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Hiroki Chikumi

Publications and source records attributed to Hiroki Chikumi.

12 recordsLinked to original sources
PubMed2006

Acute eosinophilic pneumonia caused by calcium stearate, an additive agent for an oral antihistaminic medication.

A 70-year-old man was admitted to our hospital because of dyspnea after taking an antihistaminic agent (homochlorcyclizine hydrochloride) for itching. Chest roentgenogram showed infiltration in the left lung field, and laboratory data revealed eosinophilia. Examination of the bronchoalveolar lavage fluid revealed an increased eosinophil count. A drug lymphocyte stimulation test was positive only for calcium stearate, an additive contained in the homochlorcyclizine hydrochloride tablet. The pulmonary infiltration and clinical symptoms subsided after withdrawal of all drugs and initiation of glucocorticoid therapy. Therefore, we concluded that this patient's pulmonary disease was caused by calcium stearate, an additive for an antihistaminic drug. An allergic reaction to a drug's additive material should be considered as a rare cause of drug-induced acute eosinophilic pneumonia.

Acute Disease↗
PubMed2005

Measurement of Pseudomonas aeruginosa multidrug efflux pumps by quantitative real-time polymerase chain reaction.

Multidrug efflux pumps contribute to multiple antibiotic resistance in Pseudomonas aeruginosa. Pump expression usually has been quantified by Western blotting. Quantitative real-time polymerase chain reaction has been developed to measure mRNA expression for genes of interest. Whether this method correlates with pump protein quantities is unclear. We devised a real-time PCR for mRNA expression of MexAB-OprM and MexXY-OprM multidrug efflux pumps. In laboratory strains differing in MexB and MexY expression and in several clinical isolates, protein and mRNA expression correlated well. Quantitative real-time PCR should be a useful alternative in quantitating expression of multidrug efflux pumps by P. aeruginosa isolates in clinical laboratories.

Bacterial Outer Membrane Proteins↗
PubMed2005

Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells.

A novel histone deacetylase inhibitor, FK228, is a promising anticancer agent and has been proposed to modulate intracellular signaling, in addition to regulating gene transcription. We evaluated the effect of this agent on Akt-mediated signaling in relation to its cytotoxic activity using lung adenocarcinoma cell lines. Based on MTT assay and the appearance of cleaved poly (ADP-ribose) polymerase (PARP), we regarded A549 and PC14 cells as relatively sensitive and resistant cell lines, respectively. In A549 cells, FK228 suppressed the phosphorylation of Akt at Ser-473 and glycogen synthase kinase-3 without affecting these protein levels, indicating inhibition of the Akt-mediated signaling pathway. On the other hand, in PC14 cells, these biochemical reactions were not detected after treatment with FK228. The combination of FK228 and a phosphatidylinositol 3-kinase (PI3K)/Akt pathway inhibitor, LY294002, was determined to be synergistically cytotoxic in PC14 cells by isobologram analysis. This synergistic effect was attributable to the enhancement of apoptosis, as judged by flow cytometric analysis, and the appearance of cleaved PARP. The combination of FK228 with UCN-01, another PI3K/Akt pathway inhibitor, also exerted a synergistic effect. We concluded that FK228 suppresses the PI3K/Akt signaling pathway in a cell-specific manner, and this effect is a determinant of sensitivity to FK228.

Adenocarcinoma↗
PubMed2004

Homo- and hetero-oligomerization of PDZ-RhoGEF, LARG and p115RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential.

PDZ-RhoGEF, LARG, and p115RhoGEF are members of a newly identified family of Rho-guanine nucleotide exchange factors (GEFs) exhibiting a unique structural feature consisting of the presence of an area of similarity to regulators of G protein signaling (RGS). This RGS-like (RGL) domain provides a functional motif by which Galpha(12) and Galpha(13) can bind and regulate the activity of these RhoGEFs, thus providing a direct link from these heterotrimeric G proteins to Rho. PDZ-RhoGEF and LARG can also be phosphorylated by tyrosine kinases, including FAK, and associate with Plexin B, a semaphorin receptor, which controls axon guidance during development, through their PDZ domain, thereby stimulating Rho. Interestingly, while characterizing a PDZ-RhoGEF antiserum, we found that a transfected PDZ-RhoGEF construct associated with the endogenous PDZ-RhoGEF. Indeed, we observed that PDZ-RhoGEF and LARG can form homo- and hetero-oligomers, whereas p115RhoGEF can only homo-oligomerize, and that this intermolecular interaction was mediated by their unique C-terminal regions. Deletion of the C-terminal tail of PDZ-RhoGEF had no significant effect on the GEF catalytic activity towards Rho in vitro, but resulted in a drastic increase in the ability to stimulate a serum response element reporter and the accumulation of the GTP-bound Rho in vivo. Furthermore, removal of the C-termini of each of the three RGL-containing GEFs unleashed their full transforming potential. Together, these findings suggest the existence of a novel mechanism controlling the activity of PDZ-RhoGEF, LARG, and p115RhoGEF, which involves homo- and hetero-oligomerization through their inhibitory C-terminal region.

Animals↗
PubMed2004

Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells.

Viral infection generally results in the activation of inducible nitric oxide synthase (iNOS or NOS2) in respiratory epithelial cells by inflammatory cytokines. Activated NOS2 catalyzes synthesis of nitric oxide (NO), which in excess can cause cellular injury. On the other hand, lysophosphatidic acid (LPA), a lipid mediator released from epithelial cells, platelets, and fibroblasts in injured tissue, functions in repair of cell injury. However, details of the mechanism for repair by LPA remain unknown. We demonstrated one effect of LPA favoring repair, specifically inhibition by LPA of cytokine-induced NOS2 protein and mRNA expression by human respiratory epithelial cells in vitro. NO production by LPA-treated, cytokine-stimulated cells was also reduced. These decreases were prevented by Rho kinase inhibition with Y-27632. Thus, down-regulation by LPA of cytokine-induced increases in NOS2 activity is likely to involve a Rho-dependent signaling pathway. Harmful biologic effects of NO in viral respiratory infection might be modified by therapeutic manipulations involving LPA or Rho.

Cell Line↗
PubMed2004

Cellular immune profile in patients with non-small cell lung cancer after weekly paclitaxel therapy.

Paclitaxel is a new agent for advanced non-small cell lung cancer (NSCLC). Weekly doses may enhance antitumor activity while minimizing toxicity, but little is known about immune recovery. Paclitaxel (80 mg/m2) was administered to 10 patients with NSCLC, weekly during 3-week cycles. Natural killer (NK) activity, CD3-CD16+CD56+ NK cells, and differential counts were monitored. NK activity appeared in all patients after treatment with paclitaxel therapy NK activity showed a 27 +/- 9% decrease (mean +/- SE) on protocol day 8 and a 37 +/- 7% decrease on day 15 (p < 0.05) recovering to 89 +/- 5% of baseline on day 29. With weekly paclitaxel, a decrease in NK cell function persisted through the first cycle but then recovered. Weekly paclitaxel may be less immunosuppressive than agents such as cisplatin.

Adult↗
PubMed2003

[Lung cancer].

Explore the source record for details and available documents.

Humans↗
PubMed2002

Potent activation of RhoA by Galpha q and Gq-coupled receptors.

Heterotrimeric G proteins of the G(i), G(s), and G(q) family control a wide array of physiological functions primarily by regulating the activity of key intracellular second messenger-generating systems. alpha subunits of the G(12) family, Galpha(12) and Galpha(13), however, can promote cellular responses that are independent of conventional second messengers but that result from the activation of small GTP-binding proteins of the Rho family and their downstream targets. These findings led to the identification of a novel family of guanine-nucleotide exchange factors (GEFs) that provides a direct link between Galpha(12/13) and Rho stimulation. Recent observations suggest that many cellular responses elicited by Galpha(q) and its coupled receptors also require the functional activity of Rho. However, available evidence suggests that Galpha(q) may act on pathways downstream from Rho rather than by promoting Rho activation. These seemingly conflicting observations and the recent development of sensitive assays to assess the in vivo levels of active Rho prompted us to ask whether Galpha(q) and its coupled receptors can stimulate endogenous Rho. Here we show that the expression of activated forms of Galpha(q) and the stimulation of G(q)-coupled receptors or chimeric Galpha(q) molecules that respond to G(i)-linked receptors can promote a robust activation of endogenous Rho in HEK-293T cells. Interestingly, this response was not prevented by molecules interfering with the ability of Galpha(13) to stimulate its linked RhoGEFs, together suggesting the existence of a novel molecular mechanism by which Galpha(q) and the large family of G(q)-coupled receptors can regulate the activity of Rho and its downstream signaling pathways.

Cell Line↗
PubMed2002

Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38gamma-dependent signaling pathway.

A novel branch of the Ras family, Rit, was recently identified. Rit exhibits a distinct C-terminus and effector domain, and does not activate mitogen-activated protein kinase (MAPK) but can cooperate with Raf to transform fibroblasts. Here, we found that when overexpressed, activated mutants of Rit transform NIH 3T3 cells efficiently, and stimulate p38gamma but not MAPK, p38alpha, p38gamma, p38delta, or ERK5. Furthermore, we provide evidence that p38gamma activation is required for the ability of Rit to stimulate gene expression and cellular transformation. These findings suggest that this unique GTPase stimulates proliferative pathways distinct from those regulated by other Ras family members.

3T3 Cells↗
PubMed2002

Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase.

A recently identified family of guanine nucleotide exchange factors for Rho that includes PDZ-RhoGEF, LARG, and p115RhoGEF exhibits a unique structural feature consisting in the presence of area of similarity to regulators of G protein signaling (RGS). This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho. Recently available data suggest, however, that tyrosine kinases can regulate the ability of G protein-coupled receptors (GPCRs) to stimulate Rho, although the underlying molecular mechanisms are still unknown. Here, we found that the activation of thrombin receptors endogenously expressed in HEK-293T cells leads to a remarkable increase in the levels of GTP-bound Rho within 1 min (11-fold) and a more limited but sustained activation (4-fold) thereafter, which lasts even for several hours. Interestingly, tyrosine kinase inhibitors did not affect the early phase of Rho activation, immediately after thrombin addition, but diminished the levels of GTP-bound Rho during the delayed phase. As thrombin receptors stimulate focal adhesion kinase (FAK) potently, we explored whether this non-receptor tyrosine kinase participates in the activation of Rho by GPCRs. We obtained evidence that FAK can be activated by thrombin, Galpha(12), Galpha(13), and Galpha(q) through both Rho-dependent and Rho-independent mechanisms and that PDZ-RhoGEF and LARG can in turn be tyrosine-phosphorylated through FAK in response to thrombin, thereby enhancing the activation of Rho in vivo. These data indicate that FAK may act as a component of a positive feedback loop that results in the sustained activation of Rho by GPCRs, thus providing evidence of the existence of a novel biochemical route by which tyrosine kinases may regulate the activity of Rho through the tyrosine phosphorylation of RGL-containing RhoGEFs.

Blotting, Western↗
PubMedDate not supplied

Lung cancer arising in association with middle lobe syndrome.

Middle lobe syndrome, caused mainly by benign inflammatory diseases, such as chronic bronchitis and bronchiectasis, is manifested clinically as a chronic cough with sputum production. The prognosis associated with this syndrome is considered good in most cases which are caused by chronic inflammatory diseases. A patient who developed lung cancer in the course of long-term treatment for right middle lobe syndrome is described. A 63-year-old woman was admitted to our hospital with complaints of right iliac bone pain. She had been treated for chronic bronchitis and bronchiectasis associated with middle lobe syndrome for 16 years before admission. Work-up of a lung adenocarcinoma originating from the right middle lobe disclosed bone metastasis to the illium. Tumorigenesis in association with middle lobe syndrome has not yet been reported, but this first reported case suggests the need to be alert to the possibility.

Chronic Disease↗