Takehiro Yamamoto

Bio: Takehiro Yamamoto is an academic researcher from Keio University. The author has contributed to research in topics: Heme oxygenase & Pentose phosphate pathway. The author has an hindex of 16, co-authored 35 publications receiving 1197 citations. Previous affiliations of Takehiro Yamamoto include Nagoya University & Hokkaido University.

Interactions of multiple gas-transducing systems: hallmarks and uncertainties of CO, NO, and H2S gas biology.

Abstract: The diverse physiological actions of the “biologic gases,” O2, CO, NO, and H2S, have attracted much interest. Initially viewed as toxic substances, CO, NO, and H2S play important roles as signaling molecules. The multiplicity of gas actions and gas targets and the difficulty in measuring local gas concentrations obscures detailed mechanisms whereby gases exert their actions, and many questions remain unanswered. It is now readily apparent, however, that heme-based proteins play central roles in gas-generation/reception mechanisms and provide a point where multiple gases can interact. In this review, we consider a number of key issues related to “gas biology,” including the effective tissue concentrations of these gases and the importance and significance of the physical proximity of gas-producing and gas-receptor/sensors. We also take an integrated approach to the interaction of gases by considering the physiological significance of CO, NO, and H2S on mitochondrial cytochrome c oxidase, a key target and central mediator of mitochondrial respiration. Additionally, we consider the effects of biologic gases on mitochondrial biogenesis and “suspended animation.” By evaluating gas-mediated control functions from both in vitro and in vivo perspectives, we hope to elaborate on the complex multiple interactions of O2, NO, CO, and H2S. Antioxid. Redox Signal. 13, 157–192.

Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells

Abstract: An increased glycolytic flux accompanied by activation of the pentose phosphate pathway (PPP) is implicated in chemoresistance of cancer cells. In this study, we found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia. CD44 ablation by RNA interference increased metabolic flux to mitochondrial respiration and concomitantly inhibited entry into glycolysis and the PPP. Such metabolic changes induced by CD44 ablation resulted in marked depletion of cellular reduced glutathione (GSH) and increased the intracellular level of reactive oxygen species in glycolytic cancer cells. Furthermore, CD44 ablation enhanced the effect of chemotherapeutic drugs in p53-deficient or hypoxic cancer cells. Taken together, our findings suggest that metabolic modulation by CD44 is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance.

Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway

Abstract: Haem oxygenase (HO)-1/carbon monoxide (CO) protects cancer cells from oxidative stress, but the gas-responsive signalling mechanisms remain unknown. Here we show using metabolomics that CO-sensitive methylation of PFKFB3, an enzyme producing fructose 2,6-bisphosphate (F-2,6-BP), serves as a switch to activate phosphofructokinase-1, a rate-limiting glycolytic enzyme. In human leukaemia U937 cells, PFKFB3 is asymmetrically di-methylated at R131 and R134 through modification by protein arginine methyltransferase 1. HO-1 induction or CO results in reduced methylation of PFKFB3 in varied cancer cells to suppress F-2,6-BP, shifting glucose utilization from glycolysis toward the pentose phosphate pathway. Loss of PFKFB3 methylation depends on the inhibitory effects of CO on haem-containing cystathionine β-synthase (CBS). CBS modulates remethylation metabolism, and increases NADPH to supply reduced glutathione, protecting cells from oxidative stress and anti-cancer reagents. Once the methylation of PFKFB3 is reduced, the protein undergoes polyubiquitination and is degraded in the proteasome. These results suggest that the CO/CBS-dependent regulation of PFKFB3 methylation determines directional glucose utilization to ensure resistance against oxidative stress for cancer cell survival.

Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival.

Abstract: Gold deposition with diagonal angle towards boehmite-based nanostructure creates random arrays of horse-bean-shaped nanostructures named gold-nanofeve (GNF). GNF generates many electromagnetic hotspots as surface-enhanced Raman spectroscopy (SERS) excitation sources, and enables large-area visualization of molecular vibration fingerprints of metabolites in human cancer xenografts in livers of immunodeficient mice with sufficient sensitivity and uniformity. Differential screening of GNF-SERS signals in tumours and those in parenchyma demarcated tumour boundaries in liver tissues. Furthermore, GNF-SERS combined with quantum chemical calculation identified cysteine-derived glutathione and hypotaurine (HT) as tumour-dominant and parenchyma-dominant metabolites, respectively. CD44 knockdown in cancer diminished glutathione, but not HT in tumours. Mechanisms whereby tumours sustained HT under CD44-knockdown conditions include upregulation of PHGDH, PSAT1 and PSPH that drove glycolysis-dependent activation of serine/glycine-cleavage systems to provide one-methyl group for HT synthesis. HT was rapidly converted into taurine in cancer cells, suggesting that HT is a robust anti-oxidant for their survival under glutathione-suppressed conditions.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Present and Future of Surface-Enhanced Raman Scattering

Abstract: The discovery of the enhancement of Raman scattering by molecules adsorbed on nanostructured metal surfaces is a landmark in the history of spectroscopic and analytical techniques. Significant experimental and theoretical effort has been directed toward understanding the surface-enhanced Raman scattering (SERS) effect and demonstrating its potential in various types of ultrasensitive sensing applications in a wide variety of fields. In the 45 years since its discovery, SERS has blossomed into a rich area of research and technology, but additional efforts are still needed before it can be routinely used analytically and in commercial products. In this Review, prominent authors from around the world joined together to summarize the state of the art in understanding and using SERS and to predict what can be expected in the near future in terms of research, applications, and technological development. This Review is dedicated to SERS pioneer and our coauthor, the late Prof. Richard Van Duyne, whom we lost during the preparation of this article.

Physiological Implications of Hydrogen Sulfide: A Whiff Exploration That Blossomed

Abstract: The important life-supporting role of hydrogen sulfide (H2S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H2S had only been known for its toxicity and environmental hazard. Physiological importance of H2S has been appreciated for about a decade. It started by the discovery of endogenous H2S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H2S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H2S. The physiological functions of H2S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H2S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes...

Pharmacological and Clinical Aspects of Heme Oxygenase

Abstract: This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.