Signal transduction activated by the cancer chemopreventive isothiocyanates: cleavage of BID protein, tyrosine phosphorylation and activation of JNK

Phenethyl isothiocyanate and allyl isothiocyanate induce apoptosis of human leukaemia HL60 cells in vitro. Apoptosis was associated with cleavage of p22 BID protein to p15, p13 and p11 fragments and activation of JNK and tyrosine phosphorylation (18 kDa and 45 kDa proteins). All these effects and apoptosis were prevented by exogenous glutathione (15 mM). Protein tyrosine phosphatase activity was unchanged. The general caspase inhibitor Z-VAD-fmk prevented apoptosis but not JNK activation – excluding a role for caspases in JNK activation, whereas curcumin prevented JNK activation but only delayed apoptosis. This suggests that in isothiocyanate-induced apoptosis, the caspase pathway has an essential role, the JNK pathway a supporting role, and inhibition of protein tyrosine phosphatases is not involved. © 2001 Cancer Research Campaign http://www.bjcancer.co

Grain Size Constraints on Glacial Circulation in the Southwest Atlantic

Knowledge of past deep-ocean current speeds has the potential to inform our understanding of changes in the climate system on glacial-interglacial timescales, because they may be used to help constrain changes in deep-ocean circulation rates and pathways. Of particular interest is the paleo-flow speed of southern-sourced deep water, which may have acted as a carbon store during the last glacial period. A location of importance in the northward transport of southern-sourced bottom water is the Vema Channel, which divides the Argentine and Brazil basins in the South Atlanti c. We revisit previous studies of paleo-flow in Vema Channel using updated techniques in grain size analysis (i.e., mean sortable silt grain size), in Vema Channel cores and cores from the Brazil margin. Furthermore, we update the interpretation of the previous grain size studies in the light of many years further research into the glacial circulation of the deep Atlantic. Our results are broadly consistent with the existing data and suggest that during the last glacial period there was slightly more vigorous intermediate to middepth (shallower than 2,600 m) circulation in the South Atlantic Ocean than during the Holocene, whereas around 3,500 m the circulation was generally more sluggish. Increased glacial flow speed on the eastern side of the Vema Channel was likely related to an increase in northward velocity of AABW in the channel. An increase in Antarctic Bottom Water flow through the Vema Channel may have helped to sustain the large volume of southern-sourced deep water in the Atlantic during the glacial period

A last millennium perspective on North Atlantic variability: exploiting synergies between models and proxy data

The North Atlantic is a key region for decadal prediction as it has experienced significant multi-decadal variability over the observed period. This variability, which is thought to be intrinsic to the region, can potentially modulate, either by amplifying or mitigating, the global warming signal from anthropogenic greenhouse emissions. For example, studies suggest that the North Atlantic contributed to the recent hiatus period between 1998 and 2012, by triggering an atmospheric response which impacted on the eastern tropical Pacific (e.g. McGregor et al., 2014). The subpolar North Atlantic is also a major CO2 sink, and therefore of great importance for the global carbon cycle (Perez et al., 2013). One of the key players in the North Atlantic region is the Atlantic Meridional Overturning Circulation (AMOC), which is associated with sinking due to deep water formation in the Labrador and Nordic Seas. The AMOC is the primary control of the poleward heat transport in the Atlantic region. Therefore, the AMOC is associated with important climate impacts, and plays an active role in various feedback mechanisms with, for example, sea ice (Mahajan et al., 2011) and the atmospheric circulation (Gastineau and Frankignoul, 2012). The AMOC has exhibited abrupt variations in the past (e.g. the last glacial period, Rahmstorf, 2002) and could experience a major slowdown in the future due to the combined effect of surface warming and Greenland ice sheet melting on deep water formation (Bakker et al., 2016). The possibility of such a shutdown has stimulated considerable international efforts to observe and reconstruct the past AMOC changes. Only by understanding its natural variability will we be able to detect and anticipate an anthropogenic impact on the AMOC. Decadal modulations are also found in other large-scale modes of climate variability, such as the North Atlantic Oscillation (NAO) (Stephenson et al., 2000), the Subpolar Gyre strength (SPG) (Häkkinen and Rhines, 2004) and the Atlantic Multidecadal Variability (AMV) (Enfield et al., 2001), which have all been linked with widespread climate impacts over the surrounding continents. Modelling studies suggest that all these modes interact with the AMOC (Gastineau and Frankignoul, 2012; Hátún et al., 2005; Knight et al., 2005) but the exact interrelationships are complex and remain to be disentangled. Also to be determined are the underlying mechanisms responsible for the decadal and centennial AMOC modulations, with different climate models showing different key drivers (Menary et al., 2015a). Similarly, the exact impact of the natural external forcings (e.g. volcanic aerosols, solar irradiance) on the variability of these different largescale climate modes still remains unclear

Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin

OBJECTIVE The aim of this study was to investigate whether apolipoprotein B100 of LDL suffers increased damage by glycation, oxidation, and nitration in patients with type 2 diabetes, including patients receiving metformin therapy. RESEARCH DESIGN AND METHODS For this study, 32 type 2 diabetic patients and 21 healthy control subjects were recruited; 13 diabetic patients were receiving metformin therapy (median dose: 1.50 g/day). LDL was isolated from venous plasma by ultracentrifugation, delipidated, digested, and analyzed for protein glycation, oxidation, and nitration adducts by stable isotopic dilution analysis tandem mass spectrometry. RESULTS Advanced glycation end product (AGE) content of apolipoprotein B100 of LDL from type 2 diabetic patients was higher than from healthy subjects: arginine-derived AGE, 15.8 vs. 5.3 mol% (P < 0.001); and lysine-derived AGE, 2.5 vs. 1.5 mol% (P < 0.05). Oxidative damage, mainly methionine sulfoxide residues, was also increased: 2.5 vs. 1.1 molar equivalents (P < 0.001). 3-Nitrotyrosine content was decreased: 0.04 vs. 0.12 mol% (P < 0.05). In diabetic patients receiving metformin therapy, arginine-derived AGE and methionine sulfoxide were lower than in patients not receiving metformin: 19.3 vs. 8.9 mol% (P < 0.01) and 2.9 vs. 1.9 mol% (P < 0.05), respectively; 3-nitrotyrosine content was higher: 0.10 vs. 0.03 mol% (P < 0.05). Fructosyl-lysine residue content correlated positively with fasting plasma glucose. Arginine-derived AGE residue contents were intercorrelated and also correlated positively with methionine sulfoxide. CONCLUSIONS Patients with type 2 diabetes had increased arginine-derived AGEs and oxidative damage in apolipoprotein B100 of LDL. This was lower in patients receiving metformin therapy, which may contribute to decreased oxidative damage, atherogenicity, and cardiovascular disease

Surface changes in the eastern Labrador Sea around the onset of the Little Ice Age

Despite the relative climate stability of the present interglacial, it has been punctuated by several centennial-scale climatic oscillations; the latest of which are often colloquially referred to as the Medieval Climatic Anomaly (MCA) and the Little Ice Age (LIA). The most favored explanation for the cause of these anomalies is that they were triggered by variability in solar irradiance and/or volcanic activity and amplified by ocean-atmosphere-sea ice feedbacks. As such, changes in the strength of the Atlantic Meridional Overturning Circulation (AMOC) are widely believed to have been involved in the amplification of such climatic oscillations. The Labrador Sea is a key area of deep water formation. The waters produced here contribute approximately one third of the volume transport of the deep limb of the AMOC and drive changes in the North Atlantic surface hydrography and subpolar gyre circulation. In this study, we present multiproxy reconstructions from a high-resolution marine sediment core located south of Greenland that suggest an increase in the influence of polar waters reaching the Labrador Sea close to MCA-LIA transition. Changes in freshwater forcing may have reduced the formation of Labrador Sea Water and contributed toward the onset of the LIA cooling. © 2014. The Authors

A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes

The glycation of protein and nucleic acids that occurs as a consequence of hyperglycaemia disrupts cell function and contributes to many pathologies, including those associated with diabetes and aging. Intracellular glycation occurs following the generation of the reactive 1,2-dicarbonyls methylglyoxal and glyoxal and disruption to mitochondrial function is associated with hyperglycemia. However, the contribution of these reactive dicarbonyls to mitochondrial damage in pathology is unclear due to uncertainties about their levels within mitochondria in cells and in vivo. To address this we have developed a mitochondria-targeted reagent (MitoG) designed to assess the levels of mitochondrial dicarbonyls within cells. MitoG comprises a lipophilic triphenylphosphonium cationic function, which directs the molecules to mitochondria within cells and an o-phenylenediamine moiety that reacts with dicarbonyls to give distinctive and stable products. The extent of accumulation of these diagnostic heterocyclic products can be readily and sensitively quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), enabling changes to be determined. Using the MitoG-based analysis we assessed the formation of methylglyoxal and glyoxal in response to hyperglycaemia in cells in culture and in the Akita mouse model of diabetes in vivo. These findings indicated that the levels of methylglyoxal and glyoxal within mitochondria increase during hyperglycaemia in both cells and in vivo, suggesting that they can contribute to the pathological mitochondrial dysfunction that occurs in diabetes and aging

Overexpression of Glyoxalase-I in Bovine Endothelial Cells Inhibits Intracellular Advanced Glycation Endproduct Formation and prevents hyperglycemia-induced increases in macromolecular endocytosis.

Methylglyoxal (MG), a dicarbonyl compound produced by the fragmentation of triose phosphates, forms advanced glycation endproducts (AGEs) in vitro. Glyoxalase-I catalyzes the conversion of MG to S-D-lactoylglutathione, which in turn is converted to D-lactate by glyoxalase-II. To evaluate directly the effect of glyoxalase-I activity on intracellular AGE formation, GM7373 endothelial cells that stably express human glyoxalase-I were generated. Glyoxalase-I activity in these cells was increased 28-fold compared to neo-transfected control cells (21.80+/-0.1 vs. 0. 76+/-0.02 micromol/min/mg protein, n = 3, P \u3c 0.001). In neo-transfected cells, 30 mM glucose incubation increased MG and D-lactate concentration approximately twofold above 5 MM (35.5+/-5.8 vs. 19.6+/-1.6, P \u3c 0.02, n = 3, and 21.0+/-1.3 vs. 10.0+/-1.2 pmol/ 10(6) cells, n = 3, P \u3c 0.001, respectively). In contrast, in glyoxalase-I-transfected cells, 30 mM glucose incubation did not increase MG concentration at all, while increasing the enzymatic product D-lactate by \u3e 10-fold (18.9+/-3.2 vs. 18.4+/- 5.8, n = 3, P = NS, and 107.1+/-9.0 vs. 9.4+/-0 pmol/10(6) cells, n = 3, P \u3c 0.001, respectively). After exposure to 30 mM glucose, intracellular AGE formation in neo cells was increased 13.6-fold (2.58+/-0.15 vs. 0.19+/-0.03 total absorbance units, n = 3, P \u3c 0.001). Concomitant with increased intracellular AGEs, macromolecular endocytosis by these cells was increased 2.2-fold. Overexpression of glyoxalase-I completely prevented both hyperglycemia-induced AGE formation and increased macromolecular endocytosis

Інтеграційні процеси в паливно-енергетичному комплексі як фактор забезпечення екологічної безпеки

Challenge tests stress homeostasis and may reveal deviations in health that remain masked under unchallenged conditions. Ideally, challenge tests are non-invasive and applicable in an early phase of an animal experiment. Oxygen restriction (OxR; based on ambient, mild normobaric hypoxia) is a non-invasive challenge test that measures the flexibility to adapt metabolism. Metabolic inflexibility is one of the hallmarks of the metabolic syndrome. To test whether OxR can be used to reveal early diet-induced health effects, we exposed mice to a low-fat (LF) or high-fat (HF) diet for only 5 days. The response to OxR was assessed by calorimetric measurements, followed by analysis of gene expression in liver and epididymal white adipose tissue (eWAT) and serum markers for e.g. protein glycation and oxidation. Although HF feeding increased body weight, HF and LF mice did not differ in indirect calorimetric values under normoxic conditions and in a fasting state. Exposure to OxR; however, increased oxygen consumption and lipid oxidation in HF mice versus LF mice. Furthermore, OxR induced gluconeogenesis and an antioxidant response in the liver of HF mice, whereas it induced de novo lipogenesis and an antioxidant response in eWAT of LF mice, indicating that HF and LF mice differed in their adaptation to OxR. OxR also increased serum markers of protein glycation and oxidation in HF mice, whereas these changes were absent in LF mice. Cumulatively, OxR is a promising new method to test food products on potential beneficial effects for human health