Abstract: MicroRNAs (miRNAs) are small, non-coding RNAs that have the ability to post-transcriptionally regulate gene expression. Hundreds of miRNAs have been identified in humans and they are involved in the regulation of almost every process, including cholesterol transport, metabolism, and maintenance of cholesterol homeostasis. Because of their small size and their ability to very specifically regulate gene expression, miRNAs are attractive targets for the regulation of dyslipidemias and other lipid-related disorders. However, the complex interactions between miRNAs, transcription factors, and gene expression raise great potential for side effects as a result of miRNA overexpression or inhibition. Many dietary components can also target specific miRNAs, altering the expression of downstream genes. Therefore, much more research is necessary to fully understand the role(s) of each miRNA in the body and how they may be impacted by diet and health. The present review aims to summarize the known roles of miRNAs in the regulation of reverse cholesterol transport and the maintenance of cholesterol homeostasis, as well as the potential clinical consequences of their manipulation.
Abstract: Viruses produce nucleic acids during their replication, either during genomic replication or transcription. These nucleic acids are present in the cytoplasm or endosome of an infected cell, or in the extracellular space to be sensed by neighboring cells during lytic infections. Cells have mechanisms of sensing virus-generated nucleic acids; these nucleic acids act as flags to the cell, indicating an infection requiring defense mechanisms. The viral nucleic acids are called pathogen-associated molecular patterns (PAMPs) and the sensors that bind them are called pattern recognition receptors (PRRs). This review article focuses on the most recent findings regarding nucleic acids PRRs in fish, including: Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), cytoplasmic DNA sensors (CDSs) and class A scavenger receptors (SR-As). It also discusses what is currently known of the downstream signaling molecules for each PRR family and the resulting antiviral response, either type I interferons (IFNs) or pro-inflammatory cytokine production. The review highlights what is known but also defines what still requires elucidation in this economically important animal. Understanding innate immune systems to virus infections will aid in the development of better antiviral therapies and vaccines for the future.
Abstract: In contrast to the probabilistic way of thinking about pleiotropy as the random expression of a single gene that generates two or more distinct phenotypic traits, it is actually a deterministic consequence of the evolution of complex physiology from the unicellular state. Pleiotropic novelties emerge through recombinations and permutations of cell-cell signaling exercised during reproduction based on both past and present physical and physiologic conditions, in service to the future needs of the organism for its continued survival. Functional homologies ranging from the lung to the kidney, skin, brain, thyroid and pituitary exemplify the evolutionary mechanistic strategy of pleiotropy. The power of this perspective is exemplified by the resolution of evolutionary gradualism and punctuated equilibrium in much the same way that Niels Bohr resolved the paradoxical duality of light as Complementarity.
Abstract: Aromatic compounds are the second most abundant class of molecules on the earth and frequent environmental pollutants. They are difficult to metabolize due to an inert chemical structure, and of all living organisms, only microbes have evolved biochemical pathways that can open an aromatic ring and catabolize thus formed organic molecules. In bacterial genomes, the phenylacetate (PA) utilization pathway is abundant and represents the central route for degradation of a variety of organic compounds, whose degradation reactions converge at this pathway. The PA pathway is a hybrid pathway and combines the dual features of aerobic metabolism, i.e., usage of both oxygen to open the aromatic ring and of anaerobic metabolism—coenzyme A derivatization of PA. This allows the degradation process to be adapted to fluctuating oxygen conditions. In this review we focus on the structural and functional aspects of enzymes and their complexes involved in the PA degradation by the catabolic hybrid pathway. We discuss the ability of the central PaaABCE monooxygenase to reversibly oxygenate PA, the controlling mechanisms of epoxide concentration by the pathway enzymes, and the similarity of the PA utilization pathway to the benzoate utilization Box pathway and β-oxidation of fatty acids.
Abstract: In skeletal muscle, the dystrophin-glycoprotein complex forms a membrane-associated assembly of relatively low abundance, making its detailed proteomic characterization in normal versus dystrophic tissues technically challenging. To overcome this analytical problem, we have enriched the muscle membrane fraction by a minimal differential centrifugation step followed by the comprehensive label-free mass spectrometric analysis of microsomal membrane preparations. This organelle proteomic approach successfully identified dystrophin and its binding partners in normal versus dystrophic hind limb muscles. The introduction of a simple pre-fractionation step enabled the simultaneous proteomic comparison of the reduction in the dystrophin-glycoprotein complex and secondary changes in the mdx-4cv mouse model of dystrophinopathy in a single analytical run. The proteomic screening of the microsomal fraction from dystrophic hind limb muscle identified the full-length dystrophin isoform Dp427 as the most drastically reduced protein in dystrophinopathy, demonstrating the remarkable analytical power of comparative muscle proteomics. Secondary pathoproteomic expression patterns were established for 281 proteins, including dystrophin-associated proteins and components involved in metabolism, signalling, contraction, ion-regulation, protein folding, the extracellular matrix and the cytoskeleton. Key findings were verified by immunoblotting. Increased levels of the sarcolemmal Na+/K+-ATPase in dystrophic leg muscles were also confirmed by immunofluorescence microscopy. Thus, the reduction of sample complexity in organelle-focused proteomics can be advantageous for the profiling of supramolecular protein complexes in highly intricate systems, such as skeletal muscle tissue.
Abstract: An association between sulfur amino acids (methionine, cysteine, homocysteine and taurine) and lipid metabolism has been described in several experimental and population-based studies. Changes in the metabolism of these amino acids influence serum lipoprotein concentrations, although the underlying mechanisms are still poorly understood. However, recent evidence has suggested that the enzyme stearoyl-CoA desaturase-1 (SCD-1) may be the link between these two metabolic pathways. SCD-1 is a key enzyme for the synthesis of monounsaturated fatty acids. Its main substrates C16:0 and C18:0 and products palmitoleic acid (C16:1) and oleic acid (C18:1) are the most abundant fatty acids in triglycerides, cholesterol esters and membrane phospholipids. A significant suppression of SCD-1 has been observed in several animal models with disrupted sulfur amino acid metabolism, and the activity of SCD-1 is also associated with the levels of these amino acids in humans. This enzyme also appears to be involved in the etiology of metabolic syndromes because its suppression results in decreased fat deposits (regardless of food intake), improved insulin sensitivity and higher basal energy expenditure. Interestingly, this anti-obesogenic phenotype has also been described in humans and animals with sulfur amino acid disorders, which is consistent with the hypothesis that SCD-1 activity is influenced by these amino acids, in particularly cysteine, which is a strong and independent predictor of SCD-1 activity and fat storage. In this narrative review, we discuss the evidence linking sulfur amino acids, SCD-1 and lipid metabolism.