Nardilysin in adipocytes regulates UCP1 expression and body temperature homeostasis.

Brown adipose tissue (BAT) dissipates chemical energy as heat through uncoupling protein 1 (UCP1). The induction of mitochondrial reactive oxygen species (ROS) in BAT was recently identified as a mechanism that supports UCP1-dependent thermogenesis. We previously demonstrated that nardilysin (NRDC) plays critical roles in body temperature homeostasis.

Deficiency of Nardilysin in the Liver Reduces Serum Cholesterol Levels.

Nardilysin (NRDC) has been shown to be involved in post-translational histone modifications, in addition to enhancement in ectodomain shedding of membrane-anchored protein, which play significant roles in various pathophysiology, including glucose homeostasis, inflammatory diseases and cancer. The present study sought to determine roles of NRDC in the liver on lipid and lipoprotein metabolism. We established liver-specific NRDC deficient mice by use of NRD1 floxed mice and albumin promoter-Cre recombinase (Cre) transgenic mice, and found that their serum low-density lipoprotein (LDL) cholesterol levels were significantly lower than those in control littermate mice.

Reduced Serum Cholesterol and Triglyceride Levels in a Choline-Deficient L-Amino Acid-Defined High-Fat Diet (CDAHFD)-Induced Mouse Model of Non-alcoholic Steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic seatohepatitis (NASH) is one of the major health problems world wide, because of increased abdominal obesity. To date, specific and effective medications to treat or prevent NAFLD/NASH have not been established. To identify appropriate molecular targets for that purpose, suitable animal models of NAFLD/NASH have been explored.

Effects of Ramelteon and Other Sleep-Promoting Drugs on Serum Low-Density Lipoprotein and Non-high-density Lipoprotein Cholesterol: A Retrospective Comparative Pilot Study.

Melatonin has been suggested to play important roles in lipid metabolism as well as circadian rhythm; however, very few studies explored the effects of ramelteon, a selective melatonin receptor agonist, on serum lipid profiles. In this study effects of ramelteon on serum lipid profiles were explored, comparing to those of other sleep-promoting drugs including benzodiazepines and non-benzodiazepines, in patients with insomnia. We retrospectively reviewed medical charts of outpatients who were treated with ramelteon (8 mg/d) or other sleep-promoting drugs for no less than 8 weeks during the period between October 1st, 2011 and September 30th, 2014, and compared the changes in serum lipid profiles between the two groups.

Comparison of serum lipid management between elderly and non-elderly patients with and without coronary heart disease (CHD).

Serum lipid management in patients aged ≥ 75 has not been precisely explored. We, therefore, compared the serum lipid management between the two age groups with and without coronary heart disease (CHD). We, therefore, retrospectively reviewed medical charts of patients who were hospitalized in the departments of internal medicine during a period of 14 months.

Nardilysin Is Required for Maintaining Pancreatic β-Cell Function.

Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). Several transcription factors enriched in β-cells, such as MafA, control β-cell function by organizing genes involved in GSIS. Here we demonstrate that nardilysin (N-arginine dibasic convertase; Nrd1 and NRDc) critically regulates β-cell function through MafA.

Serum Lipid Goal Attainment in Chronic Kidney Disease (CKD) Patients under the Japan Atherosclerosis Society (JAS) 2012 Guidelines.

Aim: According to the Japan Atherosclerosis Society 2012 guidelines (JAS2012-GL), chronic kidney disease (CKD) has newly been added to the high-risk group in terms of atherosclerotic cardiovascular diseases. We therefore explored the lipid target level achievement rates under the JAS2012-GL in real-world clinical practice.

Methods: We retrospectively reviewed the medical charts of patients who were hospitalized at the Nephrology Department at Kobe City Medical Center General Hospital in the period from April 1, 2012 to May 31, 2013 and explored the serum lipid target level achievement rates.

Critical roles of nardilysin in the maintenance of body temperature homoeostasis.

Body temperature homoeostasis in mammals is governed centrally through the regulation of shivering and non-shivering thermogenesis and cutaneous vasomotion. Non-shivering thermogenesis in brown adipose tissue (BAT) is mediated by sympathetic activation, followed by PGC-1α induction, which drives UCP1. Here we identify nardilysin (Nrd1 and NRDc) as a critical regulator of body temperature homoeostasis.

Nardilysin prevents amyloid plaque formation by enhancing α-secretase activity in an Alzheimer's disease mouse model.

Amyloid beta (Aβ) peptide, the main component of senile plaques in patients with Alzheimer's disease (AD), is derived from proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Alpha-cleavage of APP by α-secretase has a potential to preclude the generation of Aβ because it occurs within the Aβ domain. We previously reported that a metalloendopeptidase, nardilysin (N-arginine dibasic convertase; NRDc) enhances α-cleavage of APP, which results in the decreased generation of Aβ in vitro.

Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF-α.

Nardilysin (NRDc), a metalloendopeptidase of the M16 family, promotes ectodomain shedding of the precursor forms of various growth factors and cytokines by enhancing the protease activities of ADAM proteins. Here, we show the growth-promoting role of NRDc in gastric cancer cells. Analyses of clinical samples demonstrated that NRDc protein expression was frequently elevated both in the serum and cancer epithelium of gastric cancer patients.

Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system.

Axonal maturation and myelination are essential processes for establishing an efficient neuronal signaling network. We found that nardilysin (N-arginine dibasic convertase, also known as Nrd1 and NRDc), a metalloendopeptidase enhancer of protein ectodomain shedding, is a critical regulator of these processes. Nrd1-/- mice had smaller brains and a thin cerebral cortex, in which there were less myelinated fibers with thinner myelin sheaths and smaller axon diameters.

Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases.

Tumor necrosis factor-alpha (TNF-alpha) is released from cells by proteolytic cleavage of a membrane-anchored precursor. The TNF-alpha-converting enzyme (TACE/ADAM17) is the major sheddase for ectodomain shedding of TNF-alpha. At present, however, it is poorly understood how its catalytic activity is regulated.

Enhancement of alpha-secretase cleavage of amyloid precursor protein by a metalloendopeptidase nardilysin.

Amyloid-beta (Abeta) peptide, the principal component of senile plaques in the brains of patients with Alzheimer's disease, is derived from proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. Alternative cleavage of APP by alpha-secretase occurs within the Abeta domain and precludes generation of Abeta peptide. Three members of the ADAM (a disintegrin and metalloprotease) family of proteases, ADAM9, 10 and 17, are the main candidates for alpha-secretases.

Nardilysin enhances ectodomain shedding of heparin-binding epidermal growth factor-like growth factor through activation of tumor necrosis factor-alpha-converting enzyme.

Like other members of the epidermal growth factor family, heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a transmembrane protein that can be shed enzymatically to release a soluble growth factor. Ectodomain shedding is essential to the biological functions of HB-EGF and is strictly regulated. However, the mechanism that induces the shedding remains unclear.

Human cytochrome c enters murine J774 cells and causes G1 and G2/M cell cycle arrest and induction of apoptosis.

Cytochrome c is well known as a carrier of electrons during respiration. Current evidence indicates that cytochrome c also functions as a major component of apoptosomes to induce apoptosis in eukaryotic cells as well as an antioxidant. More recently, a prokaryotic cytochrome c, cytochrome c(551) from Pseudomonas aeruginosa, has been shown to enter in mammalian cells such as the murine macrophage-like J774 cells and causes inhibition of cell cycle progression.

A novel kinetic method for the speciation of cadmium in river water by micro solvent extraction with dithizone.

Cadmium species in river water were kinetically extracted with dithizone by varying the extraction time. The obtained extraction curve showed a three-stage stepwise profile that reflected the rate of the ligand substitution reaction between the dithizone and cadmium species. Corresponding to each stage, we divided these extracted cadmium species into three groups: "highly labile", "moderately labile" and "slowly labile" species.

Rusticyanin, a bacterial electron transfer protein, causes G1 arrest in J774 and apoptosis in human cancer cells.

During acid mine drainage, Acidithiobacillus ferrooxidans, a nonpathogenic, acidophilic, lithotrophic bacterium, utilizes rusticyanin to transfer electrons for the oxidation of Fe(2+) to Fe(3+) for deriving its energy. No other function of rusticyanin is known. We demonstrate that purified rusticyanin enters mammalian cells inducing either inhibition of cell cycle progression or caspase-8 mediated apoptosis.

Regulation of mammalian cell growth and death by bacterial redox proteins: relevance to ecology and cancer therapy.

Recent evidence indicates that bacterial redox proteins such as cupredoxins and cytochromes, that are normally involved in electron transfer during respiration, can enter mammalian cells and induce either apoptosis or inhibition of cell cycle progression. Such proteins have also been shown to demonstrate a good deal of specificity for entry and induction of cytotoxic effects in cancer cells, allowing both in vitro cell death and in vivo inhibition of cancer progression. An alteration in the hydrophobicity of the bacterial redox proteins can lead to a switch from apoptosis to growth arrest and vice versa through modulation of the intracellular levels of tumor suppressors.

Modulation of mammalian cell growth and death by prokaryotic and eukaryotic cytochrome c.

Cytochrome c(551), an 8,685-Da haem-containing protein, is known to be involved in electron transfer during dissimilative denitrification by Pseudomonas aeruginosa. Both cytochrome c(551) and copper-containing redox protein azurin have been used in vitro as partners in electron transfer. Azurin has been reported to induce apoptosis in macrophages and cancer cells.

Apoptosis or growth arrest: Modulation of tumor suppressor p53's specificity by bacterial redox protein azurin.

The tumor suppressor protein p53 is known to induce either apoptosis or growth arrest depending on cellular background. We have previously reported that a bacterial redox protein azurin induces apoptosis in J774 cell line-derived macrophages whereas a site-directed mutant M44KM64E azurin shows very little cytotoxicity and fails to induce apoptosis in J774 cells. We now report that purified M44KM64E mutant azurin protein can enter both J774 cells as well as the human breast cancer MCF-7 cells.

Flow cytometry analysis of changes in the DNA content of the polychlorinated biphenyl degrader Comamonas testosteroni TK102: effect of metabolites on cell-cell separation.

Flow cytometry was used to monitor changes in the DNA content of the polychlorinated biphenyl (PCB)-degrading bacterium Comamonas testosteroni TK102 during growth in the presence or absence of PCBs. In culture medium without PCBs, the majority of stationary-phase cells contained a single chromosome. In the presence of PCBs, the percentage of cells containing two chromosomes increased from 12% to approximately 50%.

Rapid assessment of the physiological status of the polychlorinated biphenyl degrader Comamonas testosteroni TK102 by flow cytometry.

The viability of the polychlorinated biphenyl-degrading bacterium Comamonas testosteroni TK102 was assessed by flow cytometry (FCM) with the fluorogenic ester Calcein-AM (CAM) and the nucleic acid dye propidium iodide (PI). CAM stained live cells, whereas PI stained dead cells. When double staining with CAM and PI was performed, three physiological states, i.