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Search Results: 1 - 10 of 1406 matches for " Toshihisa Ishikawa "
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Metabolic Interactions of Purine Derivatives with Human ABC Transporter ABCG2: Genetic Testing to Assess Gout Risk
Toshihisa Ishikawa,Wanping Aw,Kiyoko Kaneko
Pharmaceuticals , 2013, DOI: 10.3390/ph6111347
Abstract: In mammals, excess purine nucleosides are removed from the body by breakdown in the liver and excretion from the kidneys. Uric acid is the end product of purine metabolism in humans. Two-thirds of uric acid in the human body is normally excreted through the kidney, whereas one-third undergoes uricolysis (decomposition of uric acid) in the gut. Elevated serum uric acid levels result in gout and could be a risk factor for cardiovascular disease and diabetes. Recent studies have shown that human ATP-binding cassette transporter ABCG2 plays a role of renal excretion of uric acid. Two non-synonymous single nucleotide polymorphisms (SNPs), i.e ., 421C>A (major) and 376C>T (minor), in the ABCG2 gene result in impaired transport activity, owing to ubiquitination-mediated proteosomal degradation and truncation of ABCG2, respectively. These genetic polymorphisms are associated with hyperuricemia and gout. Allele frequencies of those SNPs are significantly higher in Asian populations than they are in African and Caucasian populations. A rapid and isothermal genotyping method has been developed to detect the SNP 421C>A, where one drop of peripheral blood is sufficient for the detection. Development of simple genotyping methods would serve to improve prevention and early therapeutic intervention for high-risk individuals in personalized healthcare.
Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis
Toshihisa Ishikawa,Hiroshi Nakagawa,Yuichiro Hagiya,Naosuke Nonoguchi,Shin-ichi Miyatake,Toshihiko Kuroiwa
Advances in Pharmacological Sciences , 2010, DOI: 10.1155/2010/587306
Abstract: Accumulating evidence indicates that ATP-binding cassette (ABC) transporter ABCG2 plays a key role in regulating the cellular accumulation of porphyrin derivatives in cancer cells and thereby affects the efficacy of photodynamic therapy and photodynamic diagnosis. The activity of porphyrin efflux can be affected by genetic polymorphisms in the ABCG2 gene. On the other hand, Nrf2, an NF-E2-related transcription factor, has been shown to be involved in oxidative stress-mediated induction of the ABCG2 gene. Since patients have demonstrated individual differences in their response to photodynamic therapy, transcriptional activation and/or genetic polymorphisms of the ABCG2 gene in cancer cells may affect patients' responses to photodynamic therapy. Protein kinase inhibitors, including imatinib mesylate and gefitinib, are suggested to potentially enhance the efficacy of photodynamic therapy by blocking ABCG2-mediated porphyrin efflux from cancer cells. This review article provides an overview on the role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis. 1. Introduction Photodynamic therapy (PDT) and photodynamic diagnosis are achieved by a photon-induced physicochemical reaction which is induced by excitation of photosensitizer exposed to light. In the 1960s Lipson and Baldes introduced a hematoporphyrin derivative (HpD), a product derived following by treatment of hematoporphyrin with a mixture of acetic and sulfuric acids and sodium hydroxide [1]. Their development of the hematoporphyrin derivative established the basis of today’s PDT and photodynamic diagnosis [2–6]. PDT utilizes porphyrin derivatives to generate singlet oxygen (1O2) and other reactive oxygen species (ROS) that are potent in killing cancer cell in vivo [7]. The modern era of PDT was founded in the 1970s with the pioneering work of Dougherty and his coworkers who purified HpD later called Photofrin. In 1978, Dougherty et al. had carried out the first human trials of Photofrin on women with advanced breast cancer [8]. Photofrin is still the most widely used photosensitizer in clinical PDT. Recent studies of modern PDT began just two decades ago; therefore there are still unsolved problems. Nevertheless, PDT has many applications in a wide range of fields of both preclinical and clinical sciences. In recent years, remarkable advances were made in photodynamic diagnosis technology that makes it easier to reliably achieve complete excision of malignant gliomas [9–11] and meningiomas [12]. The extent of tumor resection that should be undertaken in patients with
Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA)-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors
Toshihisa Ishikawa,Kenkichi Takahashi,Naokado Ikeda,Yoshinaga Kajimoto,Yuichiro Hagiya,Shun-ichiro Ogura,Shin-ichi Miyatake,Toshihiko Kuroiwa
Pharmaceutics , 2011, DOI: 10.3390/pharmaceutics3030615
Abstract: Photodynamic diagnosis (PDD) is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX) exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA) or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP)-binding cassette (ABC) transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new?approach of quantitative structure-activity relationship (QSAR) analysis to design potent ABCG2-inhibitors.
Regulation of bone mass at unloaded condition by osteocyte network
Toshihisa Komori
Arthritis Research & Therapy , 2012, DOI: 10.1186/ar3568
Abstract: We searched for the molecules responsible for disuse osteoporosis using BCL2 transgenic mice. Pyruvate dehydrogenase kinase isozymes (Pdk1, Pdk2, Pdk3, and Pdk4) are negative regulators of pyruvate dehydrogenase complex (PDC), which converts pyruvate to acetyl-CoA in the mitochondria, linking glycolysis to the energetic and anabolic functions of the tricarboxylic acid (TCA) cycle. Pdk4 was upregulated in femurs and tibiae of wild-type mice but not of BCL2 transgenic mice after tail suspension. Bone in Pdk4-/- mice developed normally and was maintained. At unloading, however, bone mass was reduced due to enhanced osteoclastogenesis and Rankl expression in wild-type mice but not in Pdk4-/- mice. Osteoclast differentiation of Pdk4-/- bone marrow-derived monocyte/macrophage lineage cells (BMMs) in the presence of M-CSF and RANKL was suppressed, and osteoclastogenesis was impaired in the coculture of wild-type BMMs and Pdk4-/- osteoblasts, in which Rankl expression and promoter activity were reduced. Further, introduction of Pdk4 into Pdk4-/- BMMs and osteoblasts enhanced osteoclastogenesis and Rankl expression and activated Rankl promoter. These findings indicate that upregulation of Pdk4 expression in osteoblasts and bone marrow cells after unloading is, at least in part, responsible for the enhancement of osteoclastogenesis and bone resorption after unloading [1].
A System of Third-Order Differential Operators Conformally Invariant under $\mathfrak{so}(8,\mathbb{C})$
Toshihisa Kubo
Mathematics , 2010,
Abstract: In earlier work, Barchini, Kable, and Zierau constructed a number of conformally invariant systems of differential operators associated to Heisenberg parabolic subalgebras in simple Lie algebras. The construction was systematic, but the existence of such a system was left open in several anomalous cases. Here, a conformally invariant system is shown to exist in the most interesting of these remaining cases. The construction may also be interpreted as giving an explicit homomorphism between generalized Verma modules for the Lie algebra of type $D_4$.
Special Values for Conformally Invariant Systems Associated to Maximal Parabolics of Quasi-Heisenberg Type
Toshihisa Kubo
Mathematics , 2012,
Abstract: In this paper we construct conformally invariant systems of first order and second order differential operators associated to a homogeneous line bundle $\Cal{L}_{s} \to G_0/Q_0$ with $Q_0$ a maximal parabolic subgroup of quasi-Heisenberg type. This generalizes the results by Barchini, Kable, and Zierau.To do so we use techniques different from ones used by them.
Stability of multidimensional skip-free Markov modulated reflecting random walks: Revisit to Malyshev and Menshikov's results and application to queueing networks
Toshihisa Ozawa
Mathematics , 2012,
Abstract: Let $\{\boldsymbol{X}_n\}$ be a discrete-time $d$-dimensional process on $\mathbb{Z}_+^d$ with a supplemental (background) process $\{J_n\}$ on a finite set and assume the joint process $\{\boldsymbol{Y}_n\}=\{(\boldsymbol{X}_n,J_n)\}$ to be Markovian. Then, the process $\{\boldsymbol{X}_n\}$ can be regarded as a kind of reflecting random walk (RRW for short) in which the transition probabilities of the RRW are modulated according to the state of the background process $\{J_n\}$; we assume this modulation is space-homogeneous inside $\mathbb{Z}_+^d$ and on each boundary face of $\mathbb{Z}_+^d$. Further we assume the process $\{\boldsymbol{X}_n\}$ is skip free in all coordinates and call the joint process $\{\boldsymbol{Y}_n\}$ a $d$-dimensional skip-free Markov modulated reflecting random walk (MMRRW for short). The MMRRW is an extension of an ordinary RRW and stability of ordinary RRWs have been studied by Malyshev and Menshikov. Following their results, we obtain stability and instability conditions for MMRRWs and apply our results to stability analysis of a two-station network.
On the homomorphisms between the generalized Verma modules arising from conformally invariant systems
Toshihisa Kubo
Mathematics , 2012,
Abstract: It is shown by Barchini, Kable, and Zierau that conformally invariant systems of differential operators yield explicit homomorphisms between certain generalized Verma modules. In this paper we determine whether or not the homomorphisms arising from such systems of first and second order differential operators associated to maximal parabolic subalgebras of quasi-Heisenberg type are standard.
Systems of Differential Operators and Generalized Verma Modules
Toshihisa Kubo
Mathematics , 2013, DOI: 10.3842/SIGMA.2014.008
Abstract: In this paper we close the cases that were left open in our earlier works on the study of conformally invariant systems of second-order differential operators for degenerate principal series. More precisely, for these cases, we find the special values of the systems of differential operators, and determine the standardness of the homomorphisms between the generalized Verma modules, that come from the conformally invariant systems.
Positive recurrence and transience of a two-station network with server states
Toshihisa Ozawa
Mathematics , 2013,
Abstract: We study positive recurrence and transience of a two-station network in which the behavior of the server in each station is governed by a Markov chain with a finite number of server states; this service process can represent various service disciplines such as a non-preemptive priority service and K-limited service. Assuming that exogenous customers arrive according to independent Markovian arrival processes (MAPs), we represent the behavior of the whole network as a continuous-time Markov chain and, by the uniformization technique, obtain the corresponding discrete-time Markov chain, which is positive recurrent (transient) if and only if the original continuous-time Markov chain is positive recurrent (resp. transient). This discrete-time Markov chain is a four-dimensional skip-free Markov modulated reflecting random walk (MMRRW) and, applying several existing results of MMRRWs to the Markov chain, we obtain conditions on which the Markov chain is positive recurrent and on which it is transient. The conditions are represented in terms of the difference of the input rate and output rate of each queue in each induced Markov chain. In order to demonstrate how our results work in two-station networks, we give several examples.
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