Abstract. The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and N ⑀ -carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre-and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action.Advanced glycation and oxidation irreversibly modify proteins over the years and thus contribute to aging phenomena (1). Their local or generalized acceleration is associated with atherosclerosis (2-6) as well as with various diabetic (7-10) and uremic complications (11-13). Inhibition of advanced glycation end products (AGE) formation has thus become a therapeutic goal.Aminoguanidine, the first AGE inhibitor discovered in 1986 (14), and (Ϯ)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195) (15) are both hydrazine-derivatives. They inhibit in vitro the formation of AGE, pentosidine (16), and N ⑀ -carboxymethyllysine (CML) (17) from a variety of individual precursors, such as ribose, glucose, and ascorbate, as well as that of advanced lipoxidation end products (ALE), malondialdehyde-lysine and 4-hydroxynonenal-protein adduct (18), from arachidonate (19). They also inhibit pentosidine generation in diabetic and uremic plasma incubated for 4 wk (20).As expected, both compounds correct several biologic effects that are associated with AGE formation. In murine thymocyte and fibroblasts, they inhibit the phosphorylation of tyrosine residues of a number of intracellular proteins induced by cell surface Schiff base formation (21). Given to diabetic animal models, such as Otsuka-Long-Evans-Tokushima-Fatty (OLETF) or streptozotocin-treated rats, they reduce urinary albumin excretion and improve glomerular morphology (15,22). Oral admi...
Abstract. Prevention or retardation of diabetic nephropathy (DN) includes anti-hypertensive treatment with angiotensinconverting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on the premises that these drugs have an added protective effect beyond their influence on BP. The present study used a strain of spontaneously hypertensive/NIHcorpulent rats [SHR/NDmc-cp (fat/fat)] as a model of type II DN to unravel the renoprotective effects of anti-hypertensive drugs. Olmesartan (1 or 5 mg/kg per d), an ARB, and hydralazine (5mg/kg per d), an anti-hypertensive drug without effect on the renin-angiotensin system (RAS), were given for 20 wk. BP, renal function, glucose and insulin levels, and proteinuria were monitored. Glomerular lesions and kidney pentosidine content were assessed at the end of the study. Olmesartan (1 and 5 mg) significantly reduced BP and kidney pentosidine content and improved histologic renal damage and proteinuria.The changes were dose-dependent. The effect of hydralazine (5 mg) was similar to that of olmesartan (1 mg) but reached statistical significance only for kidney pentosidine content. The similarity of both drugs' effects on kidney damage and proteinuria suggest that renoprotection does not hinge on manipulation of RAS in these rats. By contrast, the inhibition of renal pentosidine formation assessed both by immunohistochemistry and HPLC suggests a critical role of advanced glycation end product (AGE) formation together with hypertension in the genesis of diabetic nephropathy. This view is supported by the correlation found between renal pentosidine content and proteinuria. The unsuspected AGE-lowering effect of hydralazine was further confirmed in vitro and elucidated; it is due to both reactive carbonyl compounds trapping and modifications of the oxidative metabolism. It is concluded that AGE inhibition should be included in the therapeutic strategy of DN.Diabetic nephropathy (DN) increases dramatically worldwide and is now the first cause of end-stage renal failure requiring renal replacement therapy (reviewed in references 1 and 2). Its prevention or retardation has thus become an important issue in biomedical research.Several large clinical trials have recently demonstrated that control of hypertension by angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blocker (ARB) significantly delayed the onset and progression of DN (3-5). This effect is due to the reduction of BP together with as-yet undefined additional mechanisms. Only studies of adequate experimental models will allow an in-depth exploration of DN pathogenic mechanisms and thus the development of newer therapeutic tools.In the present study, we use a strain of a spontaneously hypertensive/NIH-corpulent rat [SHR/NDmc-cp (fat/fat)] as a model of type 2 DN (6) to unravel the mechanisms of the ARB-induced renoprotection against DN. We demonstrate a dose-dependent, renoprotective effect of olmesartan, which is an ARB associated with the inhibition of advanced glycation en...
Specialized parasites can modify host behavior to benefit transmission and reproduction. Such behavior is considered an extended phenotype of the parasite. The interactions between certain ant species and fungi of the genus Ophiocordyceps form an evident example. Once infected by Ophiocordyceps camponoti-atricipis, Camponotus atriceps ants die, biting at specific sites where abiotic conditions are optimal for fungal development. For many species of free-living fungi, light is needed to induce growth of the reproductive stage. However, the role of light in Ophiocordyceps behavioral manipulation and fruiting body development is largely unknown. Here, we investigated the association between illuminance and the incidence of dead manipulated C. atriceps ants. We identified ant graveyards in the field and experimentally changed the incident illumination for half of each graveyard using shading screens. Such screens resulted in a clear reduction of incident light, as well as slightly higher, more stable humidity levels. We measured the appearance of recently died, infected ants, the height at which they were found, and their fruiting body production. The presence of dead infected C. atriceps was strongly influenced by experimental light reduction. Shaded areas harbored fewer recently infected ants compared to naturally illuminated areas. In addition, in shaded areas, a smaller number of ants produced fruiting bodies and these ants also appeared to have climbed to higher elevations in comparison to control areas. Our findings indicate that light influences the place of the C. atriceps death, and fungal development by seemingly affecting fruiting body formation in O. camponoti-atricipis.
The antibacterial activity of 35 isolates of Lentinula edodes, a shiitake mushroom, against Bacillus subtilis was evaluated by diffusion technique in agar with a semi-solid overlay. All isolates inhibited B. subtilis and the isolate Le1 promoted the formation of the largest inhibition zone. L. edodes Le1 also presented antibacterial activity against foodborne pathogens and food contaminant bacteria, particularly Grampositive species. The antibacterial activity of the culture filtrate after 18-25 days of cultivation of L. edodes in broth at 25ºC was high. The inhibitory activity was observed only in the organic layer when the culture filtrate was partitioned between ethyl acetate and water, suggesting that the inhibitory substances have low polarity. The silica gel thin-layer zone at Rf values of 0.63-0.80, developed in chloroform -acetoneethyl acetate -methanol = 40:5:5:2, was responsible for the antibacterial activity against B. subtilis. The inhibitory activity of L. edodes was detectable in the culture filtrate after heat treatment at 100ºC for 10 min and after storage at 4ºC for 120 days.
Two new cuparene-type sesquiterpenes, enokipodins C (1) and D (2), were isolated from culture medium of an edible mushroom, Flammulina velutipes, along with enokipodins A (3) and B (4). The structures of 1 and 2 were determined using spectroscopic methods (HRMS, (1)H and (13)C, and 2D NMR). The absolute configuration of enokipodin C was determined from the observed (1)H NMR chemical shifts and NOEs in NOESY experiments after conversion into the corresponding esters with the chiral reagent 2-(2'-methoxy-1'-naphthyl)-3,4-dichlorobenzoic acid. All the metabolites showed antimicrobial activity against a fungus, Cladosporium herbarum, and Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus.
Advanced glycation irreversibly and progressively modifies proteins over time and yields the advanced glycation end-products (AGE). AGEs are thought to contribute to the development of atherosclerosis and of diabetic and uremic complications. Their inhibition has thus become a therapeutic goal. In this article, we discuss the role of various reactive carbonyl compound (RCOs) in the genesis of AGEs, postulate the existence of "carbonyl stress" in complicated diabetes and, finally, discuss therapeutic perspectives.
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