{"title":"Selenium and diabetes--evidence from animal studies.","authors":"Jun Zhou, Kaixun Huang, Xin Gen Lei","doi":"10.1016/j.freeradbiomed.2013.07.012","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.07.012","url":null,"abstract":"<p><p>Whereas selenium was found to act as an insulin mimic and to be antidiabetic in earlier studies, recent animal experiments and human trials have shown an unexpected risk of prolonged high Se intake in potentiating insulin resistance and type 2 diabetes. Elevating dietary Se intake (0.4 to 3.0mg/kg of diet) above the nutrient requirements, similar to overproduction of selenoproteins, led to insulin resistance and/or diabetes-like phenotypes in mice, rats, and pigs. Although its diabetogenic mechanism remains unclear, high Se intake elevated activity or production of selenoproteins including GPx1, MsrB1, SelS, and SelP. This upregulation diminished intracellular reactive oxygen species and then dysregulated key regulators of β cells and insulin synthesis and secretion, leading to chronic hyperinsulinemia. Overscavenging intracellular H2O2 also attenuated oxidative inhibition of protein tyrosine phosphatases and suppressed insulin signaling. High Se intake might affect expression and/or function of key regulators of glycolysis, gluconeogenesis, and lipogenesis. Future research is needed to find out if certain forms of Se metabolites in addition to selenoproteins and if mechanisms other than intracellular redox control mediate the diabetogenic effects of high Se intake. Furthermore, a potential interactive role of high Se intake in the interphase of carcinogenesis and diabetogenesis should be explored to make optimal use of Se in human nutrition and health. </p>","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1548-1556"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.07.012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31590853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Introduction to serial reviews on selenium and diabetes type 2--an unexpected link.","authors":"Regina Brigelius-Flohé","doi":"10.1016/j.freeradbiomed.2013.07.018","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.07.018","url":null,"abstract":"","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1536-1537"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.07.018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31590852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Interference of selenium and selenoproteins with the insulin-regulated carbohydrate and lipid metabolism.","authors":"Holger Steinbrenner","doi":"10.1016/j.freeradbiomed.2013.07.016","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.07.016","url":null,"abstract":"<p><p>An assumed link between supranutritional intake of the micronutrient selenium (Se) and type 2 diabetes mellitus is discussed controversially. Se concentrations in the habitual diet and in dietary supplements are probably not sufficient to induce overt diabetes in healthy individuals. On the other hand, high plasma Se and selenoprotein P (Sepp1) levels have been found to be associated with biomarkers of an impaired carbohydrate and lipid homeostasis in humans. Moreover, abundant expression of antioxidant selenoproteins due to dietary Se oversupply resulted in hyperinsulinemia and decreased insulin sensitivity in animal models. This review discusses findings from animal and cell culture studies in search of molecular mechanisms underlying an interference of Se and selenproteins such as the Se transport and supply protein Sepp1 and the hydrogen peroxide-reducing selenoenzyme glutathione peroxidase 1 (GPx1) with insulin-controlled metabolic pathways. A probable rationale derives from the positive and negative regulation of both glucose-induced insulin secretion and insulin-induced signaling by hydrogen peroxide. Se status and GPx1 expression have been reported to affect the activity of insulin-antagonistic phosphatases that are regulated by hydrogen peroxide-mediated reversible oxidation of catalytic cysteine residues. GPx1 and/or Sepp1 inhibited phosphorylation (activation) of key mediators in energy metabolism such as protein kinase B (Akt) and AMP-activated protein kinase (AMPK) in liver and/or skeletal muscle. Conversely, a dys-regulated carbohydrate metabolism in diabetes might affect plasma Se and Sepp1 levels, as the hepatic biosynthesis of Sepp1 is suppressed by insulin and stimulated under hyperglycemic conditions. </p>","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1538-1547"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.07.016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31595803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Simultaneous ultraviolet B-induced photo-oxidation of tryptophan/tyrosine and racemization of neighboring aspartyl residues in peptides.","authors":"Simin Cai, Norihiko Fujii, Takeshi Saito, Noriko Fujii","doi":"10.1016/j.freeradbiomed.2013.08.171","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.08.171","url":null,"abstract":"<p><p>Although proteins consist exclusively of l-amino acids, it is well known that d-isomers of aspartyl (Asp) residues occur at specific sites in lens crystallins of elderly people with cataracts. The presence of d-isomers is thought to result from the racemization of Asp residues in the crystallins during aging. It has been reported that this racemization progresses owing to UV-B exposure; however, the underlying mechanism remains unknown because Asp is not a photosensitive residue because there is no aromatic group in its chemical structure. In this study, we synthesized peptides in which the residue neighboring the Asp was the photosensitive residue tryptophan (Trp) or tyrosine (Tyr). After exposing these peptides to UV-B, we used RP-HPLC to confirm that racemization of Asp residues occurred in peptides in which a Trp or Tyr residue was inserted near the Asp; simultaneously, several varieties of photoproducts derived from Trp and Tyr were detected by mass spectroscopy. Promotion of the racemization of Asp residues in peptides with a neighboring Trp was much more significant than in those with Tyr. In particular, when Trp was next to an Asp residue on the C-terminal side of the peptide, the racemization reaction was accelerated. </p>","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1037-1046"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.08.171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31702784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Petri Kresanov, Markku Ahotupa, Tommi Vasankari, Jari Kaikkonen, Mika Kähönen, Terho Lehtimäki, Jorma Viikari, Olli T Raitakari
{"title":"The associations of oxidized high-density lipoprotein lipids with risk factors for atherosclerosis: the Cardiovascular Risk in Young Finns Study.","authors":"Petri Kresanov, Markku Ahotupa, Tommi Vasankari, Jari Kaikkonen, Mika Kähönen, Terho Lehtimäki, Jorma Viikari, Olli T Raitakari","doi":"10.1016/j.freeradbiomed.2013.09.023","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.09.023","url":null,"abstract":"<p><p>Scavenging and reverse transport of atherogenic oxidized lipids by high-density lipoprotein (HDL) was recently suggested to contribute to atheroprotection. We investigated the associations of oxidized HDL lipids (oxHDLlipids) with known risk factors for atherosclerosis in a population-based cross-sectional study of 1395 Finnish adults ages 24-39 years (54.9% women). Analysis of oxidized lipids in isolated HDL and LDL (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was measured also with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and risk factors were measured. In multivariable models, oxHDLlipids were associated inversely with age (partial R(2)=2.9% in men, 0.8% in women) and directly with oxLDLlipids (partial R(2)=3.4% in men, 4.2% in women) after adjustment for Apo-A1 (partial R(2)=9.6% in men, 25.2% in women). In men, oxHDLlipids were also associated inversely with insulin (partial R(2)=1.1%). In women, oxHDLlipids were additionally inversely associated with waist circumference (partial R(2)=1.8%) and daily smoking (partial R(2)=0.7%) and directly with C-reactive protein (CRP; partial R(2)=0.5%) and alcohol use (partial R(2)=0.5%). We conclude that an elevated risk profile characterized primarily by advanced age is associated with lower oxHDLlipid levels in a population of young Finnish men and women. Higher levels of oxHDLlipids are additionally associated with higher oxLDLlipid levels. In men, higher insulin levels are also associated with lower oxHDLlipid levels. In women, increased waist circumference and daily smoking are also associated with lower oxHDLlipid levels, and higher CRP levels and alcohol use are associated with higher oxHDLlipid levels. </p>","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1284-1290"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.09.023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31781585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Apostolos Zarros, Stephanie D Boomkamp, Stylianos Tsakiris, George S Baillie
{"title":"The extent and the nature of the cholinergic contribution to the hepatic encephalopathy-induced cognitive impairment.","authors":"Apostolos Zarros, Stephanie D Boomkamp, Stylianos Tsakiris, George S Baillie","doi":"10.1016/j.freeradbiomed.2013.08.165","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.08.165","url":null,"abstract":"","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1516-1517"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.08.165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31681422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Md Jamal Uddin, Yeonsoo Joe, Min Zheng, Perry J Blackshear, Stefan W Ryter, Jeong Woo Park, Hun Taeg Chung
{"title":"A functional link between heme oxygenase-1 and tristetraprolin in the anti-inflammatory effects of nicotine.","authors":"Md Jamal Uddin, Yeonsoo Joe, Min Zheng, Perry J Blackshear, Stefan W Ryter, Jeong Woo Park, Hun Taeg Chung","doi":"10.1016/j.freeradbiomed.2013.09.027","DOIUrl":"10.1016/j.freeradbiomed.2013.09.027","url":null,"abstract":"<p><p>Nicotine stimulates the cholinergic anti-inflammatory pathway and prevents excessive inflammation by inhibiting the release of inflammatory cytokines from macrophages. We have previously reported that heme oxygenase-1 (HO-1) and tristetraprolin (TTP) are induced by nicotine and mediate the anti-inflammatory function of nicotine in macrophages. However, it was not clear whether the two molecules are functionally linked. In this study, we sought to determine whether HO-1 associates with TTP to mediate the anti-inflammatory effects of nicotine. Inhibition of HO-1 activity or HO-1 expression attenuated the effects of nicotine on STAT3 activation, TTP induction, and TNF-α production in LPS-treated macrophages. Induction of HO-1 expression increased the level of TTP in the absence of nicotine. In an LPS-induced endotoxemia model, HO-1 deficiency blocked the effects of nicotine on the STAT3 phosphorylation, TTP induction, and LPS-induced TNF-α production in the liver. Downregulation of STAT3 by siRNA attenuated the effect of nicotine on TTP expression and TNF-α production but did not affect the nicotine-mediated induction of HO-1. In TTP knockout mice, nicotine treatment enhanced HO-1 expression and STAT3 activation but failed to inhibit LPS-induced TNF-α production. Our results suggest that HO-1 and TTP are functionally linked in mediating the anti-inflammatory effects of nicotine; HO-1 is necessary for the induction of TTP by nicotine. This novel nicotine-HO-1-TTP signaling pathway provides new possibilities for the treatment of inflammatory diseases. </p>","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1331-9"},"PeriodicalIF":0.0,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798239/pdf/nihms767414.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31782543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Two hypotheses for the peroxidase activity of Mn-superoxide dismutase.","authors":"Ronald P Mason","doi":"10.1016/j.freeradbiomed.2013.02.013","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.02.013","url":null,"abstract":"","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1533"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.02.013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31254694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adam L Orr, Deepthi Ashok, Melissa R Sarantos, Tong Shi, Robert E Hughes, Martin D Brand
{"title":"Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening.","authors":"Adam L Orr, Deepthi Ashok, Melissa R Sarantos, Tong Shi, Robert E Hughes, Martin D Brand","doi":"10.1016/j.freeradbiomed.2013.08.170","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.08.170","url":null,"abstract":"<p><p>Mitochondrial production of reactive oxygen species is often considered an unavoidable consequence of aerobic metabolism and currently cannot be manipulated without perturbing oxidative phosphorylation. Antioxidants are widely used to suppress effects of reactive oxygen species after formation, but they can never fully prevent immediate effects at the sites of production. To identify site-selective inhibitors of mitochondrial superoxide/H2O2 production that do not interfere with mitochondrial energy metabolism, we developed a robust small-molecule screen and secondary profiling strategy. We describe the discovery and characterization of a compound (N-cyclohexyl-4-(4-nitrophenoxy)benzenesulfonamide; CN-POBS) that selectively inhibits superoxide/H2O2 production from the ubiquinone-binding site of complex I (site I(Q)) with no effects on superoxide/H2O2 production from other sites or on oxidative phosphorylation. Structure/activity studies identified a core structure that is important for potency and selectivity for site I(Q). By employing CN-POBS in mitochondria respiring on NADH-generating substrates, we show that site I(Q) does not produce significant amounts of superoxide/H2O2 during forward electron transport on glutamate plus malate. Our screening platform promises to facilitate further discovery of direct modulators of mitochondrially derived oxidative damage and advance our ability to understand and manipulate mitochondrial reactive oxygen species production under both normal and pathological conditions.</p>","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1047-1059"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.08.170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31698559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Detection and identification of oxidized insulin-like growth factor-binding proteins and receptors in patients with colorectal carcinoma.","authors":"Olgica Nedić, Dragana Robajac, Miloš Šunderić, Goran Miljuš, Blagoje Đukanović, Vesna Malenković","doi":"10.1016/j.freeradbiomed.2013.09.003","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2013.09.003","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and also the one with the highest mortality rate. Tumor growth is assisted by various growth factors, and insulin-like growth factors (IGFs) are among the most important. A majority of the IGFs are bound to IGF-binding proteins (IGFBPs) and their release is dependent on the rate of IGFBP proteolysis. The action of free IGFs is exerted and controlled by binding to cell membrane receptors (IGF-Rs). The objective of this work was to connect two determinants of the CRC pathology: oxidation as a process that underlies tumor development and the members of the IGF system that control it. Carbonyl groups (CO) on IGFBP-2, IGFBP-3, IGF-1R, and IGF-2R were determined in samples obtained from patients with CRC, and IGF-binding properties of these proteins were analyzed. According to our results, IGFBP-2 and IGFBP-3 in serum had increased content of CO groups due to CRC. Oxidation of IGFBP-2 increased its affinity for IGF molecules, whereas oxidation of IGFBP-3 reduced it. As for receptors, only intact CO-IGF-2R was detected on solubilized colon membranes, whereas CO-IGF-1R was degraded into fragments. Oxidative changes in the IGF axis may be regarded as part of the mechanism of its action. IGFs bound to IGFBP-3 remain in the circulation, whereas those bound to IGFBP-2 freely reach target tissues. Therefore, oxidation supports IGF distribution toward tissues and, consequently, promotes tumor growth. </p>","PeriodicalId":505743,"journal":{"name":"Free radical biology & medicine","volume":" ","pages":"1195-1200"},"PeriodicalIF":7.4,"publicationDate":"2013-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.freeradbiomed.2013.09.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31745871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}