TO THE EDITORS: We thank Bhogal et al. 1 for their comments on our review, 2 and we shall address the points that they raised. Most aerobic cells will generate small amounts of reactive oxygen species (ROS) during normal cellular respiration, but these are effectively handled by the various cellular antioxidant systems to which we alluded in our review. Moreover, most aerobic cells will increase their rate of ROS generation during ischemia/reperfusion (IR). 3 Hepatocytes are no exception and do increase their rate of ROS production after IR. Indeed, this is clearly demonstrated in Fig. 2 of our review. The more imperative issue is the relative contribution of IR-generated ROS from Kupffer cells, neutrophils, and hepatocytes to the induction and propagation of liver IR injury. As outlined in our review and by others, 4 Kupffer cells and neutrophils are the main contributors to ROS generation after IR, with Kupffer cells making the greatest contribution to ROS generation in the early phase after reperfusion. Additionally, Bhogal et al. 1 remarked that hepatocytes produce proinflammatory cytokines and chemokines after IR. The available evidence supports this as we have discussed in our review. REFERENCES 1. Bhogal RH, Sutaria R, Afford SC. Hepatic Liver ischemia/ reperfusion injury: processes in inflammatory networks-a Review. Liver Transpl 2011:17:95. 2. Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: processes in inflammatory networks-a review. Liver Transpl 2010; 16:1016-1032. 3. Li C, Jackson RM. Reactive species mechanisms of cellular hypoxia-reoxygenation injury.
Evidence has been presented that the plasma concentration ratio of triglyceride (TG)/HDL-cholesterol (HDL-C) may provide a relatively simple way to identify apparently healthy insulin-resistant persons with increased cardiometabolic risk ( 1, 2 ). However, there is evidence that the actual values of the ratio that best identifi es such individuals will vary as a function of racial/ethnic background ( 3-7 ). More recently, it has also been shown that the most useful TG/ HDL-C cut-point to identify cardiometabolic risk is not the same in men and women ( 2 ). However, there is essentially no information as to whether age also modifi es the ability of the TG/HDL-C ratio to identify apparently healthy individuals with increased cardiometabolic risk. The primary goal of this analysis was to address this issue, and it is based on data obtained in an apparently healthy population of young men and women, mean age of 19 years. Second, since the diagnostic category of the metabolic syndrome (MetS) is commonly used to identify cardiometabolic risk in apparently healthy individuals ( 3, 8 ), our second goal was to compare these two approaches to identify insulin resistance (IR) and associated cardiometabolic risk in a population of young adults . In support of this effort is the recent observation that the plasma concentration ratio of TG/HDL-C was an independent determinant of arterial stiffness in adolescents and young adults ( 9 ). SUBJECTS AND METHODSThis study presents results obtained from an epidemiological study from which data of a different nature have been published previously ( 10 ).Abstract Studies in mature adults suggest that the plasma concentration ratio of triglyceride (TG)/HDL-cholesterol (HDL-C) provides a simple way to identify apparently healthy individuals who are insulin resistant (IR) and at increased cardiometabolic risk. This study extends these observations by examining the clinical utility of the TG/HDL-C ratio and the metabolic syndrome (MetS) in 2,244 healthy college students (17-24 years old) of Mexican Mestizo ancestry. The TG/HDL-C ratio separating the 25% with the highest value was used to identify IR and increased cardiometabolic risk. Cardiometabolic risk factors were more adverse in men and women whose TG/HDL-C ratios exceeded 3.5 and 2.5, respectively, and approximately one third were identifi ed as being IR. The MetS identifi ed fewer individuals as being IR, but their risk profi le was accentuated. In conclusion, both a higher TG/HDL-C ratio and a diagnosis of the MetS identify young IR individuals with an increased cardiometabolic risk profi le. The TG/HDL-C ratio identifi ed a somewhat greater number of "high risk" subjects, whereas the MetS found a group whose risk profi le was somewhat magnifi ed. These fi ndings suggest that the TG/ HDL-C ratio may serve as a simple and clinically useful approach to identify apparently healthy, young individuals who are IR and at increased cardiometabolic risk.
A comprehensive, structural and functional, in silico analysis of the medium-chain dehydrogenase/reductase (MDR) superfamily, including 583 proteins, was carried out by use of extensive database mining and the BLASTP program in an iterative manner to identify all known members of the superfamily. Based on phylogenetic, sequence, and functional similarities, the protein members of the MDR superfamily were classified into three different taxonomic categories: (a) subfamilies, consisting of a closed group containing a set of ideally orthologous proteins that perform the same function; (b) families, each comprising a cluster of monophyletic subfamilies that possess significant sequence identity among them and might share or not common substrates or mechanisms of reaction; and (c) macrofamilies, each comprising a cluster of monophyletic protein families with protein members from the three domains of life, which includes at least one subfamily member that displays activity related to a very ancient metabolic pathway. In this context, a superfamily is a group of homologous protein families (and/or macrofamilies) with monophyletic origin that shares at least a barely detectable sequence similarity, but showing the same 3D fold.The MDR superfamily encloses three macrofamilies, with eight families and 49 subfamilies. These subfamilies exhibit great functional diversity including noncatalytic members with different subcellular, phylogenetic, and species distributions. This results from constant enzymogenesis and proteinogenesis within each kingdom, and highlights the huge plasticity that MDR superfamily members possess. Thus, through evolution a great number of taxa-specific new functions were acquired by MDRs. The generation of new functions fulfilled by proteins, can be considered as the essence of protein evolution. The mechanisms of protein evolution inside MDR are not constrained to conserve substrate specificity and/or chemistry of catalysis. In consequence, MDR functional diversity is more complex than sequence diversity.MDR is a very ancient protein superfamily that existed in the last universal common ancestor. It had at least two (and probably three) different ancestral activities related to formaldehyde metabolism and alcoholic fermentation. Eukaryotic members of this superfamily are more related to bacterial than to archaeal members; horizontal gene transfer among the domains of life appears to be a rare event in modern organisms.Keywords: protein taxonomy; protein evolution; mediumchain alcohol dehydrogenase; enoyl reductase; formaldehyde dehydrogenase.Correspondence to H. Riveros-Rosas, Depto. Bioquı´mica, Fac. Medicina, UNAM, Apdo. Postal 70-159, Cd. Universitaria, Me´xico, 04510, D.F., Me´xico. Fax: + 52 55 5616 2419, Tel.: + 52 55 5622 0829, E-mail: hriveros@servidor.unam.mx Abbreviations: AADH, allyl alcohol dehydrogenase; ACR, acyl-CoA reductase; ADH, alcohol dehydrogenase; AL, alginate lyase; ARP, auxinregulated protein; AST, membrane traffic protein; BCHC, 2-desacetyl-2-hydroxyethyl bacteriochlorophyll...
Inosine, an endogenous nucleoside, has recently been shown to exert potent effects on the immune, neural, and cardiovascular systems. This work addresses modulation of intermediary metabolism by inosine through adenosine receptors (ARs) in isolated rat hepatocytes. We conducted an in silico search in the GenBank and complete genomic sequence databases for additional adenosine/inosine receptors and for a feasible physiological role of inosine in homeostasis. Inosine stimulated glycogenolysis (approximately 40%, EC50 4.2 x 10(-9) M), gluconeogenesis (approximately 40%, EC50 7.8 x 10(-9) M), and ureagenesis (approximately 130%, EC50 7.0 x 10(-8) M) compared with basal values; these effects were blunted by the selective A3 AR antagonist 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]-triazolo[1,5-c]quinazoline (MRS 1220) but not by selective A1, A2A, and A2B AR antagonists. In addition, MRS 1220 antagonized inosine-induced transient increase (40%) in cytosolic Ca2+ and enhanced (90%) glycogen phosphorylase activity. Inosine-induced Ca2+ mobilization was desensitized by adenosine; in a reciprocal manner, inosine desensitized adenosine action. Inosine decreased the cAMP pool in hepatocytes when A1, A2A, and A2B AR were blocked by a mixture of selective antagonists. Inosine-promoted metabolic changes were unrelated to cAMP decrease but were Ca2+ dependent because they were absent in hepatocytes incubated in EGTA- or BAPTA-AM-supplemented Ca2+-free medium. After in silico analysis, no additional cognate adenosine/inosine receptors were found in human, mouse, and rat. In both perfused rat liver and isolated hepatocytes, hypoxia/reoxygenation produced an increase in inosine, adenosine, and glucose release; these actions were quantitatively greater in perfused rat liver than in isolated cells. Moreover, all of these effects were impaired by the antagonist MRS 1220. On the basis of results obtained, known higher extracellular inosine levels under ischemic conditions, and inosine's higher sensitivity for stimulating hepatic gluconeogenesis, it is suggested that, after tissular ischemia, inosine contributes to the maintenance of homeostasis by releasing glucose from the liver through stimulation of A3 ARs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.