Colorful ornaments have been the focus of sexual selection studies since the work of Darwin. Yellow to red coloration is often produced by carotenoid pigments. Different hypotheses have been formulated to explain the evolution of these traits as signals of individual quality. Many of these hypotheses involve the existence of a signal production cost. The carotenoids necessary for signaling can only be obtained from food. In this line, carotenoid-based signals could reveal an individual's capacity to find sufficient dietary pigments. However, the ingested carotenoids are often yellow and became transformed by the organism to produce pigments of more intense color (red ketocarotenoids). Biotransformation often involves oxidation reactions. We tested the hypothesis that biotransformation could be costly because a certain level of oxidative stress is required. Thus, the carotenoid-based signals could reveal the efficiency of the owner in successfully managing this challenge. In a bird with ketocarotenoid-based ornaments (the red-legged partridge; Alectoris rufa), the availability of different carotenoids in the diet and oxidative stress were manipulated. We found that color and pigment levels in the ornaments depended on the relative quantity in the food of those carotenoids used as substrates in biotransformation (i.e. zeaxanthin and lutein). Moreover, we found that birds exposed to certain levels of a free radical generator (diquat) developed redder bills and deposited higher amounts of ketocarotenoids (astaxanthin) in ornaments, thus supporting the hypothesis. However, the effect also depended on the relative abundance of substrate carotenoids in the diet. This last result suggests the involvement of a resource allocation trade-off, which would support, to some extent, a signaling cost linked to carotenoid acquisition. PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.1873v1 | CC-BY 4.0 Open Access | rec Abstract 1 Colorful ornaments have been the focus of sexual selection studies since the work of 2 Darwin. Yellow to red coloration is often produced by carotenoid pigments. Different 3 hypotheses have been formulated to explain the evolution of these traits as signals of 4 individual quality. Many of these hypotheses involve the existence of a signal production 5 cost. The carotenoids necessary for signaling can only be obtained from food. In this line, 6 carotenoid-based signals could reveal an individual's capacity to find sufficient dietary 7 pigments. However, the ingested carotenoids are often yellow and became transformed by 8 the organism to produce pigments of more intense color (red ketocarotenoids). 9 Biotransformation often involves oxidation reactions. We tested the hypothesis that 10 biotransformation could be costly because a certain level of oxidative stress is required. 11 Thus, the carotenoid-based signals could reveal the efficiency of the owner in successfully 12 managing this challenge. In a bird with ketocarotenoid-based ornaments (the red-legged 13 partridge; Alectoris rufa), the ava...

In both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensitive pathways. These pathways include nuclear factor-B, p38 mitogen-activated protein kinase, NH 2 -terminal Jun kinases/stress-activated protein kinases, hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes. Diabetes

Reactive oxygen and nitrogen molecules have been typically viewed as the toxic by-products of metabolism. However, accumulating evidence has revealed that reactive species, including hydrogen peroxide, serve as signaling molecules that are involved in the regulation of cellular function. The chronic and/or increased production of these reactive molecules or a reduced capacity for their elimination, termed oxidative stress, can lead to abnormal changes in intracellular signaling and result in chronic inflammation and insulin resistance. Inflammation and oxidative stress have been linked to insulin resistance in vivo. Recent studies have found that this association is not restricted to insulin resistance in type 2 diabetes, but is also evident in obese, nondiabetic individuals, and in those patients with the metabolic syndrome. An increased concentration of reactive molecules triggers the activation of serine/threonine kinase cascades such as c-Jun N-terminal kinase, nuclear factor-kappaB, and others that in turn phosphorylate multiple targets, including the insulin receptor and the insulin receptor substrate (IRS) proteins. Increased serine phosphorylation of IRS reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1, offering an attractive explanation for the molecular basis of oxidative stress-induced insulin resistance. Consistent with this idea, studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine indicate a beneficial impact on insulin sensitivity, and offer the possibility for new treatment approaches for insulin resistance.

In diabetic patients, ␣-lipoic acid (LA) improves skeletal muscle glucose transport, resulting in increased glucose disposal; however, the molecular mechanism of action of LA is presently unknown. We studied the effects of LA on basal and insulin-stimulated glucose transport in cultured rat L6 muscle cells that overexpress GLUT4. When 2-deoxy-D-glucose uptake was measured in these cells, they were more sensitive and responsive to insulin than wild-type L6 cells. LA, at concentrations ≤1 mmol/l, had only small effects on glucose transport in cells not exposed to oxidative stress. When cells were exposed to glucose oxidase and glucose to generate H 2 O 2 and cause oxidative stress, there was a marked decrease in insulinstimulated glucose transport. Pretreatment with LA over the concentration range of 10-1,000 µmol/l protected the insulin effect from inhibition by H 2 O 2 . Both the R and S isomers of LA were equally effective. In addition, oxidative stress caused a significant decrease (~50%) in reduced glutathione concentration, along with the rapid activation of the stress-sensitive p38 mitogen-activated protein kinase. Pretreatment with LA prevented both of these events, coincident with protecting insulin action. These studies indicate that in muscle, the major site of insulin-stimulated glucose disposal, one important effect of LA on the insulin-signaling cascade is to protect cells from oxidative stress-induced insulin resistance. Diabetes 50: [404][405][406][407][408][409][410] 2001

Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the “Two Hit Theory” to the “Multiple Hit Theory”. However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first “Achilles’ heel” of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.