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Proceedings of the Japan Academy.... 2013Non-communicable diseases (NCDs), such as diabetes mellitus and coronary heart disease, are chronic, non-infectious diseases of long duration. NCDs are increasingly... (Review)
Review
Non-communicable diseases (NCDs), such as diabetes mellitus and coronary heart disease, are chronic, non-infectious diseases of long duration. NCDs are increasingly widespread worldwide and are becoming a serious health and economic burden. NCDs arise from complex interactions between the genetic make-up of an individual and environmental factors. Several epidemiological studies have revealed that the perinatal environment influences health later in life, and have proposed the concept of developmental programming or developmental origin of health and disease (DOHaD). These studies suggest the importance of life course health care from fetal life, early childhood, adulthood, and through to old age. Recent progress in genomics, proteomics and diagnostic modalities holds promise for identifying high risk groups, predicting latent diseases, and allowing early intervention. Preemptive medicine is the ultimate goal of medicine, but to achieve it, the full participation of the public and all sectors of society is imperative.
Topics: Animals; Delivery of Health Care; Disease; Humans; Preventive Medicine
PubMed: 24334510
DOI: 10.2183/pjab.89.462 -
Autophagy Oct 2019Although best understood as a degradative pathway, recent evidence demonstrates pronounced involvement of the macroautophagic/autophagic molecular machinery in cellular... (Review)
Review
Although best understood as a degradative pathway, recent evidence demonstrates pronounced involvement of the macroautophagic/autophagic molecular machinery in cellular secretion. With either overexpression or inhibition of autophagy mediators, dramatic alterations in the cellular secretory profile occur. This affects secretion of a plethora of factors ranging from cytokines, to granule contents, and even viral particles. Encompassing a wide range of secreted factors, autophagy-dependent secretion is implicated in diseases ranging from cancer to neurodegeneration. With a growing body of evidence shedding light onto the molecular mediators, this review delineates the molecular machinery involved in selective targeting of the autophagosome for either degradation or secretion. In addition, we summarize the current understanding of factors and cargo secreted through this unconventional route, and describe the implications of this pathway in both health and disease. : BECN1, beclin 1; CAF, cancer associated fibroblast; CUPS, compartment for unconventional protein secretion; CXCL, C-X-C motif chemokine ligand; ER, endoplasmic reticulum; FGF2, fibroblast growth factor 2; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IL, Interleukin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPS, misfolding associated protein secretion; MEF, mouse embryonic fibroblast; MTORC1, MTOR complex I; PtdIns, phosphatidyl inositol; SEC22B, SEC22 homolog B, vesicle trafficking protein (gene/pseudogene); SFV, Semliki forest virus; SNCA, synuclein alpha; SQSTM1, sequestosome 1; STX, Syntaxin; TASCC, TOR-associated spatial coupling compartment; TGFB, transforming growth factor beta; TRIM16, tripartite motif containing 16; UPS, unconventional protein secretion; VWF, von Willebrand factor.
Topics: Animals; Autophagy; Biological Transport; Disease; Humans; Mice; Proteins; Secretory Pathway; Secretory Vesicles
PubMed: 30894055
DOI: 10.1080/15548627.2019.1596479 -
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 -
Clinical & Translational Oncology :... Jun 2021Exosomes, the nanoscale phospholipid bilayer vesicles, enriched in selected proteins, nucleic acids and lipids, which they participated in a variety of biological... (Review)
Review
Exosomes, the nanoscale phospholipid bilayer vesicles, enriched in selected proteins, nucleic acids and lipids, which they participated in a variety of biological processes in the body, including physiology and pathology. CircRNAs (circular RNAs) are a class of single-stranded closed molecules with tissue development specific expression patterns that have crucial regulatory functions in various diseases. Non-coding RNAs (such as microRNAs and long non‑coding RNAs) in exosomes have also been shown to play an important regulatory role in humans. However, little research has focused on exosomal circRNAs. Recently, CircRNAs have been identified to be enriched and stably expressed in exosomes. In this review, we summarize the biogenesis and biological functions of exosomes and circRNA, and further revealed the potential role of exosome-derived circRNA in different diseases. Besides, we propose its use as a diagnostic marker and therapeutic punctuation for diseases, especially in cancer.
Topics: Disease; Exosomes; Humans; Neoplasms; RNA, Circular
PubMed: 32935262
DOI: 10.1007/s12094-020-02485-6 -
Genome Biology Nov 2016The wealth of available genetic information is allowing the reconstruction of human demographic and adaptive history. Demography and purifying selection affect the purge... (Review)
Review
The wealth of available genetic information is allowing the reconstruction of human demographic and adaptive history. Demography and purifying selection affect the purge of rare, deleterious mutations from the human population, whereas positive and balancing selection can increase the frequency of advantageous variants, improving survival and reproduction in specific environmental conditions. In this review, I discuss how theoretical and empirical population genetics studies, using both modern and ancient DNA data, are a powerful tool for obtaining new insight into the genetic basis of severe disorders and complex disease phenotypes, rare and common, focusing particularly on infectious disease risk.
Topics: Demography; Disease; Evolution, Molecular; Genetics, Population; Humans; Models, Genetic; Mutation; Polymorphism, Genetic; Selection, Genetic
PubMed: 27821149
DOI: 10.1186/s13059-016-1093-y -
American Journal of Epidemiology Oct 2017Genetic and environmental factors are both known to contribute to susceptibility to complex diseases. Therefore, the study of gene-environment interaction (G×E) has... (Review)
Review
Genetic and environmental factors are both known to contribute to susceptibility to complex diseases. Therefore, the study of gene-environment interaction (G×E) has been a focus of research for several years. In this article, select examples of G×E from the literature are described to highlight different approaches and underlying principles related to the success of these studies. These examples can be broadly categorized as studies of single metabolism genes, genes in complex metabolism pathways, ranges of exposure levels, functional approaches and model systems, and pharmacogenomics. Some studies illustrated the success of studying exposure metabolism for which candidate genes can be identified. Moreover, some G×E successes depended on the availability of high-quality exposure assessment and longitudinal measures, study populations with a wide range of exposure levels, and the inclusion of ethnically and geographically diverse populations. In several examples, large population sizes were required to detect G×Es. Other examples illustrated the impact of accurately defining scale of the interactions (i.e., additive or multiplicative). Last, model systems and functional approaches provided insights into G×E in several examples. Future studies may benefit from these lessons learned.
Topics: Biomedical Research; Disease; Environmental Exposure; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Models, Biological
PubMed: 28978190
DOI: 10.1093/aje/kwx230 -
Molecular Systems Biology Jan 2021A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are... (Review)
Review
A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are often mediated by interactions between proteins. Insights into the physical rewiring of protein-protein interactions in response to mutations, pathological conditions, or pathogen infection can advance our understanding of disease etiology, progression, and pathogenesis and can lead to the identification of potential druggable targets. Advances in quantitative mass spectrometry (MS)-based approaches have allowed unbiased mapping of these disease-mediated changes in protein-protein interactions on a global scale. Here, we review MS techniques that have been instrumental for the identification of protein-protein interactions at a system-level, and we discuss the challenges associated with these methodologies as well as novel MS advancements that aim to address these challenges. An overview of examples from diverse disease contexts illustrates the potential of MS-based protein-protein interaction mapping approaches for revealing disease mechanisms, pinpointing new therapeutic targets, and eventually moving toward personalized applications.
Topics: Disease; Gene Regulatory Networks; Humans; Mass Spectrometry; Protein Interaction Mapping
PubMed: 33434350
DOI: 10.15252/msb.20188792 -
Disease Models & Mechanisms Oct 2016Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have... (Review)
Review
Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease.
Topics: Animals; Disease; Genetic Association Studies; Genomics; Genotype; Phenotype; Rats; Systems Biology
PubMed: 27736746
DOI: 10.1242/dmm.026104 -
Trends in Genetics : TIG Oct 2021Somatic evolution of cells within the body is well known to lead to cancers. However, spread of somatic mutations within a tissue over time may also contribute to the... (Review)
Review
Somatic evolution of cells within the body is well known to lead to cancers. However, spread of somatic mutations within a tissue over time may also contribute to the pathogenesis of non-neoplastic diseases. Recent years have seen the publication of many studies aiming to characterize somatic evolution in healthy tissues. A logical next step is to extend such work to diseased conditions. As our understanding of the interplay between somatic mutations and non-neoplastic disease grows, opportunities for the joint study of germline and somatic variants will present themselves. Here, we present our thoughts on the utility of somatic mutations for understanding both the causes and consequences of common complex disease and the challenges that remain for the joint study of the soma and germline.
Topics: Disease; Germ-Line Mutation; Humans; Mutation; Neoplasms
PubMed: 34226062
DOI: 10.1016/j.tig.2021.06.012 -
Nucleic Acids Research Jan 2018There is a significant number of children around the world suffering from the consequence of the misdiagnosis and ineffective treatment for various diseases. To...
There is a significant number of children around the world suffering from the consequence of the misdiagnosis and ineffective treatment for various diseases. To facilitate the precision medicine in pediatrics, a database namely the Pediatric Disease Annotations & Medicines (PedAM) has been built to standardize and classify pediatric diseases. The PedAM integrates both biomedical resources and clinical data from Electronic Medical Records to support the development of computational tools, by which enables robust data analysis and integration. It also uses disease-manifestation (D-M) integrated from existing biomedical ontologies as prior knowledge to automatically recognize text-mined, D-M-specific syntactic patterns from 774 514 full-text articles and 8 848 796 abstracts in MEDLINE. Additionally, disease connections based on phenotypes or genes can be visualized on the web page of PedAM. Currently, the PedAM contains standardized 8528 pediatric disease terms (4542 unique disease concepts and 3986 synonyms) with eight annotation fields for each disease, including definition synonyms, gene, symptom, cross-reference (Xref), human phenotypes and its corresponding phenotypes in the mouse. The database PedAM is freely accessible at http://www.unimd.org/pedam/.
Topics: Animals; Child; Databases, Factual; Diagnosis; Disease; Drug Therapy; Genotype; Humans; Mice; Phenotype
PubMed: 29126123
DOI: 10.1093/nar/gkx1049