K+ loading, but not Na+ loading, and blockade of ATP-sensitive K+ channels augment renal kallikrein secretion

This study aimed to examine whether K+ loading or Na+ loading augments renal kallikrein (KK) secretion. It also investigated the effect of blockade of renal ATP-sensitive K+ channels on renal KK secretion. Rats were administered 50 mmol/kg body weight of KCl. Twelve-hour collected urine was measured for urinary excretion of K+ and Na+ and urinary activity of renal KK. Increases in urinary excretion of K+ and Na+ by K+ loading accompanied an increase in renal KK secretion. In another experiment, rats were infused intravenously with a solution of 75 mM K+ and 75 mM Na+, 150 mM Na+ or 300 mM Na+ for 150 min under anesthesia. Urinary KK activity was measured in urine collected every 30 min. Renal KK secretion began to increase within the 30 min infusion of K+ solution and persisted at more elevated levels during the infusion with K+ solution than with Na+ solutions. Furthermore, rats were given intravenous injection of ATP-sensitive K+ channel blocker, either PNU-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl) at a concentration of 10 mg/kg or glibenclamide at 30 mg/kg. Renal KK secretion increased 30 min after administration of both PNU-37883A and glibenclamide. In conclusion, it may be that augmentation of renal KK secretion by K+ loading occurred through an increase in urinary K+ excretion followed by the inhibition of K+ transport from ATP-sensitive K+ channels.     

Peritumoral brain edema in meningiomas--influence of vascular supply on its development.

In a series of 35 patients with intracranial meningiomas, factors influencing the development of peritumoral brain edema (PTBE) were analyzed. We used numbers of the Edema Index as the extent of PTBE, which was obtained from the size of the meningioma and associated PTBE on a T2-weighted image of magnetic resonance imaging. We evaluated a relationship between the Edema Index and some factors that may play a role in the development of PTBE. Tumors in the frontal region and at the sphenoid ridge tended to be associated with larger PTBE than those in other locations (P less than 0.05). Histologically, meningotheliomatous and transitional meningiomas tended to be associated with larger PTBE than fibroblastic meningiomas (P less than 0.05). The meningiomas that had a vascular supply from the intrinsic cerebral arteries on angiography significantly correlated with severe PTBE compared with those supplied only from the meningeal side (P less than 0.01). We concluded that location, histology, and vascular supply from intrinsic cerebral arteries were the factors influencing PTBE. It is stressed that the vascular supply from the intrinsic cerebral arteries may have an influence on the extensive PTBE of meningioma.     

Pharmacological characterization of a nonpeptide bradykinin B2 receptor antagonist,FR165649, and agonist,FR190997

1. The nonpeptide bradykinin (BK) B₂ receptor antagonist, {"type":"entrez-nucleotide","attrs":{"text":"FR165649","term_id":"258310103","term_text":"FR165649"}}FR165649 (8-[2,6-dichloro-3-[N-[(E)-4-(N- methylcarbamoyl)cinnamidoacetyl] -N-methylamino] benzyloxy] -2 - methylquinoline), and agonist, {"type":"entrez-nucleotide","attrs":{"text":"FR190997","term_id":"257934014","term_text":"FR190997"}}FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline) have been identified. These compounds have a common chemical structure, and the 2-pyridylmethoxy group is the only structural difference between them.
2. Both {"type":"entrez-nucleotide","attrs":{"text":"FR165649","term_id":"258310103","term_text":"FR165649"}}FR165649 and {"type":"entrez-nucleotide","attrs":{"text":"FR190997","term_id":"257934014","term_text":"FR190997"}}FR190997 displaced [³H]-BK binding to B₂ receptors in guinea-pig ileum membranes, with an IC₅₀ of 4.7×10⁻¹⁰ M and 1.5×10⁻⁹ M, respectively. They also displaced [³H]-BK binding to B₂ receptors in human lung fibroblast IMR-90 cells, with an IC₅₀ of 1.6×10⁻⁹ M and 9.8×10⁻¹⁰ M, respectively.
3. In guinea-pig isolated ileum-preparations, {"type":"entrez-nucleotide","attrs":{"text":"FR165649","term_id":"258310103","term_text":"FR165649"}}FR165649 had no agonistic effect on contraction and caused parallel rightward shifts of the concentration-response curves to BK on contraction. Analysis of the data produced a nominal pA₂ value of 9.2±0.1 (n=5) and a slope of 1.4±0.1 (n=5). On the other hand, {"type":"entrez-nucleotide","attrs":{"text":"FR190997","term_id":"257934014","term_text":"FR190997"}}FR190997 induced concentration-dependent contraction of guinea-pig ilea with a pD₂ of 7.9±0.2 and the contraction was inhibited by a specific peptide bradykinin B₂ receptor antagonist, Hoe 140 (D-Arg-[Hyp³, Thi⁵, D-Tic⁷, Oic⁸]BK) in a non-competitive manner.
4. In IMR-90 cells, {"type":"entrez-nucleotide","attrs":{"text":"FR165649","term_id":"258310103","term_text":"FR165649"}}FR165649 had no agonistic effect on phosphatidyl inositol (PI) hydrolysis and caused parallel rightward shifts (approximately 200 fold shift at 10⁻⁷ M) of the concentration-response curves to BK on PI hydrolysis. {"type":"entrez-nucleotide","attrs":{"text":"FR190997","term_id":"257934014","term_text":"FR190997"}}FR190997 induced concentration-dependent PI hydrolysis in IMR-90 cells with a pD₂ of 8.4±0.1, and this effect was inhibited by Hoe 140.
5. These results indicate that {"type":"entrez-nucleotide","attrs":{"text":"FR165649","term_id":"258310103","term_text":"FR165649"}}FR165649 and {"type":"entrez-nucleotide","attrs":{"text":"FR190997","term_id":"257934014","term_text":"FR190997"}}FR190997 are, respectively, a potent bradykinin B₂ receptor antagonist and agonist, and that the agonistic activity depends on the small part of the nonpeptide ligand. {"type":"entrez-nucleotide","attrs":{"text":"FR165649","term_id":"258310103","term_text":"FR165649"}}FR165649 and {"type":"entrez-nucleotide","attrs":{"text":"FR190997","term_id":"257934014","term_text":"FR190997"}}FR190997 may be useful tools for studying the relationship between ligands and receptors.

     

Enhanced Apoptosis in Pilocytic Astrocytoma: A Comparative Study of Apoptosis and Proliferation in Astrocytic Tumors

Both cell proliferation and cell death occur simultaneously in tumor tissue, and extent of tumor growth reflects the net balance of these events. We correlated cell proliferation, spontaneous cell death, and alterations in tumor suppressor proteins with one another and with survival of patients with primary astrocytic tumors. In 39 astrocytic tumor specimens (6 pilocytic astrocytomas, 14 fibrillary astrocytomas, 9 anaplastic astrocytomas, and 10 glioblastomas), we determined the MIB-1 labeling index, the apoptotic ratio according to nick end labeling with morphologic confirmation, the p53 labeling index, and the presence of p53 or PTEN mutations.MIB-1 labeling indices of pilocytic astrocytomas, fibrillary astrocytomas, anaplastic astrocytomas, and glioblastomas were 0.30±0.32; 1.84±1.87; 19.3±6.42; and 28.0±14.5 (mean±SD), respectively. Corresponding apoptotic ratios were 17.9±5.16; 3.96±3.57; 1.18±0.93; and 2.11± 1.60 (mean±SD). The apoptotic ratio in pilocytic astrocytomas was significantly higher than in other astrocytic tumors (fibrillary astrocytomas, p<0.05; anaplastic astrocytomas and glioblastomas, p<0.01). MIB-1 showed a significant negative correlation with apoptosis (p<0.01). MIB-1 and apoptosis showed significant negative and positive correlations with patient survival (p<0.01). Mutations of p53 and PTEN show no correlation with survival and apoptotic ratio.The apoptotic ratio can clearly distinguish pilocytic astrocytomas from other tumors, and this biological feature may reflect less aggressive growth of pilocytic astrocytomas.     

Potentiation of tumoricidal properties of murine macrophages by Nocardia rubra cell wall skeleton (N-CWS)

Intraperitoneal injection of squalene-treated cell wall skeleton of Nocardia rubra (N-CWS) caused increase in number of peritoneal exudate cells (PEC). Adherent macrophages obtained from N-CWS-treated PEC suppressed growth of methylcholanthrene-induced fibrosarcoma (Meth-A), when injected intradermally with the tumor cells into BALB/c mice. The macrophages showed strong cytotoxicity against Meth-A cells in vitro. When treated with 10 micrograms/ml of N-CWS in vitro, proteose peptone-induced macrophages acquired tumoricidal property but resident macrophages showed no cytotoxicity after the treatment. In the supernatant of spleen cells cultured for 72 hours in the presence of N-CWS (10 micrograms/ml), the presence of (a) factor(s) with macrophage activating effect was observed. This factor, shown to be identical to macrophage activating factor (MAF) in molecular weight, showed synergy with N-CWS in potentiating macrophage cytotoxicity against tumor cells.     

Effects of arginine derivatives on soluble guanylate cyclase from neuroblastoma N1E 115 cells

The effects of L-arginine (Arg) derivatives on soluble guanylate cyclase from neuroblastoma N1E 115 cells were examined. The Arg derivatives were modified at the -NH2, -COOH, C alpha-proton or guanidino group of Arg. Among the synthesized derivatives, eight compounds, i.e. the 5-(dimethylamino)-1-naphthalenesulfonyl (DNS) ones, especially N-cyclohexyl-2-(N-DNSamino)-5-guanidino-2-methylvaleramide and 1-[2-(N-DNSamino)-2-(2-imino-1,2,3,4,5,6-hexahydropyrimidin- 4-yl)acetyl]- piperidine, were found to inhibit the activity of crude guanylate cyclase in the 105,000 g supernatant fraction of the cell homogenate. The enzyme, partially purified by a column of Chelex 100 Na+, was also inhibited by these eight compounds. The mode of the inhibition was competitive. The Ki values were in the range of 2-8 microM for the enzyme in the 105,000 g supernatant fraction and 3-16 microM for the partially purified enzyme, in the presence of Mg2+ as a metal cofactor. In contrast, a new derivative, methyl 2-amino-5-guanidinovalerate (M Arg ME), as well as the Arg methyl ester (Arg ME) and Arg; were found to enhance the activity of the partially purified guanylate cyclase; KA values of M Arg ME, Arg ME and Arg were approximately 9, 4 and 3 microM respectively. From these results, the free guanidino group including 2-imino-1,2,3,4,5,6-hexahydropyrimidin-4-yl or 2-imino-1,2,3,4,5,6-hexahydropyrimidin-5-yl and modification of the --NH2 residue with a hydrophobic group such as DNS seemed to be essential for inhibition of the guanylate cyclase; however, the guanidino and --NH2 residue of Arg should be free for activation by these Arg derivatives.     

Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction

Hepatocyte-like cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are expected to be a useful source of cells drug discovery. Although we recently reported that hepatic commitment is promoted by transduction of SOX17 and HEX into human ESC- and iPSC-derived cells, these hepatocyte-like cells were not sufficiently mature for drug screening. To promote hepatic maturation, we utilized transduction of the hepatocyte nuclear factor 4α (HNF4α) gene, which is known as a master regulator of liver-specific gene expression. Adenovirus vector-mediated overexpression of HNF4α in hepatoblasts induced by SOX17 and HEX transduction led to upregulation of epithelial and mature hepatic markers such as cytochrome P450 (CYP) enzymes, and promoted hepatic maturation by activating the mesenchymal-to-epithelial transition (MET). Thus HNF4α might play an important role in the hepatic differentiation from human ESC-derived hepatoblasts by activating the MET. Furthermore, the hepatocyte like-cells could catalyze the toxication of several compounds. Our method would be a valuable tool for the efficient generation of functional hepatocytes derived from human ESCs and iPSCs, and the hepatocyte-like cells could be used for predicting drug toxicity.     

The value of dynamic imaging for standardization of abdominal ultrasonography

Purpose  

Digital video recording of dynamic images is a potential way to improve the reproducibility of abdominal ultrasonography (US). Static US and dynamic US were compared using contrast-enhanced computed tomography (CE-CT) as a reference standard, and the value of stored video images was verified.     

Acute hepatitis B virus after chemotherapy for a case with germinoma]

A 28-year old man with HCG-producing germinoma had undergone chemotherapy and radiotherapy. On admission for the fifth session of maintenance chemotherapy, he was found to be positive for hepatitis B (HB)s antigen, but negative for HBs antibody. HBs antigen had been negative during previous admissions. Since liver function was normal, the patient underwent chemotherapy. During myelosuppression after chemotherapy, liver dysfunction developed and acute HB was diagnosed. He fortunately showed seroconversion 2 months after onset. Serum immunological examinations are required for patients receiving chemotherapy.