Toxicoproteomics in human health and disease: an update

Introduction: Toxicoproteomics is an emerging area of omics, intended to explore the changes in protein expression and modifications in biological samples exposed to toxicants. The development of techniques that utilize sophisticated instruments in proteomics has facilitated the exploration of a wide-range of protein coverage and assisted the quantitative and qualitative evaluation of protein changes as a result of the toxic effects of toxic substances.

Areas covered: Studies on toxicoproteomics have an immense potential to explore the molecular mechanism of action of a variety of toxic substances through deciphering the proteomic map altered as a result of toxicant exposure. Here, we provide an overview of toxicoproteomic approaches and the current paradigm of toxicoproteomics.

Expert commentary: Research in this area continues to increase our understanding of the role of toxicants in worsening human health and toxicity driven diseases. The progress in toxicoproteomics may realize the development of novel biomarkers, drug targets and personalized medicines by incorporating the advanced proteomic applications in this field.     

唾液酸生物学与人类健康和疾病

唾液酸（sialicacid）是一类酸性九碳单糖,是所有神经氨酸或酮基一脱氧壬酮糖酸（KDN）的N-或O-衍生物的总称。唾液酸作为复合糖的组成部分镶嵌于所有细胞表面以及人多数脊椎动物糖蛋白和糖脂分予的末端最外侧。唾液酸家族成员已经达到五十多个,其分子结构多样,在生物体内分布广泛。唾液酸介导或调制了发育、炎症、病原感染、肿瘤发生发展等诸多生理和病理过程,与人类健康和疾病密切关联。对唾液酸生物学的研究已成为糖生物学研究的热点之一。对唾液酸与人类健康与疾病研究的新进展做一综述。     

tRNA fragments in human health and disease

Transfer RNA (tRNA) is traditionally considered to be an adaptor molecule that helps ribosomes to decode messenger RNA (mRNA) and synthesize protein. Recent studies have demonstrated that tRNAs also serve as a major source of small non-coding RNAs that possess distinct and varied functions. These tRNA fragments are heterogeneous in size, nucleotide composition, biogenesis and function. Here we describe multiple roles that tRNA fragments play in cell physiology and discuss their relevance to human health and disease.     

Sialic acids in human health and disease

The surfaces of all vertebrate cells are decorated with a dense and complex array of sugar chains, which are mostly attached to proteins and lipids. Most soluble secreted proteins are also similarly decorated with such glycans. Sialic acids are a diverse family of sugar units with a nine-carbon backbone that are typically found attached to the outermost ends of these chains. Given their location and ubiquitous distribution, sialic acids can mediate or modulate a wide variety of physiological and pathological processes. This review considers some examples of their established and newly emerging roles in aspects of human physiology and disease.     

Probiotics in human health and disease: from nutribiotics to pharmabiotics

Probiotics are the most useful tools for balancing the gut microbiota and thereby influencing human health and disease. Probiotics have a range of effects, from those on nutritional status to medical conditions throughout the body from the gut to non-intestinal body sites such as the brain and skin. Research interest in probiotics with nutritive claims (categorized as nutribiotics) has evolved into interest in therapeutic and pharmacological probiotics with health claims (pharmabiotics). The concept of pharmabiotics emerged only two decades ago, and the new categorization of probiotics to nutribiotics and pharmabiotics was recently suggested, which are under the different regulation depending on that they are food or drug. Information of the gut microbiome has been continuously accumulating, which will make possible the gut microbiome-based healthcare in the future, when nutribiotics show potential for maintaining health while pharmabiotics are effective therapeutic tools for human diseases. This review describes the current understanding in the conceptualization and classification of probiotics. Here, we reviewed probiotics as nutribiotics with nutritional functions and pharmabiotics with pharmaceutic functions in different diseases.     

Mitochondrial creatine kinase in human health and disease

Mitochondrial creatine kinase (MtCK), together with cytosolic creatine kinase isoenzymes and the highly diffusible CK reaction product, phosphocreatine, provide a temporal and spatial energy buffer to maintain cellular energy homeostasis. Mitochondrial proteolipid complexes containing MtCK form microcompartments that are involved in channeling energy in form of phosphocreatine rather than ATP into the cytosol. Under situations of compromised cellular energy state, which are often linked to ischemia, oxidative stress and calcium overload, two characteristics of mitochondrial creatine kinase are particularly relevant: its exquisite susceptibility to oxidative modifications and the compensatory up-regulation of its gene expression, in some cases leading to accumulation of crystalline MtCK inclusion bodies in mitochondria that are the clinical hallmarks for mitochondrial cytopathies. Both of these events may either impair or reinforce, respectively, the functions of mitochondrial MtCK complexes in cellular energy supply and protection of mitochondria form the so-called permeability transition leading to apoptosis or necrosis.     

The human secretome atlas initiative: Implications in health and disease conditions

Proteomic analysis of human body fluids is highly challenging, therefore many researchers are redirecting efforts toward secretome profiling. The goal is to define potential biomarkers and therapeutic targets in the secretome that can be traced back in accessible human body fluids. However, currently there is a lack of secretome profiles of normal human primary cells making it difficult to assess the biological meaning of current findings. In this study we sought to establish secretome profiles of human primary cells obtained from healthy donors with the goal of building a human secretome atlas. Such an atlas can be used as a reference for discovery of potential disease associated biomarkers and eventually novel therapeutic targets. As a preliminary study, secretome profiles were established for six different types of human primary cell cultures and checked for overlaps with the three major human body fluids including plasma, cerebrospinal fluid and urine. About 67% of the 1054 identified proteins in the secretome of these primary cells occurred in at least one body fluid. Furthermore, comparison of the secretome profiles of two human glioblastoma cell lines to this new human secretome atlas enabled unambiguous identification of potential brain tumor biomarkers. These biomarkers can be easily monitored in different body fluids using stable isotope labeled standard proteins. The long term goal of this study is to establish a comprehensive online human secretome atlas for future use as a reference for any disease related secretome study. This article is part of a Special Issue entitled: An Updated Secretome.     

Intestinal microbiota in human health and disease: the impact of probiotics

The complex communities of microorganisms that colonise the human gastrointestinal tract play an important role in human health. The development of culture-independent molecular techniques has provided new insights in the composition and diversity of the intestinal microbiota. Here, we summarise the present state of the art on the intestinal microbiota with specific attention for the application of high-throughput functional microbiomic approaches to determine the contribution of the intestinal microbiota to human health. Moreover, we review the association between dysbiosis of the microbiota and both intestinal and extra-intestinal diseases. Finally, we discuss the potential of probiotic microorganism to modulate the intestinal microbiota and thereby contribute to health and well-being. The effects of probiotic consumption on the intestinal microbiota are addressed, as well as the development of tailor-made probiotics designed for specific aberrations that are associated with microbial dysbiosis.     

The human mitochondrial replication fork in health and disease

Mitochondria are organelles whose main function is to generate power by oxidative phosphorylation. Some of the essential genes required for this energy production are encoded by the mitochondrial genome, a small circular double stranded DNA molecule. Human mtDNA is replicated by a specialized machinery distinct from the nuclear replisome. Defects in the mitochondrial replication machinery can lead to loss of genetic information by deletion and/or depletion of the mtDNA, which subsequently may cause disturbed oxidative phosphorylation and neuromuscular symptoms in patients. We discuss here the different components of the mitochondrial replication machinery and their role in disease. We also review the mode of mammalian mtDNA replication.     

The human microbiome: at the interface of health and disease

Interest in the role of the microbiome in human health has burgeoned over the past decade with the advent of new technologies for interrogating complex microbial communities. The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology. Deciphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community. Both the microbiome and metagenome probably have important functions in health and disease; their exploration is a frontier in human genetics.     

Mitochondrial protein import and human health and disease

The targeting and assembly of nuclear-encoded mitochondrial proteins are essential processes because the energy supply of humans is dependent upon the proper functioning of mitochondria. Defective import of mitochondrial proteins can arise from mutations in the targeting signals within precursor proteins, from mutations that disrupt the proper functioning of the import machinery, or from deficiencies in the chaperones involved in the proper folding and assembly of proteins once they are imported. Defects in these steps of import have been shown to lead to oxidative stress, neurodegenerative diseases, and metabolic disorders. In addition, protein import into mitochondria has been found to be a dynamically regulated process that varies in response to conditions such as oxidative stress, aging, drug treatment, and exercise. This review focuses on how mitochondrial protein import affects human health and disease.     

Troponin I phosphorylation in human myocardium in health and disease

Cardiac troponin I (cTnI) is well known as a biomarker for the diagnosis of myocardial damage. However, because of its central role in the regulation of contraction and relaxation in heart muscle, cTnI may also be a potential target for the treatment of heart failure. Studies in rodent models of cardiac disease and human heart samples showed altered phosphorylation at various sites on cTnI (i.e. site-specific phosphorylation). This is caused by altered expression and/or activity of kinases and phosphatases during heart failure development. It is not known whether these (transient) alterations in cTnI phosphorylation are beneficial or detrimental. Knowledge of the effects of site-specific cTnI phosphorylation on cardiomyocyte contractility is therefore of utmost importance for the development of new therapeutic strategies in patients with heart failure. In this review we focus on the role of cTnI phosphorylation in the healthy heart upon activation of the beta-adrenergic receptor pathway (as occurs during increased stress and exercise) and as a modulator of the Frank-Starling mechanism. Moreover, we provide an overview of recent studies which aimed to reveal the functional consequences of changes in cTnI phosphorylation in cardiac disease.     

DNA methylation 40 years later: Its role in human health and disease

A long path, initiated more than 40 years ago, has led to a deeper understanding of the complexity of gene regulation in eukaryotic genomes. In addition to genetic mechanisms, the imbalance in the epigenetic control of gene expression may profoundly alter the finely tuned machinery leading to gene regulation. Here, we review the impact of the studies on DNA methylation, the "primadonna" in the epigenetic scenario, on the understanding of basic phenomena, such as X inactivation and genomic imprinting. The effect of deregulation of DNA methylation on human health, will be also discussed. Finally, an attempt to predict future directions of this rapidly evolving field has been proposed, with the certainty that, fortunately, science is always better than predictions.     

Voluntary activation of the human diaphragm in health and disease

Intersubjectcomparison of the crural diaphragm electromyogram, as measured by anesophageal electrode, requires a reliable means for normalizing thesignal. The present study set out 1) to evaluate which voluntary respiratory maneuvers provide high andreproducible diaphragm electromyogram root-mean-square (RMS) values and2) to determine the relativediaphragm activation and mechanical and ventilatory outputs duringbreathing at rest in healthy subjects(n = 5), in patients with severechronic obstructive pulmonary disease (COPD,n = 5), and in restrictive patientswith prior polio infection (PPI, n = 6). In all groups, mean voluntary maximal RMS values were higher duringinspiration to total lung capacity than during sniff inhalation throughthe nose (P = 0.035, ANOVA). The RMS(percentage of voluntary maximal RMS) during quiet breathing was 8% inhealthy subjects, 43% in COPD patients, and 45% in PPI patients.Despite the large difference in relative RMS(P = 0.012), there were no differencesin mean transdiaphragmatic pressure (P = 0.977) and tidal volumes (P = 0.426). We conclude that voluntary maximal RMS is reliably obtainedduring an inspiration to total lung capacity but a sniff inhalationcould be a useful complementary maneuver. Severe COPD and PPI patientsbreathing at rest are characterized by increased diaphragm activationwith no change in diaphragm pressure generation.