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000298414 1001_ $$aLi, Shu$$b0
000298414 245__ $$aCombined loss of glyoxalase 1 and aldehyde dehydrogenase 3a1 amplifies dicarbonyl stress, impairs proteasome activity resulting in hyperglycemia and activated retinal angiogenesis.
000298414 260__ $$aOrlando, Fla.$$bElsevier$$c2025
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000298414 520__ $$aAny energy consumption results in the generation of highly reactive dicarbonyls and the need to prevent excessive dicarbonyls accumulation through the activity of several interdependent detoxification enzymes. Glyoxalase 1 (GLO1) knockout zebrafish showed only moderately elevated methylglyoxal (MG) levels, but increased Aldehyde Dehydrogenases (ALDH) activity and increased aldh3a1 expression. Elevated levels of 4-hydroxynonenal (4-HNE) but no MG increase were observed in ALDH3A1KO. The question of whether ALDH3A1 prevents MG formation as a compensatory mechanism in the absence of GLO1 remained unclear.To investigate whether ALDH3A1 detoxifies MG as a compensatory mechanism in the absence of GLO1, the GLO1/ALDH3A1 double knockout (DKO) zebrafish was first generated. Various metabolites including advanced glycation end products (AGEs), as well as glucose metabolism and hyaloid vasculature were analyzed in GLO1KO, ALDH3A1KO and GLO1/ALDH3A1DKO zebrafish.In the absence of GLO1 and ALDH3A1, MG-H1 levels were increased. MG-H1 accumulation led to a severe deterioration of proteasome function, resulting in impaired glucose homeostasis and consequently amplified angiogenic activation of the hyaloid and retinal vasculature. Rescue of these pathological processes could be observed by using L-carnosine, and proteasome activator betulinic acid.The present data, together with previous studies, suggest that ALDH3A1 and GLO1 are important detoxification enzymes that prevent the deleterious effects of MG-H1 accumulation on proteasome function, glucose homeostasis and vascular function.
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000298414 650_7 $$2Other$$aALDH3A1
000298414 650_7 $$2Other$$aDiabetes
000298414 650_7 $$2Other$$aDiabetic retinopathy
000298414 650_7 $$2Other$$aDicarbonyl stress
000298414 650_7 $$2Other$$aGLO1
000298414 650_7 $$2Other$$aMG-derived hydroimidazolone 1 (MG-H1)
000298414 650_7 $$2Other$$aProteasome dysfunction
000298414 650_7 $$2Other$$aZebrafish
000298414 7001_ $$0P:(DE-He78)5b422df679d8af3361c421d51f9420ed$$aLi, Hao$$b1$$udkfz
000298414 7001_ $$aBennewitz, Katrin$$b2
000298414 7001_ $$aPoschet, Gernot$$b3
000298414 7001_ $$aBuettner, Michael$$b4
000298414 7001_ $$aHausser, Ingrid$$b5
000298414 7001_ $$aSzendroedi, Julia$$b6
000298414 7001_ $$aNawroth, Peter Paul$$b7
000298414 7001_ $$aKroll, Jens$$b8
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