Computational and Experimental Analyses for Pathogenicity Prediction of Missense Variants in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants showed no detectable cell surface expression and impairment of bone morphogenetic protein 9 (BMP9) responsiveness of SMAD-dependent transcription in luciferase assays.

2-Oxo-Imidazole-Containing Dipeptides Play a Key Role in the Antioxidant Capacity of Imidazole-Containing Dipeptides.

There is substantial evidence for the antioxidant functions of imidazole-containing dipeptides (IDPs), including carnosine and anserine, under physiological and pathological conditions in vivo. However, the detailed mechanism underlying the antioxidant functions is still poorly understood. Recently, we discovered the endogenous production of 2-oxo-imidazole-containing dipeptides (2-oxo-IDPs), such as 2-oxo-carnosine and 2-oxo-anserine, as novel derivatives of IDPs in mouse tissues and revealed that the antioxidant capacity of 2-oxo-carnosine was much greater than that of carnosine.

Distribution and quantitative analysis of homoanserine and its 2-oxo derivative in mouse tissues.

Imidazole-containing dipeptides (IDPs), such as carnosine and anserine, are endogenously produced and have been shown to function as antioxidants. Recently, we have characterized the endogenous production of 2-oxo-imidazole-containing dipeptides (2-oxo-IDPs), such as 2-oxo-carnosine, 2-oxo-anserine, and 2-oxo-homocarnosine in mouse tissues, including brain, and demonstrated that 2-oxo-IDPs exhibit higher antioxidant activities than the corresponding IDPs. In this study, we established a highly sensitive, specific, and quantitative method for the detection of the IDP homoanserine and its oxidized derivative 2-oxo-homoanserine high-performance liquid chromatography tandem mass spectrometry coupled with a stable-isotope dilution method, and quantitatively analyzed its tissue distribution and age-related intra-brain distribution in C57BL/6J mice.

Generation of Rat Monoclonal Antibody to Detect Hydrogen Sulfide and Polysulfides in Biological Samples.

Hydrogen sulfide (HS) is endogenously produced by enzymes and via reactive persulfide/polysulfide degradation; it participates in a variety of biological processes under physiological and pathological conditions. HS levels in biological fluids, such as plasma and serum, are correlated with the severity of various diseases. Therefore, development of a simple and selective HS measurement method would be advantageous.

2-Oxo-histidine-containing dipeptides are functional oxidation products.

Imidazole-containing dipeptides (IDPs), such as carnosine and anserine, are found exclusively in various animal tissues, especially in the skeletal muscles and nerves. IDPs have antioxidant activity because of their metal-chelating and free radical-scavenging properties. However, the underlying mechanisms that would fully explain IDP antioxidant effects remain obscure.

8-Nitro-cGMP Attenuates the Interaction between SNARE Complex and Complexin through S-Guanylation of SNAP-25.

8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is the second messenger in nitric oxide/reactive oxygen species redox signaling. This molecule covalently binds to protein thiol groups, called S-guanylation, and exerts various biological functions. Recently, we have identified synaptosomal-associated protein 25 (SNAP-25) as a target of S-guanylation, and demonstrated that S-guanylation of SNAP25 enhanced SNARE complex formation.

Superoxide generation from nNOS splice variants and its potential involvement in redox signal regulation.

We previously demonstrated different spacial expression profiles of the neuronal nitric oxide (NO) synthase (nNOS) splice variants nNOS-µ and nNOS-α in the brain; however, their exact functions are not fully understood. Here, we used electron paramagnetic resonance to compare the electron-uncoupling reactions of recombinant nNOS-µ and nNOS-α that generate reactive oxygen species (ROS), in this case superoxide. nNOS-µ generated 44% of the amount of superoxide that nNOS-α generated.