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Nature Oct 2009The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults... (Review)
Review
The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
Topics: Cell Cycle; DNA Damage; DNA Repair; Disease; Genome, Human; Humans; Signal Transduction
PubMed: 19847258
DOI: 10.1038/nature08467 -
Physiological Reviews Jul 2010Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is... (Review)
Review
Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.
Topics: Animals; Bacterial Physiological Phenomena; Disease; Gastrointestinal Diseases; Genetic Techniques; Health; Host-Pathogen Interactions; Humans; Intestines; Microbiological Techniques; Signal Transduction
PubMed: 20664075
DOI: 10.1152/physrev.00045.2009 -
Annals of the New York Academy of... May 1998Adaptation in the face of potentially stressful challenges involves activation of neural, neuroendocrine and neuroendocrine-immune mechanisms. This has been called... (Review)
Review
Adaptation in the face of potentially stressful challenges involves activation of neural, neuroendocrine and neuroendocrine-immune mechanisms. This has been called "allostasis" or "stability through change" by Sterling and Eyer (Fisher S., Reason J. (eds): Handbook of Life Stress, Cognition and Health. J. Wiley Ltd. 1988, p. 631), and allostasis is an essential component of maintaining homeostasis. When these adaptive systems are turned on and turned off again efficiently and not too frequently, the body is able to cope effectively with challenges that it might not otherwise survive. However, there are a number of circumstances in which allostatic systems may either be overstimulated or not perform normally, and this condition has been termed "allostatic load" or the price of adaptation (McEwen and Stellar, Arch. Int. Med. 1993; 153: 2093.). Allostatic load can lead to disease over long periods. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. Examples will be given for each type of allostatic load from research pertaining to autonomic, CNS, neuroendocrine, and immune system activity. The relationship of allostatic load to genetic and developmental predispositions to disease is also considered.
Topics: Adaptation, Physiological; Animals; Disease; Humans; Immune System; Nervous System; Neurosecretory Systems; Stress, Physiological
PubMed: 9629234
DOI: 10.1111/j.1749-6632.1998.tb09546.x -
Molecular Aspects of Medicine Dec 2014Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death,... (Review)
Review
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
Topics: Disease; HMGB1 Protein; Health; Humans
PubMed: 25010388
DOI: 10.1016/j.mam.2014.05.001 -
RNA (New York, N.Y.) Dec 2017RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has... (Review)
Review
RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.
Topics: Animals; Disease; Humans; RNA; RNA Processing, Post-Transcriptional
PubMed: 28855326
DOI: 10.1261/rna.063503.117 -
Science (New York, N.Y.) Jan 2020Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the... (Review)
Review
Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.
Topics: Dietary Supplements; Disease; Exposome; Genome, Human; Health; Humans; Organic Chemicals; Physical Phenomena; Risk Assessment; Stress, Psychological
PubMed: 31974245
DOI: 10.1126/science.aay3164 -
Nature Reviews. Neuroscience Jan 2008In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the... (Review)
Review
In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.
Topics: Animals; Brain; Cytokines; Depression; Disease; Humans; Immune System; Inflammation
PubMed: 18073775
DOI: 10.1038/nrn2297 -
Nature Cell Biology Jan 2014Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork... (Review)
Review
Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress.
Topics: DNA Replication; Disease; Eukaryotic Cells; Humans; Models, Biological; Stress, Physiological
PubMed: 24366029
DOI: 10.1038/ncb2897 -
The Lancet. Respiratory Medicine Mar 2017Asthma is the most prevalent chronic respiratory disease both in children and adults and resembles a complex syndrome rather than a single disease. Different methods... (Review)
Review
Asthma is the most prevalent chronic respiratory disease both in children and adults and resembles a complex syndrome rather than a single disease. Different methods have been developed to better characterise distinct asthma phenotypes in childhood and adulthood. In studies of adults, most phenotyping relies on biomaterials from the lower airways; however, this information is missing in paediatric studies because of restricted accessibility. Few patients show symptoms throughout childhood, adolescence, and adulthood. Risk factors for this might be genetics, family history of asthma and atopy, infections early in life, allergic diseases, and lung function deficits. In turn, a large proportion of children with asthma lose their symptoms during school age and adolescence. This improved prognosis, which might also reflect a better treatment response, is associated with being male and with milder and less allergic disease. Importantly, whether clinical remission of symptoms equals the disappearance of underlying pathology is unknown. In fact, airway hyper-responsiveness and airway inflammation might remain despite the absence of overt symptoms. Additionally, a new-onset of asthma symptoms is apparent in adulthood, especially in women and in the case of impaired lung function. However, many patients do not remember childhood symptoms, which might reflect relapse rather than true initiation. Both relapse and adult-onset of asthma symptoms have been associated with allergic disease and sensitisation in addition to airway hyper-responsiveness. Thus, asthma symptoms beginning in adults might have originated in childhood. Equivocally, persistence into, relapse, and new-onset of symptoms in adulthood have all been related to active smoking. However, underlying mechanisms for the associations remain unclear, and future asthma research should therefore integrate standardised molecular approaches in identical ways in both paediatric and adult populations and in longitudinal studies.
Topics: Adolescent; Adult; Age of Onset; Asthma; Child; Chronic Disease; Female; Humans; Male; Recurrence; Risk Factors; Syndrome; Time Factors; Young Adult
PubMed: 27666650
DOI: 10.1016/S2213-2600(16)30187-4 -
Journal of Cellular Physiology Apr 2018The genetic information is constantly challenged by genotoxic attacks. DNA repair mechanisms evolved early in evolution and recognize and remove the various lesions. A... (Review)
Review
The genetic information is constantly challenged by genotoxic attacks. DNA repair mechanisms evolved early in evolution and recognize and remove the various lesions. A complex network of DNA damage responses (DDR) orchestrates a variety of physiological adaptations to the presence of genome instability. Erroneous repair or malfunctioning of the DDR causes cancer development and the accumulation of DNA lesions drives the aging process. For understanding the complex DNA repair and DDR mechanisms it is pivotal to employ simple metazoan as model systems. The nematode Caenorhabditis elegans has become a well-established and popular experimental organism that allows dissecting genome stability mechanisms in dynamic and differentiated tissues and under physiological conditions. We provide an overview of the distinct advantages of the nematode system for studying DDR and provide a range of currently applied methodologies.
Topics: Animals; Biological Assay; Caenorhabditis elegans; DNA Damage; DNA Repair; Disease; Genes, Helminth; Models, Theoretical
PubMed: 28463453
DOI: 10.1002/jcp.25979