NAD deficiency plays essential roles in the hyperuricemia of stroke-prone spontaneously hypertensive rat via xanthine dehydrogenase to xanthine oxidase conversion.

Inhibition of xanthine oxidoreductase (XOR) was shown to ameliorate the stroke susceptibility in the stroke-prone spontaneously hypertensive rat (SHRSP), suggesting hyperuricemia had a pathological role in this rat model. In this study, we thus aimed to explore mechanisms inducing hyperuricemia in SHRSP. XOR is known to have two forms, xanthine dehydrogenase (XDH) as the prototype and xanthine oxidase (XO) as the converted form through cleavage of a peptide bond or through formation of disulfide bonds in the enzyme.

Introduction of a carboxylic acid group into pyrazolylpyridine derivatives increased selectivity for inhibition of the 20-HETE synthase CYP4A11/4F2.

20-Hydroxyeicosatetraenoic acid (20-HETE) is a lipid mediator and one of the major arachidonic acid metabolites whose formation is mainly catalyzed by the enzymes cytochrome P450 (CYP) 4F2 and CYP4A11. Several studies have suggested that 20-HETE is involved in the pathogenesis of renal diseases, including diabetic nephropathy and autosomal dominant polycystic kidney disease, and we previously reported compound 1 as a dual inhibitor of CYP4A11/4F2 with therapeutic potential against renal fibrosis. Subsequent studies revealed that compound 1, the dual CYP4A11/4F2 inhibitor, however, exhibited low selectivity over another CYP4F subtype, CYP4F22, which catalyzes ω-hydroxylation of ultra-long-chain fatty acids (ULCFAs); ULCFAs are important for the formation of acylceramides, which play a role in skin barrier formation.

A Potent Neutralizing Monoclonal Antibody to Human Growth Hormone Suppresses Insulin-Like Growth Factor-1 in Female Rats.

Acromegaly and gigantism are disorders caused by hypersecretion of growth hormone (GH), usually from pituitary adenomas. Although somatostatin analogues (SSA), dopamine agonists, and GH receptor antagonists are important therapeutic agents, all of these have issues with their effectiveness, safety, and/or convenience of use. To overcome these, we developed a GH-specific potent neutralizing a mouse monoclonal antibody (mAb) named 13H02.

Discovery of TP0628103: A Highly Potent and Selective MMP-7 Inhibitor with Reduced OATP-Mediated Clearance Designed by Shifting Isoelectric Points.

Matrix metalloproteinase-7 (MMP-7) has been shown to play an important role in pathophysiological processes such as cancer and fibrosis. We previously discovered selective MMP-7 inhibitors by molecular hybridization and structure-based drug design. However, the systemic clearance (CL) of the biologically active lead compound was very high.

Genotypes of Stim1 and the proximal region on chromosome 1 exert opposite effects on stroke susceptibility in stroke-prone spontaneously hypertensive rat.

Background: The stroke-prone spontaneously hypertensive rat (SHRSP) is a genetic model for cerebral stroke. Although a recent study on a congenic SHRSP suggested that a nonsense mutation in stromal interaction molecule 1 ( Stim1 ) encoding a major component of store-operated Ca 2+ entry was a causal variant for stroke in SHRSP, this was not conclusive because the congenic region including Stim1 in that rat was too wide. On the other hand, we demonstrated that the Wistar-Kyoto (WKY)-derived congenic fragment adjacent to Stim1 exacerbated stroke susceptibility in a congenic SHRSP called SPwch1.

Renoprotective Effect of TP0472993, a Novel and Selective 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, in Mouse Models of Renal Fibrosis.

Kidney fibrosis is considered the essential pathophysiological process for the progression of chronic kidney disease (CKD) toward renal failure. 20-Hydroxyeicosatetraenoic acid (20-HETE) has crucial roles in modulating the vascular response in the kidney and the progression of albuminuria. However, the roles of 20-HETE in kidney fibrosis are largely unexplored.

Apolipoprotein E-depletion accelerates arterial fat deposition in the spontaneously hypertensive rat.

Hypertension and atherosclerosis are often found in one patient causing serious cardiovascular events. An animal model simultaneously expressing hypertension and atherosclerosis would be useful to study such a complex risk status. We therefore attempted to introduce a null mutation of the apolipoprotein E (ApoE) gene into the spontaneously hypertensive rat (SHR) using CRISPR/Cas9 to establish a genetic model for atherosclerosis with hypertension.

Discovery of Novel Pyrazolylpyridine Derivatives for 20-Hydroxyeicosatetraenoic Acid Synthase Inhibitors with Selective CYP4A11/4F2 Inhibition.

20-Hydroxyeicosatetraenoic acid (20-HETE) is one of the major oxidized arachidonic acid (AA) metabolites produced by cytochrome P450 (CYP) 4A11 and CYP4F2 isozymes in the human liver and kidney. Numerous studies have suggested the involvement of 20-HETE in the pathogenesis of renal diseases, and suppression of 20-HETE production by inhibition of CYP4A11 and CYP4F2 may be an attractive therapeutic strategy for renal diseases. At first, we identified methylthiazole derivative as a potent dual inhibitor of CYP4A11 and CYP4F2.

Genetic Modifications to Alter Blood Pressure Level.

Genetic manipulation is one of the indispensable techniques to examine gene functions both in vitro and in vivo. In particular, cardiovascular phenotypes such as blood pressure cannot be evaluated in vitro system, necessitating the creation of transgenic or gene-targeted knock-out and knock-in experimental animals to understand the pathophysiological roles of specific genes on the disease conditions. Although genome-wide association studies (GWAS) in various human populations have identified multiple genetic variations associated with increased risk for hypertension and/or its complications, the causal links remain unresolved.

A 3-Mbp fragment on rat chromosome 1 affects susceptibility both to stroke and kidney injury under salt loading in the stroke-prone spontaneously hypertensive rat: a genetic approach using multiple congenic strains.

We have previously reported that a major quantitative trait locus (QTL) responsible for susceptibility to salt-induced stroke in the stroke-prone spontaneously hypertensive rat (SHRSP) is located in a 3-Mbp region on chromosome 1 covered by SHRSP.SHR-(D1Rat23-D1Rat213)/Izm (termed Pr1.31), a congenic strain with segments from SHRSP/Izm introduced into the stroke-resistant SHR/Izm.

Milk Fermented with Mushrooms Prevents Stroke in the Stroke-Prone Spontaneously Hypertensive Rats Independently of Blood Pressure.

Objectives: In a previous study, a mushroom was shown to digest milk protein to a mixture of oligopeptides and free amino acids. The aim of this study was to examine effects of this mixture, i.e.

Pathophysiological significance of mutation in sympathetic response to stress and cardiovascular phenotypes in SHRSP/Izm: In vivo evaluation by creation of a novel gene knock-in rat using CRISPR/Cas9.

Genetic approach using rat congenic lines between SHRSP/Izm and WKY/Izm identified stromal interaction molecule 1 (), an essential component of store-operated Ca entry (SOCE), as a promising candidate gene responsible for the exaggerated sympathetic response to stress in SHRSP. Since SHRSP has a nonsense mutation in resulting in the expression of a truncated form of STIM1 that caused reduction of SOCE activity in primary cultured cerebral astrocytes, we created SHRSP/Izm knocked-in with the wild-type (KI SHRSP) by the CRISPR/Cas9 method to investigate whether the functional recovery of STIM1 would mitigate sympatho-excitation to stress in SHRSP. No potential off-target nucleotide substitutions/deletions/insertions were found in KI SHRSP.

Defective Function of the Blood-Brain Barrier in a Stroke-Prone Spontaneously Hypertensive Rat: Evaluation in an In Vitro Cell Culture Model.

The blood-brain barrier (BBB) comprises three cell types: brain capillary endothelial cells (BECs), astrocytes, and pericytes. Abnormal interaction among these cells may induce BBB dysfunction and lead to cerebrovascular diseases. The stroke-prone spontaneously hypertensive rat (SHRSP) harbors a defective BBB, so we designed the present study to examine the role of these three cell types in a functional disorder of the BBB in SHRSP in order to elucidate the role of these cells in the BBB more generally.

Leukotriene B receptor 1 exacerbates inflammation following myocardial infarction.

Leukotriene B receptor 1 (BLT1), a high-affinity G-protein-coupled receptor for leukotriene B4 (LTB ), is expressed on various inflammatory cells and plays critical roles in several inflammatory diseases. In myocardial infarction (MI), various inflammatory cells are known to be recruited to the infarcted area, but the function of BLT1 in MI is poorly understood. Here, we investigated the role of BLT1 in MI and the therapeutic effect of a BLT1 antagonist, ONO-4057, on MI.

Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats.

Malignant mesothelioma (MM) is one of the most lethal tumors in humans. The onset of MM is linked to exposure to asbestos, which generates reactive oxygen species (ROS). ROS are believed to be derived from the frustrated phagocytosis and the iron in asbestos.

Intratumoral pseudoaneurysm within a liver metastasis of gastric cancer: a case report.

Background: Intrahepatic artery pseudoaneurysms are mostly iatrogenic and result from hepatobiliary interventions. The incidence of intrahepatic artery pseudoaneurysms within liver tumors without prior intervention is extremely rare. We presented herein the first report of a case of an intratumoral pseudoaneurysm within a liver metastasis of gastric cancer without any prior intervention during chemotherapy.

Dual inhibition of NADPH oxidases and xanthine oxidase potently prevents salt-induced stroke in stroke-prone spontaneously hypertensive rats.

Oxidative stress has been implicated in the pathophysiology of cerebral stroke. As NADPH oxidases (NOXs) play major roles in the regulation of oxidative stress, we hypothesized that reduction of NOX activity by depletion of p22phox, an essential subunit of NOX complexes, would prevent cerebral stroke. To investigate this, we used the stroke-prone spontaneously hypertensive rat (SHRSP) and the p22phox-deleted congenic SHRSP.

Evaluation of Pathological Association between Stroke-Related QTL and Salt-Induced Renal Injury in Stroke-Prone Spontaneously Hypertensive Rat.

The stroke-prone spontaneously hypertensive rat (SHRSP) suffers from severe hypertension and hypertensive organ damage such as cerebral stroke and kidney injury under salt-loading. By a quantitative trait locus (QTL) analysis between SHRSP and SHR (the stroke-resistant parental strain of SHRSP), two major QTLs for stroke susceptibility were identified on chromosomes 1 and 18 of SHRSP, which were confirmed in congenic strains constructed between SHRSP and SHR. As the progression of renal dysfunction was suggested to be one of the key factors inducing stroke in SHRSP, we examined effects of the stroke-related QTLs on kidney injury using two congenic strains harboring either of SHRSP-derived fragments of chromosomes 1 and 18 in the SHR genome.

Effects of the Prdx2 depletion on blood pressure and life span in spontaneously hypertensive rats.

Oxidative stress is involved in the pathogenesis of hypertension and hypertensive organ damage. Our previous study suggested that stroke-prone spontaneously hypertensive rats (SHRSP) exhibited greater oxidative stress than SHR and that the stroke incidence was significantly greater in SHRSP than SHR. Therefore, we hypothesized that oxidative stress was responsible for the stroke susceptibility in SHRSP.

Further dissection of QTLs for salt-induced stroke and identification of candidate genes in the stroke-prone spontaneously hypertensive rat.

We previously revealed that two major quantitative trait loci (QTLs) for stroke latency of the stroke-prone spontaneously hypertensive rat (SHRSP) under salt-loading were located on chromosome (Chr) 1 and 18. Here, we attempted further dissection of the stroke-QTLs using multiple congenic strains between SHRSP and a stroke-resistant hypertensive rat (SHR). Cox hazard model among subcongenic strains harboring a chromosomal fragment of Chr-1 QTL region showed that the most promising region was a 2.

Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches.

Aims: Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4.

Methods And Results: Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed.

Emission Tuning of Luminescent Copper(I) Complexes by Vapor-Induced Ligand Exchange Reactions.

We have synthesized two luminescent mononuclear Cu(I) complexes, [Cu(PPhTol)(THF)(4Mepy)](BF) (1) and [Cu(PPhTol)(4Mepy)](BF) (2) (PPhTol = diphenyl(o-tolyl)phosphine, 4Mepy = 4-methylpyridine, THF = tetrahydrofuran), and investigated their crystal structures, luminescence properties, and vapor-induced ligand exchange reactions in the solid state. Both coordination complexes are tetrahedral, but one of the three 4Mepy ligands of complex 2 is replaced by a THF solvent molecule in complex 1. In contrast to the very weak blue emission of the THF-bound complex 1 (wavelength of emission maximum (λ) = 457 nm, emission quantum yield (Φ) = 0.

Reversible luminescent colour changes of mononuclear copper(i) complexes based on ligand exchange reactions by N-heteroaromatic vapours.

[CuCl(PPh)(4-Mepy)] (PPh = triphenylphosphine, 4-Mepy = 4-methylpyridine), a highly blue-luminescent mononuclear copper(i) complex, shows reversible emission colour change ranging from blue-green to red by vapour exposure to N-heteroaromatics, such as pyridine, pyrimidine, and 2-methylpyrazine. The remarkable colour changes occur due the ligand exchange reaction between the solid and gas. Such ligand exchange reactions would be applicable to various vapours with coordination ability and be useful for the sensing of such volatile organic compounds as well as a new convenient methodology for the preparation of luminescent complexes.

Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction.

Myocardial infarction (MI) results in the generation of dead cells in the infarcted area. These cells are swiftly removed by phagocytes to minimize inflammation and limit expansion of the damaged area. However, the types of cells and molecules responsible for the engulfment of dead cells in the infarcted area remain largely unknown.

Effect of p22phox depletion on sympathetic regulation of blood pressure in SHRSP: evaluation in a new congenic strain.

Oxidative stress in the rostral ventrolateral medulla (RVLM), a sympathetic center in the brainstem, was implicated in the regulation of sympathetic activity in various hypertensive models including stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we evaluated the role of the NADPH oxidases (NOX) in the blood pressure (BP) regulation in RVLM in SHRSP. The P22PHOX-depleted congenic SHRSP (called SP.