A 2015 survey of established or potential epigenetic biomarkers for the accurate detection of human cancers

Context The silencing or activation of cancer-associated genes by epigenetic mechanisms can ultimately lead to the clonal expansion of cancer cells. Objective The aim of this review is to summarize all relevant epigenetic biomarkers that have been proposed to date for the diagnosis of some prevalent human cancers. Methods A Medline search for the terms epigenetic biomarkers, human cancers, DNA methylation, histone modifications and microRNAs was performed. Results One hundred fifty-seven relevant publications were found and reviewed. Conclusion To date, a significant number of potential epigenetic cancer biomarkers of human cancer have been investigated, and some have advanced to clinical implementation.     

Minireview: Constitutively Active G Protein-Coupled Receptors: Potential Mechanisms of Receptor Activation

Abstract

Mutations of G protein-coupled receptors can increase their constitutive (agonist-independent) activity. Some of these mutations have been artificially introduced by site-directed mutagenesis, others occur spontaneously in human diseases. The analysis of the constitutively active G protein-coupled receptors has provided important informations about the molecular mechanisms underlying receptor activation and drug action.     

Transcriptome-based identification of new anti-anti-inflammatory and vasodilating properties of the n-3 fatty acid docosahexaenoic acid in vascular endothelial cell under proinflammatory conditions

ScopeHigh intakes of n-3 fatty acids exert anti-inflammatory effects and cardiovascular protection, but the underlying molecular basis is incompletely defined. By genome-wide analysis we searched for novel effects of docosahexaenoic acid (DHA) on gene expression and pathways in human vascular endothelium under pro-inflammatory conditions.ConclusionsEndothelial exposure to DHA regulates novel genes and related pathways. Such unbiased identification should increase our understanding of mechanisms by which n-3 fatty acids affect human diseases.     

Plasma membrane redox system protects cells against oxidative stress

Abstract

Aerobic organisms have developed defensive systems to survive in the presence of oxygen and its highly reactive species (ROS). The cellular mechanisms of protection against oxidative injury include: (i) specific enzymes, such as catalase, glutathione peroxidase and superoxide dismutase; (ii) small hydrophilic molecules, such as ascorbate, glutathione and uric acid; and (iii) hydrophobic agents, such as ubiquinone and α-tocopherol in membranes.¹ Among these, coenzyme Q (CoQ) is the only lipid-soluble antioxidant that can be synthesized in all organisms so far studied.     

Haemoglobinopathies and resistance to malaria

The haemoglobinopathies have a celebrated role in the study of human genetics as the first examples of balanced polymorphisms described in human populations. Over the last 50 years, considerable evidence has been provided to show that these traits do confer protection from malaria. More recently, the underlying mechanisms of protection have been examined. This short review summarizes these studies and where possible shows how the putative mechanisms of protection may be linked to redox processes.     

Glycomics and glycoproteomics focused on aging and age-related diseases — Glycans as a potential biomarker for physiological alterations

BackgroundSince glycosylation depends on glycosyltransferases, glycosidases, and sugar nucleotide donors, it is susceptible to the changes associated with physiological and pathological conditions. Therefore, alterations in glycan structures may be good targets and biomarkers for monitoring health conditions. Since human aging and longevity are affected by genetic and environmental factors such as diseases, lifestyle, and social factors, a scale that reflects various environmental factors is required in the study of human aging and longevity.Scope of reviewWe herein focus on glycosylation changes elucidated by glycomic and glycoproteomic studies on aging, longevity, and age-related diseases including cognitive impairment, diabetes mellitus, and frailty. We also consider the potential of glycan structures as biomarkers and/or targets for monitoring physiological and pathophysiological changes.Major conclusionsGlycan structures are altered in age-related diseases. These glycans and glycoproteins may be involved in the pathophysiology of these diseases and, thus, be useful diagnostic markers. Age-dependent changes in N-glycans have been reported previously in cohort studies, and characteristic N-glycans in extreme longevity have been proposed. These findings may lead to a deeper understanding of the mechanisms underlying aging as well as the factors influencing longevity.General significanceAlterations in glycosylation may be good targets and biomarkers for monitoring health conditions, and be applicable to studies on age-related diseases and healthy aging. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.     

Effects of boron-containing compounds in the fungal kingdom

BackgroundThe number of known boron-containing compounds (BCCs) is increasing due to their identification in nature and innovative synthesis procedures. Their effects on the fungal kingdom are interesting, and some of their mechanisms of action have recently been elucidated.MethodsIn this review, scientific reports from relevant chemistry and biomedical databases were collected and analyzed.ResultsIt is notable that several BCC actions in fungi induce social and economic benefits for humans. In fact, boric acid was traditionally used for multiple purposes, but some novel synthetic BCCs are effective antifungal agents, particularly in their action against pathogen species, and some were recently approved for use in humans. Moreover, most reports testing BCCs in fungal species suggest a limiting effect of these compounds on some vital reactions.ConclusionsNew BCCs have been synthesized and tested for innovative technological and biomedical emerging applications, and new interest is developing for discovering new strategic compounds that can act as environmental or wood protectors, as well as antimycotic agents that let us improve food acquisition and control some human infections.     

Polarity of mutations in tumor-associated microsatellite instability

Many factors have been implicated in influencing the rate of microsatellite mutations, including the length and base composition of the repeat motif, number of repeats, base composition of flanking sequences and, perhaps most importantly, degree of perfection of the repeats. The latter is of clinical relevance, since in both spino-cerebellar ataxia and fragile X syndrome, alleles with imperfect repeats appear to be much more stable than perfect ones. As yet, the relative importance of increased replication slippage and decreased mismatch repair efficiency in the preference of mutations to occur within perfect repeats has not been fully determined. D13S308E is an asymmetric trinucleotide repeat microsatellite with the sequence (CAT)₃CAC(CAT)CAC(CAT)₂CAC(CAT)CAC(CAT) ₁₅ , thus containing two parts: an 11-repeat imperfect portion (underlined above) and a 15-repeat perfect one (bold). We sequenced eight new mutant alleles of D13S308E from three human gastric tumors with instability in this and other microsatellites. In all mutations the size variation occurred exclusively in the perfect part of the microsatellite. These results constitute direct evidence that the molecular basis of microsatellite alterations seen in normal cells is similar to those that occur in human tumors with extensive microsatellite instability. The investigation of mechanisms involved in microsatellite mutations has been handicapped by the fact that they are rare events. The microsatellite instability observed in malignant tumors provides us with a useful general system to study these mechanisms. Received: 24 June 1997 / Accepted 7 October 1997     

低温在脊髓损伤治疗中应用的研究进展

脊髓损伤多由高空坠落、车祸、运动冲击等原因引起,是脊柱外科的一种常见疾病,至今仍是一个治疗难题。低温疗法是一种重要的物理治疗手段,以多种机制减少脊髓损伤后有害因素的产生,是一种有效的脊髓保护途径。其在脊髓损伤的研究中表现出很好的效果,为脊髓损伤的治疗提供了新的思路,然而也发现一些低温治疗导致的全身性或某些系统为主的不良影响,需要我们进一步研究和解决,以期达到更好的治疗效果。本文就低温治疗用于脊髓损伤应用中的研究进展进行综述。     

Nm23-H1 regulates the proliferation and differentiation of the human chronic myeloid leukemia K562 cell line: A functional proteomics study

AimsNm23-H1 is a suppressor of metastasis that has been implicated in the regulation of proliferation and differentiation of hematopoietic cells, although specific mechanisms for Nm23-H1 have not been well-characterized. Our study is designed to further elucidate the role of Nm23-H1 in the human chronic myeloid leukemia K562 cell line.Main methodsIn this study we generated and selected two cell clone pools of human chronic myeloid leukemia K562 cells with up-regulated and down-regulated Nm23-H1 expression.Key findingsOur data show that knockdown of Nm23-H1 decreased proliferation and increased the percentage of cells arrested in the G0/G1 phase of the cell cycle. Correspondingly, K562 cells overexpressing Nm23-H1 were more proliferative. After treatment of these two cell types with phorbol 12-myristate 13-acetate (PMA) for 48 h, cells with reduced Nm23-H1 expression had a higher percentage of 8N ploidy and higher expression of CD41 than K562 cells overexpressing Nm23-H1. A functional proteomics analysis identified ten proteins, including ANP32A, Cdc42GAP, and the isoform 2 of SET, whose expression levels were significantly altered by down-regulation of Nm23-H1. In addition, cells with decreased levels of Nm23-H1 had significantly reduced expression of Cdc42 independent of treatment with PMA. The interaction of the endogenous Nm23-H1 and Cdc42 proteins has been further validated by reciprocal immunoprecipitations.SignificanceWe provide data that complement functional studies of Nm23-H1 in regulating hematopoietic cells, and address action mechanisms of Nm23-H1 that have not previously been reported.     

Sex and Life Expectancy

BackgroundA sexual dimorphism in human life expectancy has existed in almost every country for as long as records have been kept. Although human life expectancy has increased each year, females still live longer, on average, than males. Undoubtedly, the reasons for the sex gap in life expectancy are multifaceted, and it has been discussed from both sociological and biological perspectives. However, even if biological factors make up only a small percentage of the determinants of the sex difference in this phenomenon, parity in average life expectancy should not be anticipated.ObjectiveThe aim of this review is to highlight biological mechanisms that may underlie the sexual dimorphism in life expectancy.MethodsUsing PubMed, ISI Web of Knowledge, and Google Scholar, as well as cited and citing reference histories of articles through August 2012, English-language articles were identified, read, and synthesized into categories that could account for biological sex differences in human life expectancy.ResultsThe examination of biological mechanisms accounting for the female-based advantage in human life expectancy has been an active area of inquiry; however, it is still difficult to prove the relative importance of any 1 factor. Nonetheless, biological differences between the sexes do exist and include differences in genetic and physiological factors such as progressive skewing of X chromosome inactivation, telomere attrition, mitochondrial inheritance, hormonal and cellular responses to stress, immune function, and metabolic substrate handling among others. These factors may account for at least a part of the female advantage in human life expectancy.ConclusionsDespite noted gaps in sex equality, higher body fat percentages and lower physical activity levels globally at all ages, a sex-based gap in life expectancy exists in nearly every country for which data exist. There are several biological mechanisms that may contribute to explaining why females live longer than men on average, but the complexity of the human life experience makes research examining the contribution of any single factor for the female advantage difficult. However, this information may still prove important to the development of strategies for healthy aging in both sexes.     

Protection against chemotherapy- and radiotherapy-induced side effects: A review based on the mechanisms and therapeutic opportunities of phytochemicals

BackgroundAlthough great achievements have been made in the field of cancer therapy, chemotherapy and radiotherapy remain the mainstay cancer therapeutic modalities. However, they are associated with various side effects, including cardiocytotoxicity, nephrotoxicity, myelosuppression, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, mucositis, and alopecia, which severely affect the quality of life of cancer patients. Plants harbor a great chemical diversity and flexible biological properties that are well-compatible with their use as adjuvant therapy in reducing the side effects of cancer therapy.PurposeThis review aimed to comprehensively summarize the molecular mechanisms by which phytochemicals ameliorate the side effects of cancer therapies and their potential clinical applications.MethodsWe obtained information from PubMed, Science Direct, Web of Science, and Google scholar, and introduced the molecular mechanisms by which chemotherapeutic drugs and irradiation induce toxic side effects. Accordingly, we summarized the underlying mechanisms of representative phytochemicals in reducing these side effects.ResultsRepresentative phytochemicals exhibit a great potential in reducing the side effects of chemotherapy and radiotherapy due to their broad range of biological activities, including antioxidation, antimutagenesis, anti-inflammation, myeloprotection, and immunomodulation. However, since a majority of the phytochemicals have only been subjected to preclinical studies, clinical trials are imperative to comprehensively evaluate their therapeutic values.ConclusionThis review highlights that phytochemicals have interesting properties in relieving the side effects of chemotherapy and radiotherapy. Future studies are required to explore the clinical benefits of these phytochemicals for exploitation in chemotherapy and radiotherapy.     

Kinetic and docking studies of cytosolic/tumor-associated carbonic anhydrase isozymes I,II and IX with some hydroxylic compounds

A series of hydroxylic compounds (1–10, NK-154 and NK-168) have been assayed for the inhibition of three physiologically relevant carbonic anhydrase isozymes, the cytosolic isozymes I, II and tumor-associated isozyme IX. The investigated compounds showed inhibition constants in the range of 0.068–4003, 0.012–9.9 and 0.025–115?μm at the hCA I, hCA II and hCA IX enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are calculated using scoring algorithms, namely Glide/induced fit docking. The inhibitory potencies of the novel compounds were analyzed at the human isoforms hCA I, hCA II and hCA IX as targets and the K_I values were calculated.     

Molybdenum-containing nitrite reductases: Spectroscopic characterization and redox mechanism

Objectives: This review summarizes the spectroscopic results, which will provide useful suggestions for future research. In addition, the fields that urgently need more information are also advised.

Background: Nitrite-NO-cGMP has been considered as an important signaling pathway of NO in human cells. To date, all the four known human molybdenum-containing enzymes, xanthine oxidase, aldehyde oxidase, sulfite oxidase, and mitochondrial amidoxime-reducing component, have been shown to function as nitrite reductases under hypoxia by biochemical, cellular, or animal studies. Various spectroscopic techniques have been applied to investigate the structure and catalytic mechanism of these enzymes for more than 20 years.

Methods: We summarize the published data on the applications of UV-vis and EPR spectroscopies, and X-ray crystallography in studying nitrite reductase activity of the four human molybdenum-containing enzymes.

Results: UV-vis has provided useful information on the redox active centers of these enzymes. The utilization of EPR spectroscopy has been critical in determining the coordination and redox status of the Mo center during catalysis. Despite the lack of substrate-bound crystal structures of these nitrite reductases, valuable structural information has been obtained by X-ray crystallography.

Conclusions: To fully understand the catalytic mechanisms of these physiologically/pathologically important nitrite reductases, structural studies on substrate-redox center interaction are needed.     

Composition Profile of the Human Genome at the Chromosome Level

Abstract

The compositional properties of the human genome have been extensively studied. These analyses focused mainly in isochores. With the availability of the human genome and several molecular techniques, new studies were performed, showing that nucleotide composition is related to three processes: gene expression, replication and recombination. Nevertheless, these studies usually focused on regions at the sub-chromosomal level. Here we study the compositional differences among chromosomes, considering structural and functional aspects using the chromosomes as the units of analysis. We show that: i) chromosomes are compositionally consistent units; ii) there exists a correlation between their GC content and size and location within the nucleus, and iii) the three processes mentioned above are linked to compositional properties at the chromosomal level. These results support the existence of a link between composition and spatial/structural/functional features of entire chromosomes. The Evolutionary mechanisms and forces underlying these patterns remain open questions.     

Oxidation of glycosaminoglycans by free radicals and reactive oxidative species: A review of investigative methods

Abstract

Glycosaminoglycans, in particular hyaluronan (HA), and proteoglycans are components of the extracellular matrix (ECM). The ECM plays a key role in the regulation of cellular behaviour and alterations to it can modulate both the development of human diseases as well as controlling normal biochemical processes such as cell signalling and pro-inflammatory responses. For these reasons, in vitro fragmentation studies of glycosaminoglycans by free radicals and oxidative species are seen to be relevant to the understanding of in vivo studies of damage to the ECM. A wide range of investigative techniques have therefore been applied to gain insights into the relative fragmentation effects of several reactive oxidative species with the ultimate goal of determining mechanisms of fragmentation at the molecular level. These methods are reviewed here.     

Clinical significance of Verocytotoxin-producing Escherichia coli O157

In 1977, Konowalchuk and colleagues (Konowalchuk, J., Speirs, J.I. & Stavric, S. 1977 Infection and Immunity 18, 775–779) were the first to describe Verocytotoxin-producing strains of Escherichia coli or VTEC. The surveillance of infection caused by VTEC demonstrated strains of E. coli belonging to serogroup O157 as the main cause of human infection capable of causing haemorrhagic colitis (HC) and haemolytic uraemic syndrome (HUS). Infection with O157 VTEC results in a range of disease manifestations including abdominal cramps, vomiting and fever. This frequently leads to cases with bloody diarrhoea and HC, and approximately 10% of patients develop HUS. The symptoms of disease caused by VTEC O157 have been well documented and the pathogenic mechanisms expressed by VTEC have been the focus of considerable attention. However, the role of putative pathogenic mechanisms in the pathogenesis of disease is not fully understood. The aim of this review is to consider the clinical aspects of infection with strains of VT-producing E. coli O157 in terms of the putative pathogenic mechanisms expressed by these bacteria. This revised version was published online in November 2006 with corrections to the Cover Date.     

Nucleosides VIII: 1 Synthesis of 2′, 3′-Dideoxy- and 2′, 3′-Didehydro-2′, 3′-Di Deoxyisoguanosine as Potential Antiretroviral Agents

Abstract

2′, 3′-Didehydro-2′, 3′-dideoxyisoguanosine (2) and 2′, 3′- dideoxyisoguanosine (3) have been synthesized by utilizing the Corey-Winter approach starting from isoguanosine. The 6-amino and 5′-hydroxy biprotected isoguanosine derivative was converted to the corresponding 2′, 3′- thionocarbonate, which was heated with triethyl phosphite to afford the 2′,3′- olefinic product. Either a tert-butyldimethylsilyl or a 4, 4′-dimethoxytrityl group was used in the protection of 5′-hydroxy function. Compounds 2 and 3 were found inactive against human immunodeficiency virus (HIV), human cytomegalovirus (HCMV), and herpes simplex virus type 1 (HSV-1).

     

Beyond PM2.5: The role of ultrafine particles on adverse health effects of air pollution

BackgroundAir pollution constitutes the major threat to human health, whereas their adverse impacts and underlying mechanisms of different particular matters are not clearly defined.Scope of reviewUltrafine particles (UFPs) are high related to the anthropogenic emission sources, i.e. combustion engines and power plants. Their composition, source, typical characters, oxidative effects, potential exposure routes and health risks were thoroughly reviewed.Major conclusionsUFPs play a major role in adverse impacts on human health and require further investigations in future toxicological research of air pollution.General significanceUnlike PM_2.5, UFPs may have much more impacts on human health considering loads of evidences emerging from particulate matters and nanotoxicology research fields. The knowledge of nanotoxicology contributes to the understanding of toxicity mechanisms of airborne UFPs in air pollution. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.