Oxidation hypothesis

Heinecke JW (2001) Is the emperor wearing clothes Clinical trials of vitamin E and the LDL oxidation hypothesis. Arterioscler Thromb Vase Biol 21 1261—1264... 

There is now strong evidence that LDL oxidation does indeed occur in vivo (see later) and strong clinical validation of the oxidation hypothesis has been achieved. The... 

It is well known that high concentrations of LDL, specifically oxidized LDL, are risk factors for coronary artery disease. This fact is explained by the oxidative hypothesis of atherogenesis. According to this hypothesis, the atheroma is formed by foam cells from the vascular subendothelium that derive from macrophages that have picked up previously oxidized LDL in an uncontrolled manner. These lipoproteins are cytotoxic to the endothelium and, in addition, chemotactic to macrophages and monocytes,... 

Results for the hydroxyl value determination were inconclusive the precision of the method and the normal range of results for receipts of EO were not significantly different. Combined with the finding of zero for the peroxide value, the oxidation hypothesis seems less likely. Moisture content and pH results were more interesting. Normally, pH readings on the ethoxylate were above 10. The moisture values were somewhat above typical values. These two results do not really support or refute the hypothesis of EO oxidation, but when solving a problem, any unusual or unexpected results are noteworthy. 

Two different instrumental measurements were used to test the oxidation hypothesis GC and atomic absorption (AA). GC was used to determine the chain length distribution of the EO. From the GC results, an average chain length number was calculated. The gas chromatogram is shown in Fig. 21.1. In addition, headspace GC measurement of the gaseous compounds dissolved in the liquid ethoxylate was made and compared to typical or good product. Atomic absorption spectroscopy was used to determine the levels of several trace metals known to catalyze oxidation of fatty chemicals. 

The oxidation hypothesis of atherosclerosis states that oxidation of lipids in LDL is required for LDL uptake by macrophages and smooth muscle cells in the in-tima of arteries, leading to their transformation to foam... 

The oxidation hypothesis of atherosclerosis states that the oxidative modification of LDL (or other lipoproteins) is important and possibly obligatory in the pathogenesis of the atherosclerotic lesion thus, it has been suggested that inhibiting the oxidation of LDL will decrease or prevent atherosclerosis and clinical sequelae. LDL oxidation also has important implications for vascular health function. High concentrations of LDL may inhibit arterial function in terms of the release of nitric oxide from the endothelium and many of these effects are mediated by lipid oxidation products. Furthermore, oxidized LDL inhibits endothelium-dependent nitric oxide-mediated relaxations in isolated rabbit coronary arter-... 

Given this background, it is only possible at present to pose hypotheses and to test them against the available data. The two main hypotheses regarding the source and mobilization of As that have emerged are (i) the pyrite oxidation hypothesis, and (ii) the iron oxide reduction hypothesis. A number of other hypotheses have also been proposed but so far, at least, with less widespread support. We discuss these below. A more detailed discussion is given in Kinniburgh (2001). 

The pyrite oxidation hypothesis would predict that arsenic concentrations would be greatest in the shallowest groundwaters close to the water table since this is where the influence of oxidation would be greatest. The NHS results indicate that this is not the case the Lakshmipur piezometers show that arsenic concentrations increase sharply between 10 and 20 m rather than decrease. This is also supported by the NHS data which shows that the very shallowest wells (<15 m) tend to have lower As concentrations than the deeper wells. Dug weUs would also be expected to be the source of high As concentrations whereas the evidence is precisely the opposite. 

There are two schools of thought about the time of the initial As mobilization either (i) it is recent and has been induced by man s activities [there are proponents of this who support both the pyrite oxidation hypothesis and the iron oxide reduction hypothesis (Acharyya et al., 2000)], or (ii) it occurred much earlier and is therefore dominantly a natural process. While we believe that an early release date, (ii) above, is the more likely, this is not to imply that man s recent activities have not had, or will not have, any impact on the extent of the groundwater arsenic problem. For example, recent changes in land use such as irrigation will not only alter the groundwater flow patterns but could also affect the boundary conditions for oxygen diffusion into the aquifer and so could also affect its redox status (Bhattacharya et al., 1997). 

A corollary of the oxidation hypothesis of atherogenesis is that antioxidants may reduce the progression of the disease (114). Antioxidants present in LDL, including alpha-tocopherol, and antioxidants present in the extracellular fluid of the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation (132), and this action is extended to multiple oxLDL-mediated signaling pathways (133). Vitamin C may potentiate NO activity and normalize vascular function in patients with CHD and classical risk factors (132). Thus, NO may restore endothelial dysfunction and ameliorate vascular remodeling in several clinical correlates to experimental... 

Another difficulty with the metal oxide hypothesis is that the observed sum of the vertical electron equivalent gradients of Mn(II) and Fe(II) is much less than that of sulfide (Figure 7). In a simple vertical, steady-state system where the upward flux of Mn(II) and Fe(II) results in oxidized particulate metal oxides, which in turn settle to oxidize sulfide, the electron gradients of Mn(II) + Fe(II) would equal that for sulfide. The fact that they do not equal it suggests that the vertical flux of Mn(II) + Fe(II) would not produce sufficient particulate metal oxides. This problem would be solved if the particulate oxides were produced primarily at the boundaries and transported into the interior (40). 

McCann SM, Licinio J, Wong ML, Yu WH, Karanth S, Rettorri V. The nitric oxide hypothesis of aging. Exp Gerontol 1998 33 813-326. 

However, there are some gaps in the photochemical oxidant hypothesis. Probably, the decline is caused by ozone acting in combination of other stress as acid mist, drought, frost or pathogens. 

Felten, D.L., Felten, S.Y., Steece-Collier, K., Date, I. and Clemens, J.A. (1992) Age-related decline in the dopaminergic nigrostriatal system the oxidative hypothesis and protective strategies. Ann. Neurol. 32 (Suppl.) 133-136. 

Fig. 1. Oxidation hypothesis. Proposes minimally modified LDL is formed due to oxidation in the arterial intimal space. This LDL can still be taken up by the LDL receptor, but minimally modified LDL promotes release of proinflammatory mediators from monocytes and acts as a monocyte inhibition factor (MIF), reducing the motility of monocytes and thus leading to recruitment of macrophages (J4, W9). Macrophages further oxidize LDL (OxLDL), release inflammatory mediators, and rapidly take up OxLDL and other lipoproteins via the unregulated scavenger receptor that binds modified apo B to form lipid-laden foam cells. OxLDL is cytotoxic to a variety of cells in culture and may disrupt endothelial tissue, causing the release of inflammatory mediators and the entry of more LDL into the intimal space. Continued accumulation of monocytes and their differentiation into macrophages leads to a vicious cycle (J4, W9). Adapted from reference J4.

The oxidant hypothesis of IHD suggests that increased oxidant stress inside the vessel (either as the result of activated monocytes and macrophages secreting superoxide anion and hydrogen peroxide, or because of a defective antioxidant defense system) leads to peroxidation of unsatu-... 

The oxidation hypothesis that oxidatively modified LDL particles are retained in the intima of arteries leading to atherosclerosis is supported by considerable evidence, but remains unproven. The inflammation hypothesis has recently been emphasized in the mediation of all stages of atherosclerosis including initiation, and acute thrombotic complications of atheroma. Since many lipid oxidation products are pro-inflammatory, the inflammation and oxidation hypotheses are closely linked. Oxidized LDL and the oxidized phosphatidylcholine components of LDL are in fact pro-inflammatory and have proatherogenic properties. In addition to LDL, other lipoprotein particles including VLDL and a subfraction called beta VLDL and IDL may undergo oxidation, activate inflammation and become atherogenic. 

Studies indicate that extracts of berries cardioprotective effect (Whitson et al. 2004). For example, mechanisms for the prevention of atherosclerosis by dietary antioxidants in fruits have been proposed. In the LDL oxidation hypothesis, oxidized LDL cholesterol by free radicals has been suggested as the atherogenic factor that contributes to cardiovascular disease (CVD) (Berliner et al. 1997 Witztum and Berliner 1998). When circulating LDLs are present at high levels in blood, they infiltrate the artery wall and increase intimal LDL, which can then be oxidized by free radicals. This oxidized LDL, in the intima is more atherogenic than native LDL and serves as a chemotactic factor in the recruitment of circulating monocytes and macrophages. Dietary phytochemicals served as antioxidants that are incorporated into LDL are themselves oxidized when the LDL is exposed to free radicals this... 

This oxidation hypothesis was put to practice by Buchi in 1982 in an elegant synthesis of dibromophakeUin [37] (Scheme 13.7). After coupling of pyrrole 47 and aminoimid-azole 48 to yield dihydrooroidin (40), oxidation with bromine in acetic acid produced an insoluble material that was not fully characterized but was assumed to be compound 49. Treatment of 49 with base then led to quantitative conversion to dibromophakeUin. Home later improved the process by... 

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