, Anna Brunet-Vega, Toni Gabaldón

    The gastrointestinal tract harbors most of the microbiota associated with humans. In recent years, there has been a surge of interest in assessing the relationships between the gut microbiota and several gut alterations, including colorectal cancer. Changes in the gut microbiota in patients suffering colorectal cancer suggest a possible role of host-microbe interactions in the origin and development of this malignancy and, at the same time, open the door for novel ways of preventing, diagnosing, or treating this disease. In this review we survey current knowledge on the healthy microbiome of the gut and how it is altered in colorectal cancer and other related disease conditions. In describing past studies we will critically assess technical limitations of different approaches and point to existing challenges in microbiome research. We will have a special focus on host-microbiome interaction mechanisms that may be important to explain how dysbiosis can lead to chronic inflammation and drive processes that influence carcinogenesis and tumor progression in colon cancer. Finally, we will discuss the potential of recent developments of novel microbiota-based therapeutics and diagnostic tools for colorectal cancer.

  • DNA methylation and chromatin modifiers in colorectal cancer
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-04-30
    Veronika Vymetalkova, Pavel Vodicka, Sona Vodenkova, Sergio Alonso, Regine Schneider-Stock

    Colorectal carcinogenesis is a multistep process involving the accumulation of genetic alterations over time that ultimately leads to disease progression and metastasis. Binding of transcription factors to gene promoter regions alone cannot explain the complex regulation pattern of gene expression during this process. It is the chromatin structure that allows for a high grade of regulatory flexibility for gene expression. Posttranslational modifications on histone proteins such as acetylation, methylation, or phosphorylation determine the accessibility of transcription factors to DNA. DNA methylation, a chemical modification of DNA that modulates chromatin structure and gene transcription acts in concert with these chromatin conformation alterations. Another epigenetic mechanism regulating gene expression is represented by small non-coding RNAs. Only very recently epigenetic alterations have been included in molecular subtype classification of colorectal cancer (CRC). In this chapter, we will provide examples of the different epigenetic players, focus on their role for epithelial-mesenchymal transition and metastatic processes and discuss their prognostic value in CRC.

  • Circulating biomarkers for early detection and clinical management of colorectal cancer
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-06-14
    María Marcuello, Veronika Vymetalkova, Rui P.L. Neves, Saray Duran-Sanchon, Hege Marie Vedeld, Emma Tham, Guus van Dalum, Georg Flügen, Vanesa Garcia-Barberan, Remond JA. Fijneman, Antoni Castells, Pavel Vodicka, Guro E. Lind, Nikolas H. Stoecklein, Ellen Heitzer, Meritxell Gironella

    New non-invasive approaches that can complement and improve on current strategies for colorectal cancer (CRC) screening and management are urgently needed. A growing number of publications have documented that components of tumors, which are shed into the circulation, can be detected in the form of liquid biopsies and can be used to detect CRC at early stages, to predict response to certain therapies and to detect CRC recurrence in a minimally invasive way. The analysis of circulating tumor DNA (ctDNA), tumor-derived cells (CTC, circulating tumor cells) or circulating microRNA (miRNA) in blood and other body fluids, have a great potential to improve different aspects of CRC management. The challenge now is to find which types of components, biofluids and detection methods would be the most suitable to be applied in the different steps of CRC detection and treatment. This chapter will provide an up to date review on ctDNA, CTCs and circulating miRNAs as new biomarkers for CRC, either for clinical management or early detection, highlighting their advantages and limitations.

  • Colorectal cancer: A paradigmatic model for cancer immunology and immunotherapy
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-06-04
    Marieke E. IJsselsteijn, Rebeca Sanz-Pamplona, Fabienne Hermitte, Noel F.C.C. de Miranda

    Colorectal cancer can be categorized into two major molecular subtypes according to the status of their DNA proofreading and repair machinery. The DNA repair status of tumor cells plays a major role in shaping the immune landscape of tumors and in determining the clinical response of colorectal cancer patients to immune checkpoint blockade therapies. Colorectal cancers that develop in a context of DNA mismatch repair or polymerase proofreading deficiency are generally conspicuously infiltrated by effector memory T cells and are associated with an improved clinical prognosis relative to their replication repair-proficient counterpart. While mismatch repair-deficient colorectal cancers, and most likely POLE and POLD1-mutated cancers, are amenable to immune checkpoint blockade therapies, the promise of immunotherapy still remains unfulfilled for for the majority of colorectal cancer patients. This review focusses on the role of the immune system in the tumorigenesis and clinical behavior of colorectal cancer. Furthermore, we discuss how latest advances in the fields of genomics and oncoimmunology may pave the way to broaden the scope of immunotherapy for this disease.

  • Quantification of mitochondrial DNA from peripheral tissues: Limitations in predicting the severity of neurometabolic disorders and proposal of a novel diagnostic test
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-11-16
    Christos Chinopoulos

    Neurometabolic disorders stem from errors in metabolic processes yielding a neurological phenotype. A subset of those disorders encompasses mitochondrial abnormalities partially due to mitochondrial DNA (mtDNA) depletion. mtDNA depletion can be attributed to inheritance, spontaneous mutations or acquired from drug-related toxicities. In the armamentarium of diagnostic procedures, mtDNA quantification is a standard for disease classification. However, alterations in mtDNA obtained from peripheral tissues such as skin fibroblasts and blood cells do not often reflect the severity of the affected organ, in this case, the brain. The purpose of this review is to highlight the pitfalls of quantitating mtDNA from peripheral –and not limited to-tissues for diagnosing patients suffering from a variety of mtDNA depletion syndromes exhibiting neurologic abnormalities. In lieu, a qualitative test of mitochondrial substrate-level phosphorylation –even from peripheral tissues-reflecting the ability of mitochondria to rely on glutaminolysis in the presence of respiratory chain defects is proposed as a novel diagnostic assessment of mitochondrial functionality.

  • The importance of long non-coding RNAs in neuropsychiatric disorders
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-07-19
    Ebrahim Hosseini, Zahra Bagheri-Hosseinabadi, Ilario De Toma, Moslem Jafarisani, Iman Sadeghi

    In the last decade, transcriptome analyses have discovered thousands of long non-coding RNAs (lncRNAs) which are assumed as a fundamental part of the gene regulatory networks in the cell. Intriguingly, lncRNAs are abundantly enriched in the brain, displaying elaborate spatiotemporal expression profiles and modulation. They diversely participate in the delicate regulation of the central nervous system (CNS) development including self-renewal maintenance, cell fate decision, synapse plasticity, synaptogenesis and memory formation. Moreover, lncRNAs have vastly demonstrated correlations with mental illnesses such as neuropsychiatric disorders (NPDs), implying the vital jobs of these yet poorly-understood transcripts. Here, we underlie the accumulating evidence for the significance of lncRNAs in neural networks and their impairment in several NPDs including autism spectrum disorder (ASD), schizophrenia (SZ), intellectual disability (ID), major depressive disorder (MDD), Rett syndrome (RTT) and others.

  • MicroRNA-215: From biology to theranostic applications
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-03-26
    Petra Vychytilova-Faltejskova, Ondrej Slaby

    MicroRNA-215 (miR-215) is one of the extensively studied microRNAs (miRNAs) in human diseases, especially in different types of cancer, where it plays various roles in the initiation and progression of tumors. There is also a high conservation of miR-215 among wide range of different species indicating that this miRNA may have vital functions that are maintained during evolution. During the last ten years, significant efforts were dedicated to uncover molecular mechanisms of miR-215 regulation and cellular functioning. In addition, miR-215 was repeatedly identified to have the causal roles in pathology of various diseases, where it may serve as a promising diagnostic, prognostic or predictive biomarker and as a therapeutic target. Here, we overview more than 150 reports focused on miR-215 to allow the synthesis of knowledge on its transcriptional and post-transcriptional regulation, and functioning in essential biological processes like cell and tissue development, cell survival, cell cycle and proliferation, cell migration and invasion, cellular microenvironment communication, and metabolism. Further, we summarized the findings on miR-215 roles in pathology of nonmalignant diseases and various types of cancer with special focus on miR-215 as a promising molecule for future development of theranostic miRNA-based approaches. Although it is difficult to evaluate the full theranostic potential of miR-215, it is probable that during the following years, an increasing number of theranostic miRNA modalities that overcome the current technological obstacles will appear, and enable the translation of miR-215 knowledge into the clinic.

  • Functional roles of the human ribonuclease A superfamily in RNA metabolism and membrane receptor biology
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-03-25
    Heng-Huan Lee, Ying-Nai Wang, Mien-Chie Hung

    The human ribonuclease A (hRNase A) superfamily is comprised of 13 members of secretory RNases, most of which are recognized as catabolic enzymes for their ribonucleolytic activity to degrade ribonucleic acids (RNAs) in the extracellular space, where they play a role in innate host defense and physiological homeostasis. Interestingly, human RNases 9–13, which belong to a non-canonical subgroup of the hRNase A superfamily, are ribonucleolytic activity-deficient proteins with unclear biological functions. Moreover, accumulating evidence indicates that secretory RNases, such as human RNase 5, can be internalized into cells facilitated by membrane receptors like the epidermal growth factor receptor to regulate intracellular RNA species, in particular non-coding RNAs, and signaling pathways by either a ribonucleolytic activity-dependent or -independent manner. In this review, we summarize the classical role of hRNase A superfamily in the metabolism of extracellular and intracellular RNAs and update its non-classical function as a cognate ligand of membrane receptors. We further discuss the biological significance and translational potential of using secretory RNases as predictive biomarkers or therapeutic agents in certain human diseases and the pathological settings for future investigations.

  • MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance
    Mol. Aspects Med. (IF 8.313) Pub Date : 2018-08-18
    Mohammad Askandar Iqbal, Shweta Arora, Gopinath Prakasam, George A. Calin, Mansoor Ali Syed

    Lung cancer is the cardinal cause of cancer-related deaths with restricted recourse of therapy throughout the world. Clinical success of therapies is not very promising due to - late diagnosis, limited therapeutic tools, relapse and the development of drug resistance. Recently, small ∼20–24 nucleotides molecules called microRNAs (miRNAs) have come into the limelight as they play outstanding role in the process of tumorigenesis by regulating cell cycle, metastasis, angiogenesis, metabolism and apoptosis. miRNAs essentially regulate gene expression via post-transcriptional regulation of mRNA. Nevertheless, few studies have conceded the role of miRNAs in activation of gene expression. A large body of data generated by numerous studies is suggestive of their tumor-suppressing, oncogenic, diagnostic and prognostic biomarker roles in lung cancer. They have also been implicated in regulating cancer cell metabolism and resistance or sensitivity towards chemotherapy and radiotherapy. Further, miRNAs have also been convoluted in regulation of immune checkpoints – Programmed death 1 (PD-1) and its ligand (PD-L1). These molecules play a significant role in tumor immune escape leading to the generation of a microenvironment favouring tumor growth and progression. Therefore, it is imperative to explore the expression of miRNA and understand its relevance in lung cancer and development of anti-cancer strategies (anti – miRs, miR mimics and micro RNA sponges). In view of the above, the role of miRNA in lung cancer has been dissected and the associated mechanisms and pathways are discussed in this review.

  • Targets, pitfalls and reference materials for liquid biopsy tests in cancer diagnostics
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-11-08
    Edward Geeurickx, An Hendrix

    Assessment of cell free DNA (cfDNA) and RNA (cfRNA), circulating tumor cells (CTC) and extracellular vesicles (EV) in blood or other bodily fluids can enable early cancer detection, tumor dynamics assessment, minimal residual disease detection and therapy monitoring. However, few liquid biopsy tests progress towards clinical application because results are often discordant and challenging to reproduce. Reproducibility can be enhanced by the development and implementation of standard operating procedures and reference materials to identify and correct for pre-analytical variables. In this review we elaborate on the technological considerations, pre-analytical variables and the use and availability of reference materials for the assessment of liquid biopsy targets in blood and highlight initiatives towards the standardization of liquid biopsy testing.

  • Cell-free DNA in blood as a noninvasive insight into the sarcoma genome
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-11-06
    Heidi Maria Namløs, Kjetil Boye, Leonardo A. Meza-Zepeda

    Sarcomas are malignant tumors of mesenchymal origin that arise mainly from connective and supportive tissue. Sarcomas include a wide range of histological subtypes, showing a large diversity at the molecular level, from simple to highly complex karyotypes but with few recurrent somatic changes. Therapeutic decisions increasingly rely on the molecular characteristics of the individual tumor. Circulating cell-free DNA (ctDNA) is released into peripheral blood and can be used for the genomic analysis of sarcomas. However, the diversity and heterogeneity of somatic changes observed in sarcomas pose a challenge when choosing an adequate assay for the detection of ctDNA in body fluids. In this review, we provide an overview of different studies on ctDNA from blood in bone and soft tissue sarcomas, including gastrointestinal stromal tumors. We will specifically address the technological challenges that must be considered to achieve the sensitive detection of ctDNA and discuss the clinical applications of ctDNA in the management and treatment of sarcomas.

  • Altered expression of miR-181 affects cell fate and targets drug resistance-related mechanisms
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-11-06
    Cornelia Braicu, Diana Gulei, Lajos Raduly, Antonia Harangus, Alexandru Rusu, Ioana Berindan-Neagoe

    MicroRNAs (miRNAs) are non-coding transcripts which regulate genetic and epigenetic events by interfering with mRNA translation. miRNAs are involved in regulation of cell fate due to their ability of interfering with physiological or pathological processes. In this review paper, we evaluate the role of miR-181 family members as prognostic or diagnostic markers or therapeutic targets in malignant pathologies in connection with the main hallmarks of cancer that are modulated by the family. Also, we take over the dual role of this family in dependency with the tumour suppressor and oncogenic features presented in cell and cancer type specific manner. Restoration of the altered expression levels contributes to the activation of cell death pathways or to a reduction in the invasion and migration mechanism; moreover, the mechanism of drug resistance is also modulated by miR-181 sequences with important applications in therapeutic strategies for malignant cells sensitisation. Overall, the main miR-181 family regulatory mechanisms are presented in a cancer specific context, emphasizing the possible clinical application of this family in terms of novel diagnosis and therapy approaches.

  • Circular RNAs: The star molecules in cancer
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-10-31
    Jianhong Liu, Dongpei Li, Hui Luo, Xiao Zhu

    Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs with a closed loop structure. These RNAs are produced by pre-mRNA through variable shear processing and are highly conserved. Such highly conserved molecules play an important role in biology, especially in cancer biology. With the development of experimental techniques such as circRNA microarray screening and high-throughput sequencing technologies, the mystery of circRNAs has gradually been unveiled and the values of function and application have gradually emerged. Among them, cancer-related circRNAs are the most eye-catching. Numerous studies have shown that some circRNAs were involved in the pathogenesis of cancer. This review systematically introduced the cancer-related circRNAs and their origin, formation mechanisms, functions, and applications in the diagnosis and treatment of sixteen kinds of tumors.

  • Molecular aspects of medicine - Editorial 2019.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2019-11-19
    George A Calin,Linda Fabris

  • Is there a room for vitamins?
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-12-24
    Tommaso Galeotti,Gabriella Calviello,Paola Palozza,Sancia Gaetani

  • Regulation of extrarenal synthesis of 1,25-dihydroxyvitamin D3--relevance for colonic cancer prevention and therapy.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Heide S Cross,Enikö Kállay,Maya Khorchide,Daniel Lechner

    Epidemiological studies have demonstrated a high incidence of colonic tumors in populations living in areas of low sunlight exposure. This suggests 1,25-dihydroxyvitamin D3, an antimitotic prodifferentiating steroid hormone, as a potentially preventive factor since levels of the precursor 25-hydroxyvitamin D3 in serum are, to a major part, dependent upon sun exposure. Conversion into the active metabolite from the precursor is effected by CYP27B1, and degradation by CYP24. Both p450 hydroxylases are known to be located in the kidney. However, we were able to demonstrate presence, and activity of both enzymes also in the colon. We have shown also that during early tumor progression expression of CYP27B1 and of the vitamin D receptor is upregulated. Therefore the vitamin D system may function as a potent physiological defense against further tumor progression in cancer patients. We suggest that estrogenic substances, and also phytoestrogens present in soy food could, by increasing tumor tissue-located CYP27B1 activity and decreasing degradative CYP24 activity, augment tumor-localized 1,25-dihydroxyvitamin D3 levels and activity.

  • Carotenoid and retinoid transport to fish oocytes and eggs: what is the role of retinol binding protein?
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    E Lubzens,L Lissauer,B Levavi-Sivan,J-C Avarre,M Sammar

    Fish eggs contain carotenoids, retinals (retinal and dehydroretinal) and retinols (retinol, dehydroretinol and retinyl-esters) that are utilized during embryonic development, after fertilization. The carotenoids (mainly astaxanthins) are transported in the plasma by the low density lipoproteins, high density lipoproteins, and very high density lipoproteins (VHDL) and were found to be associated also with serum albumin. Retinals were found to be associated vitellogenin (VTG), a component of the plasma VHDL fraction that is internalized by oocytes during vitellogenesis. However, the transport of retinols and retinyl-esters that were located in the oil droplet fraction of homogenized eggs, has yet to be elucidated. Retinols are more abundant in freshwater fish eggs than in eggs of marine fish species. Since retinol is transported in the plasma of vertebrates in association with retinol binding protein (RBP), recent studies on the molecular characterization and expression sites of RBP, could contribute to determining the involvement of RBP in transporting retinol to developing oocytes in vertebrates.Recently, results from our laboratory show that RBP mRNA levels in the liver and RBP plasma levels did not significantly change with the onset and during vitellogenesis in the Rainbow trout. These results were in contrast with a dramatic elevation in the mRNA levels of VTG in the liver and an increase in VTG plasma levels that was observed in the same females. Moreover, 17beta-estradiol treatment of immature fish, resulted in relatively lower mRNA levels of RBP in the liver, concomitantly with an increase in the level of VTG transcripts and the appearance of VTG in the plasma of treated fish. In addition, RBP was localized in the cytosol of ovulated oocytes. These results for Rainbow trout are similar to those reported for the chicken but differ from those of Xenopus, where an increase in RBP mRNA was reported in the liver and higher levels of retinal and retinol were found in the plasma of 17beta-estradiol treated animals. The results, reported here for the first time in Rainbow trout, showing RBP transcripts in the ovary, oviduct (the ovarian tissue adjacent to the gonopore) and oocytes, suggest a modulating role for RBP in follicular development, as has been suggested for the bovine ovary.

  • Importance of vitamin-A for lung function and development.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    H K Biesalski,D Nohr

    Vitamin-A is essential for growth and development of cells and tissues. In its active form, retinoic acid, it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations [Nature 37 (1994) 528; International Review of Cytology. San Diego Academic Press, 1-31]. Vitamin-A plays a substantial role, especially in the respiratory epithelium and the lung. During moderate vitamin-A-deficiency, the incidence for diseases of the respiratory tract is considerably increased and repeated respiratory infections can be influenced therapeutically by a moderate vitamin-A-supplementation [Aust. Paediatr. J. 22 (1986) 95; Lancet 338 (1991) 67]. In addition to the importance of the vitamin for the lung function, vitamin-A is also responsible for the development of many tissues and cells as well as for the embryonic lung development. Recent studies proved that the control occurs by different expressions of retinoid receptors as well as by time-dependent changes of the vitamin-A-metabolism respectively via cellular vitamin-A-binding proteins (CRBP: cytoplasmatic retinol binding protein; CRABP: cytoplasmatic retinoic acid binding protein).

  • Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Loredana Quadro,Leora Hamberger,Vittorio Colantuoni,Max E Gottesman,William S Blaner

    Retinoids (vitamin A and its derivatives) play an essential role in many biological functions. However mammals are incapable of de novo synthesis of vitamin A and must acquire it from the diet. In the intestine, dietary retinoids are incorporated in chylomicrons as retinyl esters, along with other dietary lipids. The majority of dietary retinoid is cleared by and stored within the liver. To meet vitamin A requirements of tissues, the liver secretes retinol (vitamin A alcohol) into the circulation bound to its sole specific carrier protein, retinol-binding protein (RBP). The single known function of this protein is to transport retinol from the hepatic stores to target tissues. Over the last few years, the generation of knockout and transgenic mouse models has significantly contributed to our understanding of RBP function in the metabolism of vitamin A. We discuss below the role of RBP in maintaining normal vision and a steady flux of retinol throughout the body in times of need.

  • Vitamin A transport: in vitro models for the study of RBP secretion.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    D Bellovino,M Apreda,S Gragnoli,M Massimi,S Gaetani

    Retinol-binding protein (RBP) is the specific plasma carrier of retinol, encharged of the vitamin transport from the liver to target cells. Ligand binding influences the RBP affinity for transthyretin (TTR), a homotetrameric protein involved in the RBP/TTR circulating complex, and the secretion rate of RBP. In fact, in vitamin A deficiency, the RBP release from the hepatocytes dramatically decreases and the protein accumulates in the cells, until retinol is available again. The mechanism is still not clear and new cellular models are needed to understand in detail how the soluble RBP can be retained inside the cell. In fish, a vitamin A transport system similar to that of higher vertebrates is emerging, although with significant differences.

  • Structure and function of retinol dehydrogenases of the short chain dehydrogenase/reductase family.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Martin Lidén,Kristian Tryggvason,Ulf Eriksson

    All-trans-retinol is the common precursor of the active retinoids 11-cis-retinal, all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9cRA). Genetic and biochemical data supports an important role of the microsomal members of the short chain dehydrogenases/reductases (SDRs) in the first oxidative conversion of retinol into retinal. Several retinol dehydrogenases of this family have been reported in recent years. However, the structural and functional data on these enzymes is limited. The prototypic enzyme RDH5 and the related enzyme CRAD1 have been shown to face the lumen of the endoplasmic reticulum (ER), suggesting a compartmentalized synthesis of retinal. This is a matter of debate as a related enzyme has been proposed to have the opposite membrane topology. Recent data indicates that RDH5, and presumably other members of the SDRs, occur as functional homodimers, and need to interact with other proteins for proper intracellular localization and catalytic activity. Further analyses on the compartmentalization, membrane topology, and functional properties of microsomal retinol dehydrogenases, will give important clues about how retinoids are processed.

  • Effects of vitamin E and carotenoid status on oxidative stress in health and disease. Evidence obtained from human intervention studies.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Brigitte M Winklhofer-Roob,Edmond Rock,Josep Ribalta,David H Shmerling,Johannes M Roob

    Vitamin E and carotenoids are known to act as antioxidants both in vitro and in vivo. In this review we present a series of studies in healthy subjects and in patients who exhibit either acute or chronic oxidative stress. In the EU-Commission funded VITAGE project we investigated the status and effects of vitamin E and carotenoids on oxidative stress in 300 healthy volunteers. Depletion studies limiting dietary vitamin E or carotenoid intake to approximately 25% of the dietary reference intakes and subsequent repletion by supplementation with either large doses of vitamin E or intermediate doses of carotenoids showed significant changes in ex vivo LDL oxidizability, total plasma peroxide concentrations and urinary 8-oxo-7,8-dihydro-2(')-deoxyguanosine excretion. Patients on chronic hemodialysis present with oxidative stress in the presence of normal vitamin E but impaired vitamin C status and, due to anemia, need to be treated with parenteral iron. We studied the effects of a single oral dose of vitamin E taken 6 h prior to intravenous infusion of 100 mg iron, which exceeded the iron-binding capacity of transferrin. Vitamin E significantly reduced and in combination with a single dose of vitamin C completely abrogated acute oxidative stress induced by the iron load. Patients with cystic fibrosis are exposed to chronic oxidative stress due to an overproduction of reactive oxygen species as a result of neutrophil-dominated lung inflammation and impaired antioxidant status. Biochemical vitamin E and carotenoid deficiencies could be fully corrected even in the presence of fat malabsorption using intermediate doses of either RRR alpha-tocopherol or all-rac alpha-tocopheryl acetate and water-miscible all-trans beta-carotene. Long-term supplementation reduced ex vivo LDL oxidizability, in vivo lipid peroxidation and lung inflammation.

  • Rosehip -- a "new" source of lycopene?
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Volker Böhm,Kati Fröhlich,Roland Bitsch

    Lycopene, an efficient antioxidant and singlet oxygen quencher, is mainly delivered within the human diet out of tomatoes and tomato products. Processing liberates this carotenoid from complexes with proteins and thus makes it more bioavailable. Rosehip, a wild fruit which is used more often recently to produce mark, jams and juices, showed remarkable contents of lycopene (12.9-35.2 mg/100 g) with an unexpected isomer pattern.

  • Modulation of transcriptional activity by antioxidant carotenoids.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Yoav Sharoni,Riad Agbaria,Hadar Amir,Anat Ben-Dor,Irene Bobilev,Noga Doubi,Yudit Giat,Keren Hirsh,Gaby Izumchenko,Marina Khanin,Elena Kirilov,Rita Krimer,Amit Nahum,Michael Steiner,Yossi Walfisch,Shlomo Walfisch,Gabi Zango,Michael Danilenko,Joseph Levy

    It is widely accepted that diet changes are a powerful means to prevent cancer. The possible involvement of transcriptional activity in the anticancer activity of carotenoids will be the focus of this review. Carotenoids function as potent antioxidants, and this is clearly a major mechanism of their action. In addition carotenoids action involves interference in several pathways related to cancer cell proliferation and includes changes in the expression of many proteins participating in these processes such as connexins, phase II enzymes, cyclins, cyclin-dependent kinases and their inhibitors. These changes in protein expression suggest that the initial effect involves modulation of transcription by ligand-activated nuclear receptors or by other transcription factors. It is feasible to suggest that carotenoids and their oxidized derivatives interact with a network of transcription systems that are activated by different ligands at low affinity and specificity and that this activation leads to the synergistic inhibition of cell growth.

  • Carotenoids as prooxidants?
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Gordon M Lowe,Konstantinos Vlismas,Andrew J Young

  • Prooxidant effects of beta-carotene in cultured cells.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Paola Palozza,Simona Serini,Fiorella Di Nicuolo,Elisabetta Piccioni,Gabriella Calviello

    There is a growing body of interest on the role of beta-carotene and other carotenoids in human chronic diseases, including cancer. While epidemiological evidence shows that people who ingest more dietary carotenoids exhibit a reduced risk for cancer, results from intervention trials indicate that supplemental beta-carotene enhances lung cancer incidence and mortality among smokers. A possible mechanism which can explain the dual role of beta-carotene as both a beneficial and a harmful agent in cancer as well as in other chronic diseases is its ability in modulating intracellular redox status. beta-Carotene may serve as an antioxidant or as a prooxidant, depending on its intrinsic properties as well as on the redox potential of the biological environment in which it acts. This review summarizes the available evidence for a prooxidant activity of beta-carotene in cultured cells, focusing on biochemical and molecular markers of oxidative stress, which have been reported to be enhanced by the carotenoid.

  • Homologous metabolic and gene activating routes for vitamins E and K.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Nico Landes,Marc Birringer,Regina Brigelius-Flohé

    Vitamins E and K share structurally related side chains and are degraded to similar final products. For vitamin E the mechanism has been elucidated as initial omega-hydroxylation and subsequent beta-oxidation. For vitamin K the same mechanism can be suggested analogously. omega-Hydroxylation of vitamin E is catalyzed by cytochrome p450 enzymes, which often are induced by their substrates themselves via the activation of the nuclear receptor PXR. Vitamin E is able to induce CYP3A-forms and to activate a PXR-driven reporter gene. It is shown here that K-type vitamins are also able to activate PXR. A ranking showed that compounds with an unsaturated side chain were most effective, as are tocotrienols and menaquinone-4 (vitamin K(2)), which activated the reporter gene 8-10-fold. Vitamers with a saturated side chain, like tocopherols and phylloquinone were less active (2-5-fold activation). From the fact that CYPs commonly responsible for the elimination of xenobiotics are involved in the metabolism of fat-soluble vitamins and the ability of the vitamins to activate PXR it can be concluded that supranutritional amounts of these vitamins might be considered as foreign.

  • Antioxidant activity of carotenoids.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    Wilhelm Stahl,Helmut Sies

    Carotenoids are pigments which play a major role in the protection of plants against photooxidative processes. They are efficient antioxidants scavenging singlet molecular oxygen and peroxyl radicals. In the human organism, carotenoids are part of the antioxidant defense system. They interact synergistically with other antioxidants; mixtures of carotenoids are more effective than single compounds. According to their structure most carotenoids exhibit absorption maxima at around 450 nm. Filtering of blue light has been proposed as a mechanism protecting the macula lutea against photooxidative damage. There is increasing evidence from human studies that carotenoids protect the skin against photooxidative damage.

  • The role of alpha-tocopherol in preventing disease: from epidemiology to molecular events.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-10-31
    A Azzi,R Gysin,P Kempná,R Ricciarelli,L Villacorta,T Visarius,J-M Zingg

    The function of vitamin E has been attributed to its capacity to protect the organism against the attack of free radicals by acting as a lipid based radical chain breaking molecule. More recently, alternative non-antioxidant functions of vitamin E have been proposed and in particular that of a "gene regulator". Effects of vitamin E have been observed at the level of mRNA or protein and could be consequent to regulation of gene transcription, mRNA stability, protein translation, protein stability and post-translational events. Given the high priority functions assigned to vitamin E, it can be speculated that it would be inefficient to consume it as a radical scavenger. Rather, it would be important to protect vitamin E through a network of cellular antioxidant defences, similarly to what occurs with proteins, nucleic acids and lipids.

  • 更新日期:2019-11-01
  • Hydroxynonenal, toxic carbonyls, and Alzheimer disease.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Quan Liu,Arun K Raina,Mark A Smith,Lawrence M Sayre,George Perry

    Cytoskeletal disruption is one of the distinguishing characteristics of the vulnerable neurons in Alzheimer disease (AD). It has been suggested that these cytoskeletal changes occur secondarily to covalent modifications of the protein components. Despite the abundance and probable importance of these changes, there has been very little data regarding the identity of the modified proteins or the precise chemistry of the modifications. Here we review a specific type of modification, namely carbonylation of proteins, which has been shown to be a common result of cellular oxidative stress. Hopefully, the following discussion will help elucidate the relationship between oxidative stress, protein modification and the pathogenesis of AD.

  • 4-hydroxynonenal and neurodegenerative diseases.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Kamelija Zarkovic

    The development of oxidative stress, in which production of highly reactive oxygen species (ROS) overwhelms antioxidant defenses, is a feature of many neurological diseases: ischemic, inflammatory, metabolic and degenerative. Oxidative stress is increasingly implicated in a number of neurodegenerative disorders characterized by abnormal filament accumulation or deposition of abnormal forms of specific proteins in affected neurons, like Alzheimer's disease (AD), Pick's disease, Lewy bodies related diseases, amyotrophic lateral sclerosis (ALS), and Huntington disease. Causes of neuronal death in neurodegenerative diseases are multifactorial. In some familiar cases of ALS mutation in the gene for Cu/Zn superoxide dismutase (SOD1) can be identified. In other neurodegenerative diseases ROS have some, usually not clear, role in early pathogenesis or implications on neuronal death in advanced stages of illness. The effects of oxidative stress on "post-mitotic cells", such as neurons may be cumulative, hence, it is often unclear whether oxidative damage is a cause or consequence of neurodegeneration. Peroxidation of cellular membrane lipids, or circulating lipoprotein molecules generates highly reactive aldehydes among which one of most important is 4-hydroxynonenal (HNE). The presence of HNE is increased in brain tissue and cerebrospinal fluid of AD patients, and in spinal cord of ALS patients. Immunohistochemical studies show presence of HNE in neurofibrilary tangles and in senile plaques in AD, in the cytoplasm of the residual motor neurons in sporadic ALS, in Lewy bodies in neocortical and brain stem neurons in Parkinson's disease (PD) and in diffuse Lewy bodies disease (DLBD). Thus, increased levels of HNE in neurodegenerative disorders and immunohistochemical distribution of HNE in brain tissue indicate pathophysiological role of oxidative stress in these diseases, and especially HNE in formation of abnormal filament deposites.

  • 4-hydroxynonenal as a bioactive marker of pathophysiological processes.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Neven Zarkovic

    The review is focused on the currently major aspect of 4-hydroxynonenal (HNE) research--studies that combine biological activities of the aldehyde together with the methods of its identification in cells and tissues. Because there were some excellent reviews on HNE published in recent years, starting in 1990 and 1991 with supreme reviews done by Hermann Esterbauer, who discovered the aldehyde, and colleagues from the Institute of Biochemistry in Graz, this article pays most of attention to the most recent articles, published in the last 15 months. Additionally, an overview on the relevance of HNE is given with respect to the research and publication trends in the period of 10 years (1993-2002) according to the data in the Current Contents and Medline data bases. It is obvious that HNE started in 1993 as a "toxic product of lipid peroxidation" and "second toxic messenger of free radicals", to become in 2002 a reliable marker of oxidative stress, a possible causative agent of several diseases (such as Alzheimer's disease), growth modulating factor and a signaling molecule. Novel analytical methods developed suitable pathways for HNE to become a clinically applicable marker of lipid peroxidation on one side and on the other a standardized parameter of food quality control. As it is also present physiologically in various cells and tissues, it is likely that HNE will soon become one of the most attractive factors for those who search for a small and reactive molecular link between genomics and proteomics.

  • 4-hydroxynonenal and transforming growth factor-beta1 expression in colon cancer.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    D Zanetti,G Poli,B Vizio,B Zingaro,E Chiarpotto,F Biasi

    In vivo studies on human colon adenocarcinoma showed decreased transforming growth factor-beta1 (TGF-beta1) antiproliferative cytokine content in tumour tissue related to malignancy progression, with a corresponding decrease in lipid peroxidation aldehydic end-product, 4-hydroxynonenal (HNE). The tumour mechanism to escape TGF-beta1-mediated growth inhibition may be due to an altered TGF-beta1 receptor system. Subsequent in vitro analyses showed a differential distribution of TGF-beta1 receptors depending on the human colon cancer cell line considered (CaCo-2 or HT-29): compared to HT-29 cells, CaCo-2 cells showed a decrease of the two main TGF-beta1 receptors, RI and RII. Notwithstanding their partial TGF-beta1 RI and RII deficiency, treatment of CaCo-2 cells with adequate doses of the cytokine (10 ng/ml) was able to induce apoptosis. Of note, co-treatment of these cells with 1 microM HNE increased the apoptotic effect. The constant low concentration of TGF-beta1 in the tumour mass may be related to the low content of antiproliferative HNE observed in colon cancer: the latter phenomenon, which reduces TGF-beta1 production in the tumour area, may represent a favourable condition for neoplastic progression. The enhancement of TGF-beta1-induced apoptosis by HNE in CaCo-2 cells supports this hypothesis. The different transcriptional components regulated by the distinct signaling pathways of these two molecules might be proposed; in particular, crosstalk between the MAPK and the Smad pathway could modulate and co-operate in the transcription of target genes involved in regulation of cell proliferation.

  • 4-hydroxynonenal from pathology to physiology.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Mario Umberto Dianzani

    4-hydroxynonenal is a major product of lipid peroxidation. It was firstly studied under the point of view of its toxicity, as it is an easily diffusable substance, thought to be able to explain the "far damages" seen in conditions of increased lipid peroxidation. Really, when used at concentration from 10 microM to 1 mM, usually referred to as high concentrations, the aldehyde is able to produce strong inhibitions of several enzymatic activities. When used, however, at concentration of 1 microM or lower, it displays a lot of activities regarding especially cell multiplication and differentiation. As the concentrations indicated above are usually found in normal tissues, these effects may be considered as physiological. As a low level of lipid peroxidation exists in normal tissues, the aldehyde displays signalling activities in normal cells. Among them, it is to consider the stimulation of neutrophil chemotaxis, the strong activation of plasmamembrane adenylate kinase, the strong activation of membrane phospholipase C, both in hepatocytes and neutrophils, the block in the expression of the oncogene c-myc in human leukemic cells, accompanied by differentiation of the same cells, the effects on the cyclins and the activity of E2F transcription factor, the strong increase of the expression of the gene for procollagen alfa1(I), occurring due to the activation of the c-jun/junkinases/AP-1 pathway. Moreover, it is able to block the activity of the PDGF-beta receptor. The last facts allow to think that a hydroxynonenal pathway works in the production of fibrosis.

  • Oxidized LDL and 4-hydroxynonenal modulate tyrosine kinase receptor activity.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Anne Negre-Salvayre,Otilia Vieira,Isabelle Escargueil-Blanc,Robert Salvayre

    Among the diverse risk factors involved in atherosclerosis, LDL are thought to become atherogenic after undergoing oxidative modifications, characterized by oxidized lipid formation and structural alterations of apoB. Oxidized LDL alter various signaling pathways and exhibit a broad range of biological responses including inflammation, gene expression, cell proliferation or apoptosis. The biological effects of oxidized LDL are related to the presence of peroxidation products such as hydroperoxides, lysophosphatidylcholines, oxysterols and aldehydes.4-Hydroxynonenal (HNE) is one of the most abundant aldehydes formed during the oxidation of polyunsaturated fatty acids in LDL and in membranes. It is able to react with thiols and free amino group residues of proteins. HNE is involved in apoB modifications that alter LDL metabolism and cell protein-adduct formation which may mediate in part the biological effects of oxidized LDL. We report here that HNE delivered to cells by oxidized LDL reacts with cellular proteins, for instance with tyrosine kinase receptors (RTK) such as EGFR and PDGFR. HNE induces in vitro derivatization and tyrosine phosphorylation of RTK (the fine molecular mechanism and conformational changes remain to be elucidated). In intact living cells, oxidized LDL (and pure HNE) trigger HNE-adduct formation and activation of PDGFR and EGFR, through an antioxidant-insensitive and reactive oxygen species independent mechanism. The presence of HNE-PDGFR adducts in atherosclerotic areas lead one to hypothesize that oxidized lipids may also react in vivo with membrane RTK, thereby disturbing their cellular functions.

  • Cholesteryl ester oxidation products in atherosclerosis.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Norbert Leitinger

    Lipid oxidation products are formed at sites of increased oxidant stress and have been shown to accumulate in atherosclerotic lesions. Although recent studies have focused on the formation and metabolism of oxidized lipids, very little is known about their biological activities and possible (patho)physiological functions. Oxidation of cholesteryl esters containing unsaturated fatty acids leads to the formation of hydroperoxides that are either reduced to alcohols or degrade into biologically active "core-aldehydes". In this review, the mechanisms of formation and metabolic fate of oxidized cholesteryl esters, their occurrence, as well as possible biological activities are discussed. Based on the current knowledge, cholesteryl ester oxidation leads to the formation of biologically active substances, which could actively contribute to the progression of atherosclerotic lesions and their resulting complications.

  • 4-hydroxynonenal triggers multistep signal transduction cascades for suppression of cellular functions.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Izumi Nakashima,Wei Liu,Anwarul A Akhand,Kozue Takeda,Yoshiyuki Kawamoto,Masashi Kato,Haruhiko Suzuki

    4-hydroxynonenal (HNE), an aldehyde product of membrane lipid peroxidation, has been suggested to mediate a number of oxidative stress-linked pathological events in humans, including cellular growth inhibition and apoptosis induction. Because HNE is potentially reactive to a number of both cell surface and intracellular proteins bearing sulfhydryl, amino and imidazole groups, it seems that there are multiple signal transduction cascades. Here we briefly review the HNE-triggered signal transduction cascades that lead to suppression of cellular functions and to cell death, based mainly on our own recent study results. We first showed that formation of HNE-cell surface protein adducts, which mimicked ligand-cell surface receptor binding, induced activation of receptor-type protein tyrosine kinases such as epithelial growth factor receptor (EGFR) and that this caused growth inhibition through a cascade of activation of EGFR, Shc and ERK. Next, we showed that HNE-mediated scavenging of cellular glutathione led to activation of caspases and to DNA fragmentation through a Fas-independent and mitochondria-linked pro-apoptotic signal pathway. More recently, we have obtained evidence that the HNE-triggered signal cascade for caspase activation encounters complex positive feedback regulatory mechanisms that are linked to the inhibition of anti-apoptotic signals and are dependent on caspase activity. Underlying multiple regulatory mechanisms, including mechanisms of activation of Akt-dephosphorylating PP2A activity, activities of protein tyrosine kinases have been shown to be biphasically controlled by HNE. In addition, we have obtained results suggesting that HNE inhibits phosphorylation of IkappaB, possibly by targeting some elements upstream of IkappaB, which might downregulate the NF-kappaB-mediated cellular responses, including serum deprivation-induced iNOS expression and generation of anti-apoptotic signals. These results suggest that HNE reacts with multiple cell surface and intracellular sites for triggering a network of signal transduction that is ultimately focused on suppression of cellular functions.

  • Role of 4-hydroxynonenal in stress-mediated apoptosis signaling.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Yogesh C Awasthi,Rajendra Sharma,J Z Cheng,Yusong Yang,Abha Sharma,Sharad S Singhal,Sanjay Awasthi

    In this mini review we summarize recent studies from our laboratory, which show the involvement of 4-hydroxynonenal (4-HNE) in cell cycle signaling. We demonstrate 4-HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase and caspase-3 activation. Cells exposed to mild, transient, heat or oxidative stress acquire capacity to exclude intracellular 4-HNE at a faster rate by inducing hGST5.8 which conjugate 4-HNE to GSH, and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4-HNE. The cells preconditioned with mild transient stress acquire resistance to H(2)O(2) and 4-HNE induced apoptosis by excluding intracellular 4-HNE at an accelerated pace. Furthermore, a decrease in intracellular concentration of 4-HNE achieved by transfecting cells with mGSTA4-4 or hGSTA4-4 results in a faster growth rate. These studies strongly suggest a role of 4-HNE in stress mediated signaling.

  • 4-hydroxy-2-nonenal as a COX-2 inducer.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Koji Uchida,Takeshi Kumagai

    4-hydroxy-2-nonenal (HNE) activates a variety of signaling pathways. We have recently evaluated the effect of oxidized fatty acid metabolites on cyclooxygenase-2 (COX-2) induction in rat liver epithelial RL34 cells and found that, among the compounds tested, HNE most dramatically induced COX-2. A p38 mitogen-activated protein kinase (p38 MAPK) pathway has been shown to play a key role in the mechanism of the HNE-induced COX-2 expression. It appears that the HNE-induced activation of p38 MAPK leads to the stabilization of COX-2 mRNA.

  • Role of PKC-dependent pathways in HNE-induced cell protein transport and secretion.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Umberto Maria Marinari,Mariapaola Nitti,Maria Adelaide Pronzato,Cinzia Domenicotti

    The beta isoforms of protein Kinase C (PKC) are closely involved in the regulation of cell protein transport and secretion. We have shown in different cellular types that treatment with HNE in a concentration range detectable in many pathophysiological conditions is able to induce selective activation of betaPKCs through direct interaction between the aldehyde and these isoenzymes. In isolated rat hepatocytes this specific isoenzyme activation plays a key role in the transport of procathepsin D from the trans-Golgi network to the endosomal-lysosomal compartment and in the exocytosis of mature cathepsin D. In NT2 neurons, HNE-mediated betaPKC activation induces an increase in intracellular amyloid beta production, without affecting full-length amyloid precursor protein expression. In a mouse macrophage-like cell line, the same beta isoform activation increases the release of the MCP-1 chemokine. Thus, pathophysiological HNE concentrations (0.1-1 microM) derived from a slight imbalance of the redox state are able to alter protein trafficking through beta PKC activation. These results suggest that mild oxidative stress and the PKC signal transduction pathway are closely involved in the pathophysiology of many diseases caused by changes in protein trafficking and release.

  • The proteasomal system and HNE-modified proteins.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Tilman Grune,Kelvin J A Davies

    Metabolic processes and environmental conditions cause the constant formation of oxidizing species over the lifetime of cells and organisms. This leads to a continuous oxidation of intracellular components, including lipids, DNA and proteins. During the extensively studied process of lipid peroxidation, several reactive low-molecular weight products are formed, including reactive aldehydes as 4-hydroxynonenal (HNE). These aldehydic lipid peroxidation products in turn are able to modify proteins. The degradation of oxidized and oxidatively modified proteins is an essential part of the oxidant defenses of cells. The major proteolytic system responsible for the removal of oxidized cytosolic and nuclear proteins is the proteasomal system. The proteasomal system by itself is a multicomponent system responsible for the degradation of the majority of intracellular proteins. It has been shown that some, mildly cross-linked, HNE-modified proteins are preferentially degraded by the proteasome, but extensive modification with this cross-linking aldehyde leads to the formation of protein aggregates, that can actually inhibit the proteasome. This review summarizes our knowledge of the interactions between lipid peroxidation products, proteins, and the proteasomal system.

  • HNE--signaling pathways leading to its elimination.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Henry Jay Forman,Dale A Dickinson,Karen E Iles

    The oxidation of polyunsaturated fatty acids results in the production of HNE, which can react through both non-enzymatic and enzyme catalyzed reactions to modify a number of cellular components, including proteins and DNA. Multiple pathways for its enzyme catalyzed elimination include oxidation of the aldehyde to a carboxylic acid, reduction of the aldehyde to an alcohol, and conjugation of the carbon-carbon double bond to glutathione (GSH). Interestingly, the enzymes that result in HNE elimination are induced by HNE itself although the chemical mechanism for signaling is not well understood. One of the striking effects of HNE is that after a transient decrease in GSH, synthesis of GSH is elevated through induction of glutamate cysteine ligase (GCL), which catalyzes the first step in de novo synthesis of GSH. GCL has two subunits, which are transcriptionally regulated by a wide variety of agents, including oxidants and electrophiles, such as HNE, which elevates both. The transcriptional regulation of GCL has been the subject of many investigations yielding a complex picture in which the pathways for up-regulation of the subunits appear to be independent and vary with inducing agent and cell type. We have found that in human bronchial epithelial cells, HNE acts through AP-1 activation with signaling through the JNK pathway, and that neither the ERK nor p38(MAPK) pathways is involved. With these results we review what is currently known about the signaling mechanisms for removal of HNE, focusing principally on conjugation mechanisms involving GSH.

  • Fate of 4-hydroxynonenal in vivo: disposition and metabolic pathways.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Jacques Alary,Françoise Guéraud,Jean-Pierre Cravedi

    Due to the cytotoxicity of 4-hydroxynonenal (HNE), and to the fact that this major product of lipid peroxidation is a rather long-living compound compared with reactive oxygen species, the capability of organisms to inactivate and eliminate HNE has received increasing attention during the last decade. Several recent in vivo studies have addressed the issue of the diffusion, kinetics, biotransformation and excretion of HNE. Part of these studies are primarily concerned with the toxicological significance of HNE biotransformation and more precisely with the metabolic pathways by which HNE is inactivated and eliminated. The other aim of in vivo metabolic study is the characterisation of end-metabolites, especially in urine, in order to develop specific and non-invasive biomarkers of lipid peroxidation. When HNE is administered intravenously or intraperitoneally, it is mainly excreted into urine and bile as conjugated metabolites, in a proportion that is dependent on the administration route. However, biliary metabolites undergo an enterohepatic cycle that limits the final excretion of faecal metabolites. Only a very low amount of metabolites is found to be bound to macromolecules. The main urinary metabolites are represented by two groups of compounds. One comes from the mercapturic acid formation from (i) 1,4 dihydroxynonene-glutathione (DHN-GSH) which originates from the conjugation of HNE with GSH by glutathione-S-transferases and the subsequent reduction of the aldehyde by a member of aldo-keto reductase superfamily; (ii) the lactone of 4-hydroxynonanoic-GSH (HNA-lactone-GSH) which originates from the conjugation of HNE followed by the oxidation of the aldehyde by aldehyde dehydrogenase; (iii) HNA-GSH which originates from the hydrolysis of the corresponding lactone. The other one is a group of metabolites issuing from the omega-hydroxylation of HNA or HNA-lactone by cytochromes P450 4A, followed eventually, in the case of omega-oxidized-HNA-lactone, by conjugation with GSH and subsequent mercapturic acid formation. Biliary metabolites are GSH or mercapturic acid conjugates of DHN, HNE and HNA. Stereochemical aspects of HNE metabolism are also discussed.

  • Intracellular metabolism of 4-hydroxynonenal.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Werner Siems,Tilman Grune

    4-hydroxynonenal (HNE) is a major aldehydic product of lipid peroxidation known to exert a multitude of biological, cytotoxic, and signal effects. Mammalian cells possess highly active pathways of HNE metabolism. The metabolic fate of HNE was investigated in various mammalian cells and organs such as hepatocytes, intestinal enterocytes, renal tubular cells, aortic and brain endothelial cells, synovial fibroblasts, neutrophils, thymocytes, heart, and tumor cells. The experiments were carried out at 37 degrees C at initial HNE concentrations between 1 microM--that means in the range of physiological and pathophysiologically relevant HNE levels--to 100 microM. In all cell types which were investigated, 90-95% of 100 microM HNE were degraded within 3 min of incubation. At 1 microM HNE the physiological blood serum level of about 0.1-0.2 microM was restored already after 10-30 s. As primary products of HNE in hepatocytes and other cell types the glutathione-HNE-1:1-conjugate, the hydroxynonenoic acid and the corresponding alcohol of HNE, the 1,4-dihydroxynonene, were identified. Furthermore, the beta-oxidation of hydroxynonenoic acid including the formation of water was demonstrated. The quantitative share of HNE binding to proteins was low with about 2-8% of total HNE consumption. The glycine-cysteine-HNE, cysteine-HNE adducts and the mercapturic acid from glutathione-HNE adduct were not formed in the most cell types, but in kidney cells and neutrophils. The rapid metabolism underlines the role of HNE degrading pathways in mammalian cells as important part of the secondary antioxidative defense mechanisms in order to protect proteins from modification by aldehydic lipid peroxidation products.

  • Genotoxicity of HNE.
    Mol. Aspects Med. (IF 8.313) Pub Date : 2003-08-02
    Peter M Eckl

    Since previous investigations on the genotoxicity of 4-hydroxynonenal (HNE) were carried out with prokaryotic systems or eukaryotic cell lines which may not adequately reflect the response of cells in vivo due to differences in the metabolism, the genotoxic potential of HNE was further evaluated in primary cells (hepatocytes) and cell clones of cerebral endothelial cells expressing specific functions, i.e. blood-brain barrier (BBB) and capillary formation associated phenotypes. Treatment of hepatocytes with HNE induced statistically significant levels of SCE at concentrations >/=0.1 microM, micronuclei at concentrations >/=1 microM and chromosomal aberrations at a concentration of 10 microM. Treatment of cloned cerebral microvascular endothelial cells induced significantly elevated levels of chromosomal aberrations at concentrations >/=1 microM and micronuclei at concentrations >/=10 microM in both cEC phenotypes, compared to the controls. Additionally, cytotoxicity was observed at a concentration of 50 microM HNE and was significantly higher in type II cells. These results indicate that cells expressing differentiated functions representative for the in vivo situation react more sensitive to HNE than cell lines, and may reflect the sensitivity of the target cells. The different response with respect to the endpoints of genotoxicity tested most probably depends on the different metabolizing capacities and thus the action of different metabolites of HNE.

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上海纽约大学William Glover