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. 2009 Apr 9;8:21.
doi: 10.1186/1475-2859-8-21.

Medical Bioremediation of Age-Related Diseases

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Free PMC article

Medical Bioremediation of Age-Related Diseases

Jacques M Mathieu et al. Microb Cell Fact. .
Free PMC article

Abstract

Catabolic insufficiency in humans leads to the gradual accumulation of a number of pathogenic compounds associated with age-related diseases, including atherosclerosis, Alzheimer's disease, and macular degeneration. Removal of these compounds is a widely researched therapeutic option, but the use of antibodies and endogenous human enzymes has failed to produce effective treatments, and may pose risks to cellular homeostasis. Another alternative is "medical bioremediation," the use of microbial enzymes to augment missing catabolic functions. The microbial genetic diversity in most natural environments provides a resource that can be mined for enzymes capable of degrading just about any energy-rich organic compound. This review discusses targets for biodegradation, the identification of candidate microbial enzymes, and enzyme-delivery methods.

Figures

Figure 1
Figure 1
Coronary heart disease. A, Fibrous plaque from a 65-year old white male showing lipid-laden smooth muscle cells (SMCs) (short arrows). Cells vary greatly in size and some appear to be coalescing (long arrows). The SMC nucleus is flattened against the side of the lacunar space (open arrows). B, High-power view of the subendothelial area from A. Foam cells (white arrows) have formed beneath the endothelium and lumen (asterisk). Two large, lipid-filled spaces likely formed by the joining of adjacent SMCs that are now dead (black arrows). C, Micrograph of a coronary artery cross-section narrowed by a plaque. Images A and B courtesy of ncbi.nlm.nih.gov. Image C courtesy of genome.gov.
Figure 2
Figure 2
7-ketocholesterol. 7KC is an oxidized derivative of cholesterol with cytotoxic properties. It has been associated with atherosclerosis as well as Alzheimer's disease and is thought to destabilize cellular membranes due to its altered physicochemical properties. It is found in high concentrations within atherosclerotic plaques and can be produced from cholesterol by Aβ.
Figure 3
Figure 3
Amyloid accumulation in Alzheimer's disease. PET scans reveal Aβ deposits in the brains of three patients with AD (left) and three normal patients (right). Yellow areas indicate high levels of uptake of an Aβ label while red signifies medium uptake. Image courtesy of lbl.gov.
Figure 4
Figure 4
Advanced glycation end-products. Two of the most abundant AGEs are glucosepane and carboxymethyl lysine. AGE modification of long-lived proteins contributes to extracellular matrix dysfunction, leading to an array of conditions related to aging and diabetes. These include atherosclerosis, amyloidosis, cataracts, retinopathy, neuropathy, nephropathy, and impaired wound healing.
Figure 5
Figure 5
Age-related macular degeneration. A, A2E deposits in the retinal pigment epithelial (RPE) cells and Bruch's membrane of a senescent CCL2-/- mouse. B, Several round, yellow subretinal lesions in the same mouse. Images courtesy of nei.nih.gov.
Figure 6
Figure 6
The pyridinium bisretinoid A2E. A2E is derived from vitamin A aldehyde (retinal) and phosphatidyl ethanolamine. It accumulates in postmitotic retinal pigment epithelial cells over the life span, and it has been implicated in the ethiology of various forms of macular degeneration.
Figure 7
Figure 7
Gene discovery flowchart. The search for novel biocatalysts begins with the enrichment of environmental samples. This may be culture, genome, or gene enrichment, and serves to narrow the library size for effective screening. After nucleic acid extraction (DNA or RNA), several avenues are available for gene and enzyme discovery. These can include construction of a metagenomic library followed by functional screening, microarray analysis, or sequence-based assays. Final expression requires full-length gene expression in a heterologous host.

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