N-(6-phenylpyridazin-3-yl)benzenesulfonamides as highly potent, brain-permeable, and orally active kynurenine monooxygenase inhibitors.

Huntington's disease (HD) is one of the serious neurodegenerative diseases and no disease modifiers are available to date. The correction of unbalanced kynurenine pathway metabolites may be useful to treat disease progression and kynurenine monooxygenase (KMO) is considered an ideal drug target. A couple of KMO inhibitors have been reported, but their brain permeability was very poor.

Impaired p53/CEP-1 is associated with lifespan extension through an age-related imbalance in the energy metabolism of C. elegans.

In the nematode Caenorhabditis elegans, the mammalian tumor suppressor p53 ortholog CEP-1 mediates the stress response, activates germ line apoptosis and regulates meiotic chromosome segregation. A reduction in its expression, which frequently occurs in mammalian cancer cells, extends lifespan and induces an adaptive response in C. elegans.

Biophysical and biological meanings of healthspan from C. elegans cohort.

Lifespan among individuals ranges widely in organisms from yeast to mammals, even in an isogenic cohort born in a nearly uniform environment. Needless to say, genetic and environmental factors are essential for aging and lifespan, but in addition, a third factor or the existence of a stochastic element must be reflected in aging and lifespan. An essential point is that lifespan or aging is an unpredictable phenomenon.

Noise-driven onset time of biodemographic aging.

The lifespan of each individual, even in an isogenic cohort and a uniform environment, is quite different. The genetic factors influencing the lifespan in humans as well as animal models are few. The balance is attributed to "chance" variations.

Timing mechanism and effective activation energy concerned with aging and lifespan in the long-lived and thermosensory mutants of Caenorhabditis elegans.

The lifespans of many poikilothermic animals, including the nematode Caenorhabditis elegans, depend significantly on environmental temperature. Using long-living, thermosensory mutants of C. elegans, we tested whether the temperature dependency of the mean lifespan is compatible with the Arrhenius equation, which typically represents one of the chemical reaction rate theories.

A further test of the equation of lifespan by C. elegans: effective activation energy for aging and lifespan.

We previously proposed a rate theory of chemical reaction as well as a lifespan equation derived by a stochastic fluctuation theory. Both were applied to biodemographic data by C. elegans to quantitatively explain that respiratory activity declines exponentially with age and that it has a physiological decline rate and a finite value (threshold) in advanced age.

Interrelationships between mitochondrial fusion, energy metabolism and oxidative stress during development in Caenorhabditis elegans.

Mitochondria are known to be dynamic structures with the energetically and enzymatically mediated processes of fusion and fission responsible for maintaining a constant flux. Mitochondria also play a role of reactive oxygen species production as a byproduct of energy metabolism. In the current study, interrelationships between mitochondrial fusion, energy metabolism and oxidative stress on development were explored using a fzo-1 mutant defective in the fusion process and a mev-1 mutant overproducing superoxide from mitochondrial electron transport complex II of Caenorhabditis elegans.

Analyzing observed or hidden heterogeneity on survival and mortality in an isogenic cohort.

It is generally difficult to understand the rates of human mortality from biological and biophysical standpoints because there are no cohorts or genetic homogeneity; in addition, information is limited regarding the various causes of death, such as the types of accidents and diseases. Despite such complexity, Gompertz's rule is useful in humans. Thus, to characterize the rates of mortality from a demographic viewpoint, it would be interesting to research a single disease in one of the simplest organisms, the nematode , which dies naturally under identically controlled circumstances without predators.

Decline in oxygen consumption correlates with lifespan in long-lived and short-lived mutants of Caenorhabditis elegans.

In humans, the basal energy metabolism is thought to decline linearly with age. On the other hand, in the nematode Caenorhabditis elegans, two research groups reported independently that it declined exponentially. In this study, furthermore, we used various lifespan-mutant strains to determine whether the previous conclusion is more likely to be true.

Basic principle of the lifespan in the nematode C. elegans.

We present a biophysical model based on the principles of fluctuation and regulation to explain the effect of stochastics on survival. The model is a good fit for the survivorship and mortality rates observed in the nematode Caenorhabditis elegans. A parameter included in the theory, which is called the fluctuation constant, correlates well with a change (or declining rate) of respiration with age, which we term the physiological decline rate.

Analysis of mismatched DNA by mismatch binding ligand (MBL)-Sepharose affinity chromatography.

Mismatch binding molecules (MBLs), strongly and selectively bound to the mismatched base pair in duplex DNA, were immobilized on Sepharose. Three MBL-Sepharose columns were prepared with three MBLs, naphthyridine dimer (ND), naphthyridine-azaquinolone (NA), and aminonaphthyridine dimer (amND), which exhibited different binding profiles to the mismatched base pairs. These three MBL-Sepharose columns showed characteristic elution profiles for DNA duplexes containing mismatched base pairs.

Allele specific C-bulge probes with one unique fluorescent molecule discriminate the single nucleotide polymorphism in DNA.

A combination of an allele specific C-bulge probe and the fluorescent molecule N,N'-bis(3-aminopropyl)-2,7-diamino-1,8-naphthyridine (DANP) that binds specifically to the C-bulge provides a method for single nucleotide polymorphism (SNP) typing with only one fluorescent molecule without covalent modification of the DNA probe. The allele specific C-bulge probe contains one additional cytosine and produces a C-bulge directly flanking the SNP site upon hybridization to the target DNA. The C-bulge is a scaffold to recruit and retain DANP directly neighboring the SNP site.

Evidence for the existence of a soybean resistant protein that captures bile acid and stimulates its fecal excretion.

Feeding HMF, an insoluble "high-molecular-weight fraction" from an industrial enzymatic digest of a soy protein isolate, increased the fecal excretion of bile acid concomitant with increased fecal nitrogen. An amino acid analysis revealed that this increased fecal nitrogen could be explained by an increase in the insoluble protein fraction. This suggests the existence of an indigestible protein or peptide that can be called a "resistant protein" in the feces.

Separation of mismatched DNA by using the affinity column immobilizing mismatch-binding ligands.

Mismatch binding ligands (MBL), ND and NA, bind to DNA containing mismatch base pairs. These MBLs were immobilized to NHS-activated affinity column via amine linker. Affinity chromatographic analyses of mismatched DNAs by using the ND-immobilized column showed clear separation of G-G and G-A from other mismatched DNAs.

Age-related changes of mitochondrial structure and function in Caenorhabditis elegans.

A number of observations have been made to examine the role that mitochrondrial energetics and superoxide anion production play in the aging of wild-type Caenorhabditis elegans. Ultrastructural analyses reveal the presence of swollen mitochondria, presumably produced by fusion events. Two key mitochondrial functions - the activity of two electron transport chain complexes and oxygen consumption - decreased as animals aged.

N,N'-Bis(3-aminopropyl)-2,7-diamino-1,8-naphthyridine stabilized a single pyrimidine bulge in duplex DNA.

We here show the first identified ligand 2,7-diamino-1,8-naphthyridine (DANP) that strongly and specifically binds to the single cytosine and thymine bulges with exclusively 1:1 stoichiometry.

Direct measurement of oxygen consumption rate on the nematode Caenorhabditis elegans by using an optical technique.

It is well known that aging and longevity strongly correlate with energy metabolism. The nematode Caenorhabditis elegans is widely used as an ultimate model of experimental animals. Thus, we developed a novel tool, which is constructed from an optical detector, using an indirect method that can measure simply the energy metabolism of C.

2-Ureidoquinoline: a useful molecular element for stabilizing single cytosine and thymine bulges.

We have demonstrated that aromatic heterocycles having hydrogen-bonding surfaces complementary to those of nucleotide bases are effective molecular elements for the binding to single nucleotide bulges and base mismatches. We here report that a new molecule, 2-ureidoquinoline having an alignment of hydrogen-bonding groups in the order of acceptor-donor-donor stabilizes single cytosine and thymine bulges in duplex DNAs. Furthermore, a dimeric form of 2-ureidoquinoline stabilizes cytosine-cytosine and cytosine-thymine mismatches.

Force generation by recombinant myosin heads trapped between two functionalized surfaces.

Fluorescence resonance energy transfer measurements have revealed that the lever-arm domain of myosin swings when it hydrolyzes Mg-ATP. It is generally accepted that this swing of the lever arm of myosin is the molecular basis of force generation. On the other hand, the possibility that the force might be generated at the interface between actin and myosin cannot be ignored.

The SPR sensor detecting cytosine[bond]cytosine mismatches.

We have synthesized the first surface plasmon resonance (SPR) sensor that detects cytosine-cytosine (C[bond]C) mismatches in duplex DNA by immobilizing aminonaphthyridine dimer on the gold surface. The ligand consisting of two 2-aminonaphthyridine chromophores and an alkyl linker connecting them strongly stabilized the C[bond]C mismatches regardless of the flanking sequences. The fully matched duplexes were not stabilized at all under the same conditions.

2,6-Diaminonaphthyridine derivatives bind to a single nucleotide bulge in DNA.

2,6-Diamino-1,8-naphthyridine derivative (daNpt), which possesses hydrogen bonding groups in an alignment of donor-acceptor-acceptor-donor binds to a single nucleotide bulge in the duplex. The melting temperatures (Tm) of all duplexes containing a bulge were increased, especially for the cytosine (C) and thymine (T) bulges, in the presence of daNpt, whereas only a small increase of Tm was observed for the fully matched duplexes. It was suggested by pH dependency of Tm and UV spectra, that a protonation of daNpt should play an important role for the recognition of C and T bulges.

Detection of the C-C mismatched base pair by small ligands.

We synthesized 2-aminonaphthyridine derivatives that specifically bind to cytosine-cytosine (C-C) mismatch. The binding of ligands was verified by observing an increase of melting temperature for 11-mer duplexes containing a mismatch in the presence of ligands. It was found that the aminonaphthyridine dimer stabilized C-C mismatch more strongly than the monomer.