-
Systems Biology in Reproductive Medicine Dec 2018Exposure to environmental stressors during susceptible windows of development can result in negative health outcomes later in life, a concept known as the Developmental... (Review)
Review
Exposure to environmental stressors during susceptible windows of development can result in negative health outcomes later in life, a concept known as the Developmental Origins of Health and Disease (DOHaD). There is a growing body of evidence that exposures to metals early in life (in utero and postnatal) increase the risk of developing adult diseases such as cancer, cardiovascular disease, non-alcoholic fatty liver disease, and diabetes. Of particular concern is exposure to the metalloid arsenic, a drinking water contaminant and worldwide health concern. Epidemiological studies of areas with high levels of arsenic in the drinking water, such as some regions in Chile and Bangladesh, indicate an association between in utero arsenic exposure and the development of adult diseases. Therefore, the need for experimental models to address the mechanism underlining early onset of adult diseases have emerged including the in utero and whole-life exposure models. This review will highlight the epidemiological events and subsequent novel experimental models implemented to study the impact of early life exposure to arsenic on the development of adult diseases. In addition, current research using these models will be discussed as well as possible underlying mechanism for the early onset of disease. Abbreviations: ALT: alanine aminotransferase; AMI: acute myocardial infarction; AST: aspartate aminotransferase; ATSDR: Agency for Toxic Substances and Disease Registry; CVD: cardiovascular disease; DMA: dimethylarsinate; DOHaD: Developmental Origins of Health and Disease; EPA: U.S. Environmental Protection Agency; ER-α: estrogen receptor alpha; HDL: high-density lipoprotein; HOMA-IR: homeostatic model assessment of insulin resistance; iAs: inorganic arsenic; LDL: low-density lipoprotein; MetS: metabolic syndrome; MMA: monomethylarsonate; NAFLD: non-alcoholic fatty liver disease; PND: postnatal day; ppb: parts per billion; ppm: parts per million; SAM: S-adenosylmethionine; USFDA: United States Food and Drug Administration.
Topics: Animals; Arsenic; Chronic Disease; Disease; Disease Models, Animal; Female; Humans; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 29873257
DOI: 10.1080/19396368.2018.1480076 -
The American Journal of Pathology Apr 2020This Guest Editorial introduces the theme reviews focusing on the glycocalyx in human disease.
This Guest Editorial introduces the theme reviews focusing on the glycocalyx in human disease.
Topics: Disease; Glycocalyx; Humans
PubMed: 32061726
DOI: 10.1016/j.ajpath.2020.02.002 -
Trends in Molecular Medicine Aug 2012In metazoans, alternative splicing of genes is essential for regulating gene expression and contributing to functional complexity. Computational predictions, comparative... (Review)
Review
In metazoans, alternative splicing of genes is essential for regulating gene expression and contributing to functional complexity. Computational predictions, comparative genomics, and transcriptome profiling of normal and diseased tissues indicate that an unexpectedly high fraction of diseases are caused by mutations that alter splicing. Mutations in cis elements cause missplicing of genes that alter gene function and contribute to disease pathology. Mutations of core spliceosomal factors are associated with hematolymphoid neoplasias, retinitis pigmentosa, and microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Mutations in the trans regulatory factors that control alternative splicing are associated with autism spectrum disorder, amyotrophic lateral sclerosis (ALS), and various cancers. In addition to discussing the disorders caused by these mutations, this review summarizes therapeutic approaches that have emerged to correct splicing of individual genes or target the splicing machinery.
Topics: Animals; Disease; Genetic Therapy; Humans; Mutation; RNA Precursors; RNA Splicing; Spliceosomes
PubMed: 22819011
DOI: 10.1016/j.molmed.2012.06.006 -
Nature Reviews. Genetics May 2021Nearly all genetic variants that influence disease risk have human-specific origins; however, the systems they influence have ancient roots that often trace back to... (Review)
Review
Nearly all genetic variants that influence disease risk have human-specific origins; however, the systems they influence have ancient roots that often trace back to evolutionary events long before the origin of humans. Here, we review how advances in our understanding of the genetic architectures of diseases, recent human evolution and deep evolutionary history can help explain how and why humans in modern environments become ill. Human populations exhibit differences in the prevalence of many common and rare genetic diseases. These differences are largely the result of the diverse environmental, cultural, demographic and genetic histories of modern human populations. Synthesizing our growing knowledge of evolutionary history with genetic medicine, while accounting for environmental and social factors, will help to achieve the promise of personalized genomics and realize the potential hidden in an individual's DNA sequence to guide clinical decisions. In short, precision medicine is fundamentally evolutionary medicine, and integration of evolutionary perspectives into the clinic will support the realization of its full potential.
Topics: Disease; Evolution, Molecular; Genetic Variation; Health Status; Humans
PubMed: 33408383
DOI: 10.1038/s41576-020-00305-9 -
IET Systems Biology Feb 2012Complex diseases are commonly believed to be caused by the breakdown of several correlated genes rather than individual genes. The availability of genome-wide data of... (Review)
Review
Complex diseases are commonly believed to be caused by the breakdown of several correlated genes rather than individual genes. The availability of genome-wide data of high-throughput experiments provides us with new opportunity to explore this hypothesis by analysing the disease-related biomolecular networks, which are expected to bridge genotypes and disease phenotypes and further reveal the biological mechanisms of complex diseases. In this study, the authors review the existing network biology efforts to study complex diseases, such as breast cancer, diabetes and Alzheimer's disease, using high-throughput data and computational tools. Specifically, the authors categorise these existing methods into several classes based on the research topics, that is, disease genes, dysfunctional pathways, network signatures and drug-target networks. The authors also summarise the pros and cons of those methods from both computation and application perspectives, and further discuss research trends and future topics of this promising field.
Topics: Disease; Drug Combinations; Drug Discovery; Humans; Molecular Targeted Therapy; Systems Biology
PubMed: 22360268
DOI: 10.1049/iet-syb.2010.0052 -
Philosophical Transactions of the Royal... Jan 2018Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in... (Review)
Review
Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory 'danger signals' for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells. The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals/non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining/regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins, therefore, form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
Topics: Disease; Heat-Shock Proteins; Humans; Immunity; Immunity, Innate; Signal Transduction
PubMed: 29203707
DOI: 10.1098/rstb.2016.0522 -
Cells Oct 2019Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient... (Review)
Review
Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient uptake to signaling responses. Consequently, their surface levels have to be dynamically controlled. Endocytosis constitutes a powerful mechanism to regulate the surface proteome and to recycle vesicular transmembrane proteins that strand at the plasma membrane after exocytosis. For efficient internalization, the cargo proteins need to be linked to the endocytic machinery via adaptor proteins such as the heterotetrameric endocytic adaptor complex AP-2 and a variety of mostly monomeric endocytic adaptors. In line with the importance of endocytosis for nutrient uptake, cell signaling and neurotransmission, animal models and human mutations have revealed that defects in these adaptors are associated with several diseases ranging from metabolic disorders to encephalopathies. This review will discuss the physiological functions of the so far known adaptor proteins and will provide a comprehensive overview of their links to human diseases.
Topics: Adaptor Proteins, Signal Transducing; Animals; Clathrin-Coated Vesicles; Disease; Endocytosis; Health; Humans; Membrane Proteins; Models, Animal; Mutation
PubMed: 31671891
DOI: 10.3390/cells8111345 -
Wiley Interdisciplinary Reviews.... 2011Contemporary views of human disease are based on simple correlation between clinical syndromes and pathological analysis dating from the late 19th century. Although this...
Contemporary views of human disease are based on simple correlation between clinical syndromes and pathological analysis dating from the late 19th century. Although this approach to disease diagnosis, prognosis, and treatment has served the medical establishment and society well for many years, it has serious shortcomings for the modern era of the genomic medicine that stem from its reliance on reductionist principles of experimentation and analysis. Quantitative, holistic systems biology applied to human disease offers a unique approach for diagnosing established disease, defining disease predilection, and developing individualized (personalized) treatment strategies that can take full advantage of modern molecular pathobiology and the comprehensive data sets that are rapidly becoming available for populations and individuals. In this way, systems pathobiology offers the promise of redefining our approach to disease and the field of medicine.
Topics: Disease; Humans; Precision Medicine; Systems Biology; Therapeutics
PubMed: 21928407
DOI: 10.1002/wsbm.144 -
Cold Spring Harbor Perspectives in... Aug 2021Much research effort is invested in attempting to determine causal influences on disease onset and progression to inform prevention and treatment efforts. However, this... (Review)
Review
Much research effort is invested in attempting to determine causal influences on disease onset and progression to inform prevention and treatment efforts. However, this is often dependent on observational data that are prone to well-known limitations, particularly residual confounding and reverse causality. Several statistical methods have been developed to support stronger causal inference. However, a complementary approach is to use design-based methods for causal inference, which acknowledge sources of bias and attempt to mitigate these through the design of the study rather than solely through statistical adjustment. Genetically informed methods provide a novel and potentially powerful extension to this approach, accounting by design for unobserved genetic and environmental confounding. No single approach will be absent from bias. Instead, we should seek and combine evidence from multiple methodologies that each bring different (and ideally uncorrelated) sources of bias. If the results of these different methodologies align-or triangulate-then we can be more confident in our causal inference. To be truly effective, this should ideally be done prospectively, with the sources of evidence specified in advance, to protect against one final source of bias-our own cognitions, expectations, and fondly held beliefs.
Topics: Causality; Disease; Genetics; Research Design
PubMed: 33355252
DOI: 10.1101/cshperspect.a040659 -
Cold Spring Harbor Perspectives in... May 2021Major biotechnological advances have facilitated a tremendous boost to the collection of (gen-/transcript-/prote-/methyl-/metabol-)omics data in very large sample sizes... (Review)
Review
Major biotechnological advances have facilitated a tremendous boost to the collection of (gen-/transcript-/prote-/methyl-/metabol-)omics data in very large sample sizes worldwide. Coordinated efforts have yielded a deluge of studies associating diseases with genetic markers (genome-wide association studies) or with molecular phenotypes. Whereas omics-disease associations have led to biologically meaningful and coherent mechanisms, the identified (non-germline) disease biomarkers may simply be correlates or consequences of the explored diseases. To move beyond this realm, Mendelian randomization provides a principled framework to integrate information on omics- and disease-associated genetic variants to pinpoint molecular traits causally driving disease development. In this review, we show the latest advances in this field, flag up key challenges for the future, and propose potential solutions.
Topics: Biomarkers; Biotechnology; Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Phenotype
PubMed: 32816877
DOI: 10.1101/cshperspect.a040493