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Annual Review of Pathology 2015The ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics.... (Review)
Review
The ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics. Although great advances have been made in terms of developing disease models in animals, such as transgenic mice, many of these models fail to faithfully recapitulate the human condition. In addition, it is difficult to identify critical cellular and molecular contributors to disease or to vary them independently in whole-animal models. This challenge has attracted the interest of engineers, who have begun to collaborate with biologists to leverage recent advances in tissue engineering and microfabrication to develop novel in vitro models of disease. As these models are synthetic systems, specific molecular factors and individual cell types, including parenchymal cells, vascular cells, and immune cells, can be varied independently while simultaneously measuring system-level responses in real time. In this article, we provide some examples of these efforts, including engineered models of diseases of the heart, lung, intestine, liver, kidney, cartilage, skin and vascular, endocrine, musculoskeletal, and nervous systems, as well as models of infectious diseases and cancer. We also describe how engineered in vitro models can be combined with human inducible pluripotent stem cells to enable new insights into a broad variety of disease mechanisms, as well as provide a test bed for screening new therapies.
Topics: Animals; Disease; Humans; In Vitro Techniques; Models, Biological; Pathology
PubMed: 25621660
DOI: 10.1146/annurev-pathol-012414-040418 -
BMJ (Clinical Research Ed.) Jun 2011
Topics: Disease; Global Health; Humans
PubMed: 21724543
DOI: 10.1136/bmj.d3823 -
The Biochemical Journal Jul 2009In addition to polyamine homoeostasis, it has become increasingly clear that polyamine catabolism can play a dominant role in drug response, apoptosis and the response... (Review)
Review
In addition to polyamine homoeostasis, it has become increasingly clear that polyamine catabolism can play a dominant role in drug response, apoptosis and the response to stressful stimuli, and contribute to the aetiology of several pathological states, including cancer. The highly inducible enzymes SSAT (spermidine/spermine N1-acetyltransferase) and SMO (spermine oxidase) and the generally constitutively expressed APAO (N1-acetylpolyamine oxidase) appear to play critical roles in many normal and disease processes. The dysregulation of polyamine catabolism frequently accompanies several disease states and suggests that such dysregulation may both provide useful insight into disease mechanism and provide unique druggable targets that can be exploited for therapeutic benefit. Each of these enzymes has the potential to alter polyamine homoeostasis in response to multiple cell signals and the two oxidases produce the reactive oxygen species H2O2 and aldehydes, each with the potential to produce pathological states. The activity of SSAT provides substrates for APAO or substrates for the polyamine exporter, thus reducing the intracellular polyamine concentration, the net effect of which depends on the magnitude and rate of any increase in SSAT. SSAT may also influence cellular metabolism via interaction with other proteins and by perturbing the content of acetyl-CoA and ATP. The goal of the present review is to cover those aspects of polyamine catabolism that have an impact on disease aetiology or treatment and to provide a solid background in this ever more exciting aspect of polyamine biology.
Topics: Acetyltransferases; Animals; Disease; Humans; Oxidoreductases Acting on CH-NH Group Donors; Polyamines; Therapeutics; Polyamine Oxidase
PubMed: 19589128
DOI: 10.1042/BJ20090598 -
Journal Der Deutschen Dermatologischen... Mar 2021Autoinflammatory syndromes are a steadily growing group of inflammatory diseases caused by abnormal regulations of the innate immune system. The clinical presentation is...
Autoinflammatory syndromes are a steadily growing group of inflammatory diseases caused by abnormal regulations of the innate immune system. The clinical presentation is multifaceted, but recurrent fever, skin involvement, joint inflammation and other systemic symptoms of inflammation are characteristic. In contrast to classic autoimmune diseases, autoantibodies or specific T cells are not involved in the pathogenesis. In fact, innate immunity plays the most important role in autoinflammation. While activation of the innate immune system is usually self-limiting in healthy individuals, mutations and dysregulation can lead to chronic and excessive activation of innate immune responses and to the development of autoinflammatory diseases.
Topics: Autoimmune Diseases; Humans; Immunity, Innate; Inflammation; Syndrome
PubMed: 33620111
DOI: 10.1111/ddg.14332 -
Drug Metabolism Reviews 1978
Review
Topics: Animals; Disease; Environment; Genetics; Humans; Liver Diseases; Pharmaceutical Preparations
PubMed: 363385
DOI: 10.3109/03602537808993788 -
Advances in Experimental Medicine and... 2020The study of epigenetics has its roots in the study of organism change over time and response to environmental change, although over the past several decades the... (Review)
Review
The study of epigenetics has its roots in the study of organism change over time and response to environmental change, although over the past several decades the definition has been formalized to include heritable alterations in gene expression that are not a result of alterations in underlying DNA sequence. In this chapter, we discuss first the history and milestones in the 100+ years of epigenetic study, including early discoveries of DNA methylation, histone posttranslational modification, and noncoding RNA. We then discuss how epigenetics has changed the way that we think of both health and disease, offering as examples studies examining the epigenetic contributions to aging, including the recent development of an epigenetic "clock", and explore how antiaging therapies may work through epigenetic modifications. We then discuss a nonpathogenic role for epigenetics in the clinic: epigenetic biomarkers. We conclude by offering two examples of modern state-of-the-art integrated multi-omics studies of epigenetics in disease pathogenesis, one which sought to capture shared mechanisms among multiple diseases, and another which used epigenetic big data to better understand the pathogenesis of a single tissue from one disease.
Topics: Animals; DNA Methylation; Disease; Epigenesis, Genetic; Epigenomics; Histone Code; Humans; RNA, Untranslated
PubMed: 32445091
DOI: 10.1007/978-981-15-3449-2_2 -
Genes & Development Jul 1988
Review
Topics: Animals; Body Temperature; Disease; Genes; Heat-Shock Proteins; Humans
PubMed: 3061874
DOI: 10.1101/gad.2.7.783 -
Current Pharmaceutical Design 2017Productivity in drug R&D continues seeing significant attrition in clinical stage testing. Approval of new molecular entities proceeds with slow pace specifically when... (Review)
Review
BACKGROUND
Productivity in drug R&D continues seeing significant attrition in clinical stage testing. Approval of new molecular entities proceeds with slow pace specifically when it comes to chronic, age-related diseases, calling for new conceptual approaches, methodological implementation and organizational adoption in drug development.
METHODS
Detailed phenotyping of disease presentation together with comprehensive representation of drug mechanism of action is considered as a path forward, and a big data spectrum has become available covering behavioral, clinical and molecular characteristics, the latter combining reductionist and explorative strategies. On this basis integrative analytics in the realm of Systems Biology has emerged, essentially aiming at traversing associations into causal relationships for bridging molecular disease specifics and clinical phenotype surrogates and finally explaining drug response and outcome.
RESULTS
From a conceptual perspective bottom-up modeling approaches are available, with dynamical hierarchies as formalism capable of describing clinical findings as emergent properties of an underlying molecular process network comprehensively resembling disease pathology. In such representation biomarker candidates serve as proxy of a molecular process set, at the interface of a corresponding representation of drug mechanism of action allowing patient stratification and prediction of drug response. In practical implementation network analytics on a protein coding gene level has provided a number of example cases for matching disease presentation and drug molecular effect, and workflows combining computational hypothesis generation and experimental evaluation have become available for systematically optimizing biomarker candidate selection.
CONCLUSION
With biomarker-based enrichment strategies in adaptive clinical trials, implementation routes for tackling development attrition are provided. Predictive biomarkers add precision in drug development and as companion diagnostics in clinical practice.
Topics: Animals; Biomarkers, Pharmacological; Disease; Humans; Pharmaceutical Preparations; Systems Biology
PubMed: 27719641
DOI: 10.2174/1381612822666161006153639 -
Psychological Medicine Aug 1980
Topics: Disease; Humans; Philosophy, Medical
PubMed: 7443896
DOI: 10.1017/s0033291700047309 -
Methods in Molecular Biology (Clifton,... 2010Autophagy is a cellular quality control process by which cytoplasmic constituents including proteins, protein aggregates, organelles, and invading pathogens can be... (Review)
Review
Autophagy is a cellular quality control process by which cytoplasmic constituents including proteins, protein aggregates, organelles, and invading pathogens can be delivered to lysosomes for degradation. Autophagy is activated in response to changes in the internal status of the cell and/or changes in the extracellular environment. It is therefore essential for the maintenance of cellular homeostasis and for an efficient response to cellular stresses. As such autophagy has been implicated either in the pathogenesis, or response to a wide variety of diseases, bacterial, and viral infections, and ageing.
Topics: Animals; Autophagy; Disease; Health; Humans
PubMed: 20700706
DOI: 10.1007/978-1-60761-756-3_5