Hybrid ubiquinone: novel inhibitor of mitochondrial complex I

AbstractWe synthesized novel ubiquinone analogs by hybridizing the natural ubiquinone ring (2,3-dimethoxy-5-methyl-1,4-benzoquinone) and hydrophobic phenoxybenzamide unit, and named them hybrid ubiquinones (HUs). The HUs worked as electron transfer substrates with bovine heart mitochondrial succinate–ubiquinone oxidoreductase (complex II) and ubiquinol–cytochrome c oxidoreductase (complex III), but not with NADH–ubiquinone oxidoreductase (complex I). With complex I, they acted as inhibitors in a noncompetitive manner against exogenous short-chain ubiquinones irrespective of the presence of the natural ubiquinone ring. Elongation of the distance between the ubiquinone ring and the phenoxybenzamide unit did not recover the electron accepting activity. The structure/activity study showed that high structural specificity of the phenoxybenzamide moiety is required to act as a potent inhibitor of complex I. These findings indicate that binding of the HUs to complex I is mainly decided by some specific interaction of the phenoxybenzamide moiety with the enzyme. It is of interest that an analogous bulky and hydrophobic substructure can be commonly found in recently registered synthetic pesticides the action site of which is mitochondrial complex I

Tim23–Tim50 pair coordinates functions of translocators and motor proteins in mitochondrial protein import

Mitochondrial protein traffic requires coordinated operation of protein translocator complexes in the mitochondrial membrane. The TIM23 complex translocates and inserts proteins into the mitochondrial inner membrane. Here we analyze the intermembrane space (IMS) domains of Tim23 and Tim50, which are essential subunits of the TIM23 complex, in these functions. We find that interactions of Tim23 and Tim50 in the IMS facilitate transfer of precursor proteins from the TOM40 complex, a general protein translocator in the outer membrane, to the TIM23 complex. Tim23–Tim50 interactions also facilitate a late step of protein translocation across the inner membrane by promoting motor functions of mitochondrial Hsp70 in the matrix. Therefore, the Tim23–Tim50 pair coordinates the actions of the TOM40 and TIM23 complexes together with motor proteins for mitochondrial protein import

Abnormal Cystatin C Levels in Two Patients with Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-14. In the Western countries, the prevalence of this disease ranges from 1/13,500 to 1/160,000, while only a few Japanese patients have been reported in the English-language literature. The incidence of renal dysfunction or anomalies in previous reports varies considerably ranging from ∼20% to universal occurrence. We here report that two Japanese patients who had BBS with normal BUN and creatinine levels had elevated levels of cystatin C, a sensitive marker of glomerular filtration rate. A urine albumin level increased only in the elder patient. Thus, cystatin C may be useful for detecting renal abnormalities in patients with an apparent normal renal function. Because this disease is diagnosed by accumulation of symptoms, such a sensitive marker might help early diagnosis of BBS

ショクサイ ニ ヨル ジュウタク シンニュウトウ タイサク ノ タメ ノ ニンゲン コウガク ジッケン

This study is composed of three ergonomic experiments for prevention of burglary. 1. Research on territoriality of detached house：Verification of element that relates to improvement of territoriality in open outdoor facilities. 2. Study about performance to watch of the house: Study about visibility of hedge and transmission factor of eyes. 3. Crime prevention effects of shrubs in front of burglaries approach. These results suggested a definite crime prevention effects and building design standards. Crime prevention through environmental design is constituted various principles

Deterioration of high-resolution computed tomography findings predicts disease progression after initial decline in forced vital capacity in idiopathic pulmonary fibrosis patients treated with pirfenidone

Background Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline. Methods This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled. Results We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009). Conclusions We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone

Variantes genéticas en el locus 9p21 contribuyen al desarrollo de arteriosclerosis a través de la modulación de ANRIL y CDKN2A/B

Registro creado en correspondencia al grado de doctora de Ada Congrains Castillo.Los estudios de asociación de todo el genoma (GWAS) han identificado variantes genéticas que contribuyen al riesgo de enfermedad cardiovascular (ECV) en el locus del cromosoma 9p21. La región asociada a CVD es adyacente a los dos inhibidores de quinasas dependientes de ciclina (CDKN) 2A y 2B y los últimos exones del ARN no codificante, ANRIL. Todavía no está claro cuál de estas transcripciones o cómo están involucradas en la patogénesis de la aterosclerosis.Genome-wide association studies (GWAS) have identified genetic variants contributing to the risk of cardiovascular disease (CVD) at the chromosome 9p21 locus. The CVD-associated region is adjacent to the two cyclin dependent kinase inhibitors (CDKN)2A and 2B and the last exons of the non-coding RNA, ANRIL. It is still not clear which of or how these transcripts are involved in the pathogenesis of atherosclerosis.Japón. Programa de Promoción de Estudios Fundamentales en el Instituto Nacional de Innovación Biomédica de Japón (HR: 22-2-5), el Ministerio de Educación, Cultura, Deportes, Ciencia y Tecnología de Japón (KK: 22510211) y la Fundación NOVARTIS para la Investigación Gerontológica (KK).Tesi

An Active C-Terminally Truncated Form of Ca2+/Calmodulin-Dependent Protein Kinase Phosphatase-N (CaMKP-N/PPM1E)

Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) and its nuclear homolog CaMKP-N (PPM1E) are Ser/Thr protein phosphatases that belong to the PPM family. CaMKP-N is expressed in the brain and undergoes proteolytic processing to yield a C-terminally truncated form. The physiological significance of this processing, however, is not fully understood. Using a wheat-embryo cell-free protein expression system, we prepared human CaMKP-N (hCaMKP-N(WT)) and the truncated form, hCaMKP-N(1–559), to compare their enzymatic properties using a phosphopeptide substrate. The hCaMKP-N(1–559) exhibited a much higher value than the hCaMKP-N(WT) did, suggesting that the processing may be a regulatory mechanism to generate a more active species. The active form, hCaMKP-N(1–559), showed Mn2+ or Mg2+-dependent phosphatase activity with a strong preference for phospho-Thr residues and was severely inhibited by NaF, but not by okadaic acid, calyculin A, or 1-amino-8-naphthol-2,4-disulfonic acid, a specific inhibitor of CaMKP. It could bind to postsynaptic density and dephosphorylate the autophosphorylated Ca2+/calmodulin-dependent protein kinase II. Furthermore, it was inactivated by H2O2 treatment, and the inactivation was completely reversed by treatment with DTT, implying that this process is reversibly regulated by oxidation/reduction. The truncated CaMKP-N may play an important physiological role in neuronal cells.This work was supported, in part, by Grants-in-Aid for Scientific Research (21590334) from the Ministry of Education, Science, Sports, and Culture of Japan and by a grant from the Japan Foundation for Applied Enzymology