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4. Modulation of Ca2+ oscillation following ischemia and nicotinic acetylcholine receptors in primary cortical neurons by high-throughput analysis.

Author

Sasaki, Tsutomu, Hisada, Sunao, Kanki, Hideaki, Nunomura, Kazuto, Lin, Bangzhong, Nishiyama, Kumiko, Kawano, Tomohito, Matsumura, Shigenobu, and Mochizuki, Hideki

Subjects
NICOTINIC acetylcholine receptors, FREQUENCIES of oscillating systems, NEURON analysis, CEREBRAL ischemia, METHYL aspartate receptors, NICOTINIC receptors
Abstract

Calcium oscillations in primary neuronal cultures and iPSCs have been employed to investigate arrhythmogenicity and epileptogenicity in drug development. Previous studies have demonstrated that Ca2+ influx via NMDA and nicotinic acetylcholine receptors (nAChRs) modulates Ca2+ oscillations. Nevertheless, there has been no comprehensive investigation into the impact of ischemia or nAChR-positive allosteric modulators (PAM) drugs on Ca2+ oscillations at a level that would facilitate high-throughput screening. We investigated the effects of ischemia and nAChR subtypes or nAChR PAM agonists on Ca2+ oscillations in high-density 2D and 3D-sphere primary neuronal cultures using 384-well plates with FDSS-7000. Ischemia for 1 and 2 h resulted in an increase in the frequency of Ca2+ oscillations and a decrease in their amplitude in a time-dependent manner. The NMDA and AMPA receptor inhibition significantly suppressed Ca2+ oscillation. Inhibition of NR2A or NR2B had the opposite effect on Ca oscillations. The potentiation of ischemia-induced Ca2+ oscillations was significantly inhibited by the NMDA receptor antagonist, MK-801, and the frequency of these oscillations was suppressed by the NR2B inhibitor, Ro-256981. In the 3D-neurosphere, the application of an α7nAChR agonist increased the frequency of Ca2+ oscillations, whereas the activation of α4β2 had no effect. The combination of nicotine and PNU-120596 (type II PAM) affected the frequency and amplitude of Ca2+ oscillations in a manner distinct from that of type I PAM. These systems may be useful not only for detecting epileptogenicity but also in the search for neuroprotective agents against cerebral ischemia. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Discontinuation of Oral Anticoagulants in Atrial Fibrillation Patients: Impact of Treatment Strategy and on Patients’ Health Status

Author

Nakamaru, Ryo, primary, Ikemura, Nobuhiro, additional, Kimura, Takehiro, additional, Katsumata, Yoshinori, additional, Sherrod, Charles F., additional, Miyama, Hiroshi, additional, Shiraishi, Yasuyuki, additional, Kanki, Hideaki, additional, Negishi, Koji, additional, Ueda, Ikuko, additional, Fukuda, Keiichi, additional, Takatsuki, Seiji, additional, and Kohsaka, Shun, additional

Published
2023
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9. Effect of Tricuspid Regurgitation on the Reported Quality of Life and Subsequent Outcomes in Patients With Atrial Fibrillation

Author

Fujisawa, Taishi, primary, Kimura, Takehiro, additional, Ikemura, Nobuhiro, additional, Miyama, Hiroshi, additional, Katsumata, Yoshinori, additional, Ueda, Ikuko, additional, Tanimoto, Kojiro, additional, Kanki, Hideaki, additional, Fukuda, Keiichi, additional, Kohsaka, Shun, additional, and Takatsuki, Seiji, additional

Published
2022
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12. Abstract MP2: An Older Thrombus Delays Reperfusion in Mechanical Thrombectomy for Ischemic Stroke

Author

Kitano, Takaya, primary, Hori, Yumiko, additional, Shimada, Yuki, additional, Iwamoto, Takanori, additional, Okazaki, Shuhei, additional, Nakamura, Hajime, additional, Kanki, Hideaki, additional, Sasaki, Tsutomu, additional, Beck, Goichi, additional, Kishima, Haruhiko, additional, Murayama, Shigeo, additional, Morii, Eiichi, additional, Sakaguchi, Manabu, additional, Yagita, Yoshiki, additional, Mochizuki, Hideki, additional, and Todo, Kenichi, additional

Published
2021
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14. Effect of Tricuspid Regurgitation on the Reported Quality of Life and Subsequent Outcomes in Patients With Atrial Fibrillation.

Author

Taishi Fujisawa, Takehiro Kimura, Nobuhiro Ikemura, Hiroshi Miyama, Yoshinori Katsumata, Ikuko Ueda, Kojiro Tanimoto, Hideaki Kanki, Keiichi Fukuda, Shun Kohsaka, Seiji Takatsuki, Fujisawa, Taishi, Kimura, Takehiro, Ikemura, Nobuhiro, Miyama, Hiroshi, Katsumata, Yoshinori, Ueda, Ikuko, Tanimoto, Kojiro, Kanki, Hideaki, and Fukuda, Keiichi

Published
2022
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18. Promising Effect of a New Ketogenic Diet Regimen in Patients with Advanced Cancer

Author

Hagihara, Keisuke, primary, Kajimoto, Katsufumi, additional, Osaga, Satoshi, additional, Nagai, Naoko, additional, Shimosegawa, Eku, additional, Nakata, Hideyuki, additional, Saito, Hitomi, additional, Nakano, Mai, additional, Takeuchi, Mariko, additional, Kanki, Hideaki, additional, Kagitani-Shimono, Kuriko, additional, and Kijima, Takashi, additional

Published
2020
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21. New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death

Author

Hirata, Yoshiyuki, primary, Sasaki, Tsutomu, additional, Kanki, Hideaki, additional, Choong, Chi-Jing, additional, Nishiyama, Kumiko, additional, Kubo, Genki, additional, Hotei, Ayana, additional, Taniguchi, Masahiko, additional, Mochizuki, Hideki, additional, and Uesato, Shinichi, additional

Published
2018
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26. Atrial Fibrillation in KCNE1-Null Mice

Author

Temple, Joel, primary, Frias, Patricio, additional, Rottman, Jeffrey, additional, Yang, Tao, additional, Wu, Yuejin, additional, Verheijck, E. Etienne, additional, Zhang, Wei, additional, Siprachanh, Chanthaphaychith, additional, Kanki, Hideaki, additional, Atkinson, James B., additional, King, Paul, additional, Anderson, Mark E., additional, Kupershmidt, Sabina, additional, and Roden, Dan M., additional

Published
2005
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31. Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes

Author

Yang, Ping, primary, Kanki, Hideaki, additional, Drolet, Benoit, additional, Yang, Tao, additional, Wei, Jian, additional, Viswanathan, Prakash C., additional, Hohnloser, Stefan H., additional, Shimizu, Wataru, additional, Schwartz, Peter J., additional, Stanton, Marshall, additional, Murray, Katherine T., additional, Norris, Kris, additional, George, Alfred L., additional, and Roden, Dan M., additional

Published
2002
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38. A Structural Requirement for Processing the Cardiac K+ Channel KCNQ1.

Author

Kanki, Hideaki, Kupershmidt, Sabina, Tao Yang, Wells, Sam, and Roden, Dan M.

Subjects
*MEMBRANE proteins, *AMINO acids, *ENDOPLASMIC reticulum, *PROTEINS, *GENES, *LONG QT syndrome
Abstract

Normal membrane protein function requires trafficking from the endoplasmic reticulum. Here, we studied processing of the KCNQ1 channel mutated in LQT1, the commonest form of the long QT syndrome. Serial C terminus truncations identified a small region (amino acids (aa) 610–620) required for normal cell surface expression. Non-trafficked truncations assembled as tetramers but were nevertheless retained in the endoplasmic reticulum. Further mutagenesis did not identify specific residues mediating channel processing;, cell surface expression was preserved with the mutation of known trafficking motifs in the channel and with alanine scanning across aa 610–620. Structural prediction algorithms place aa 610–620 at the C-terminal end of an α-helix (aa 586–618) that includes a leucine zipper and is part of a coiled coil. Mutants disrupting the leucine zipper but preserving the predicted coiled coil reached the cell surface, whereas those disrupting the coil did not. These data suggest that specific protein-protein interactions are required for normal channel processing. Further biochemical studies ruled out three candidate proteins, namely KCNE1, yotiao, and KCNQ1 itself, as effectors of this coiled coil-mediated trafficking. Four LQT1 mutations within this helix generated little or no current and were not expressed on the cell surface, whereas LQT1 mutations in adjacent residues, which produce a milder clinical phenotype, generate only slightly reduced current and are expressed on the cell surface. These data suggest that mutations within this domain cause human disease by interfering with normal channel processing. More generally, we have identified a domain whose structural integrity is required for normal surface expression of the KCNQ1 channel. [ABSTRACT FROM AUTHOR]

Published
2004
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39. Driver gene KRAS aggravates cancer-associated stroke outcomes

Author

Yan, Haomin, Sasaki, Tsutomu, Gon, Yasufumi, Nishiyama, Kumiko, Kanki, Hideaki, Mochizuki, Hideki, Yan, Haomin, Sasaki, Tsutomu, Gon, Yasufumi, Nishiyama, Kumiko, Kanki, Hideaki, and Mochizuki, Hideki

Abstract

Yan Haomin, Sasaki Tsutomu, Gon Yasufumi, et al. Driver gene KRAS aggravates cancer-associated stroke outcomes. Thrombosis Research 233, 55 (2023); https://doi.org/10.1016/j.thromres.2023.11.015., The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/− and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/− cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/− allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/− cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/− group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.

40. Driver gene KRAS aggravates cancer-associated stroke outcomes

Author

Yan, Haomin, Sasaki, Tsutomu, Gon, Yasufumi, Nishiyama, Kumiko, Kanki, Hideaki, Mochizuki, Hideki, Yan, Haomin, Sasaki, Tsutomu, Gon, Yasufumi, Nishiyama, Kumiko, Kanki, Hideaki, and Mochizuki, Hideki

Abstract

Yan Haomin, Sasaki Tsutomu, Gon Yasufumi, et al. Driver gene KRAS aggravates cancer-associated stroke outcomes. Thrombosis Research 233, 55 (2023); https://doi.org/10.1016/j.thromres.2023.11.015., The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/− and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/− cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/− allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/− cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/− group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.

41. Abstract 12033: Value of BNP in Prediction of Major Bleeding Events Among Patients With Atrial Fibrillation in the Era of Direct Oral Anticoagulants

Author

Miyama, Hiroshi, Takatsuki, Seiji, Kimura, Takehiro, Ikemura, Nobuhiro, Katsumata, Yoshinori, Ueda, Ikuko, Hashimoto, Kenji, Yamashita, Terumasa, Fujisawa, Taishi, Nakajima, Kazuaki, Kanki, Hideaki, Negishi, Koji, Nagami, Keiichi, Fukuda, Keiichi, and Kohsaka, Shun

Abstract

Introduction:In the present era, the direct oral anticoagulants (DOACs) are prevailing for the stroke prevention of atrial fibrillation (AF) albeit the risk stratification for major bleeding is still scarce in such milieu. We aimed to investigate the prevalence and predictive risk factors of major bleeding by using an outpatient-based contemporary registry which enrolled patients with newly diagnosed AF, with particular attention on the baseline level of natriuretic peptides (BNP).Methods:Using a prospective, multicenter Japanese registry of newly diagnosed or referred AF patients (KiCS-AF), we investigated 1,311 consecutive cases (mean age: 68.2 ? 11.0 years, 904 males [69.0%], CHADS2 score 1.5?1.2, DOAC used in 1,043 cases [79.6%]) taking oral anticoagulants and completed 2-year clinical follow-up (1.9?0.3years). The bleeding event which required hospitalization was defined as major bleeding events. Biomarkers and clinical variables significantly contributing to predicting major bleeding events were assessed by Cox-regression analysis. Model discrimination was assessed using the area under the receiver operating curve (AUC).Results:Overall, major bleeding occurred in 41 patients with annual incidence of 15.6 per 1,000 patients. Baseline BNP level, along with patients? age, was the dominant predictor of these events, and cut-off level 133pg/ml for BNP level and age of 70 most effectively predict the risk for bleeding (adjusted HR 3.59; 95% CI 1.44-8.99 [p=0.006] for dichotomized BNP value, and HR 2.79; 95% CI, 1.11-6.97 [p=0.02] for age). We also developed two-factor AB score consist of BNP level and age, and found that the patients that met both cutoff were particularly high risk for bleeding (HR 8.26, 95% CI 2.65-25.7, p<0.001) with the predictability of the risk model 0.721 (c-statistics calculated from AUC).Conclusions:Among AF patients undergoing anticoagulation, advanced age and high BNP level were independent risk factors for major bleeding and combined risk factors associated with significantly high risk.

Published
2019
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42. Abstract W P186.

Author

Kajimoto, Katsufumi, Kanki, Hideaki, and Nagatsuka, Kazuyuki

Published
2014

43. A Case of Refractory Vasospastic Angina Complicated by Bronchial Asthma with Eosinophilia 1 .

Author

Nakazawa N, Katsuki T, Fujisawa T, Nakajima K, Kobayashi A, Kanki H, and Koyama T

Abstract

A 48-year-old woman with a history of bronchial asthma and allergic rhinitis presented with cardiac arrest due to ventricular fibrillation and was resuscitated by defibrillation. Coronary angiography revealed coronary vasospasm. Various antispastic agents were unable to control recurrent coronary spasms. We searched for other points of intervention and found a significant increase in the eosinophil count. The patient received mepolizumab for bronchial asthma with eosinophilia, which normalized the eosinophil count. Since then, the patient has remained free from coronary vasospasm, suggesting that mepolizumab may be a viable option for treating refractory coronary angina associated with bronchial asthma and eosinophilia.

Published
2024
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44. Phosphorylation of the IKs channel complex inhibits drug block: novel mechanism underlying variable antiarrhythmic drug actions.

Author

Yang T, Kanki H, and Roden DM

Subjects
Adrenergic alpha-Antagonists pharmacology, Amino Acid Substitution, Animals, CHO Cells, Cricetinae, Cyclic AMP-Dependent Protein Kinases drug effects, Cyclic AMP-Dependent Protein Kinases metabolism, Dose-Response Relationship, Drug, Drug Interactions, Female, KCNQ Potassium Channels, KCNQ1 Potassium Channel, Macromolecular Substances, Ovary cytology, Ovary metabolism, Phosphorylation drug effects, Potassium Channels genetics, Quinidine pharmacology, Structure-Activity Relationship, Transfection, Anti-Arrhythmia Agents pharmacology, Arrhythmias, Cardiac drug therapy, Potassium Channels drug effects, Potassium Channels metabolism, Potassium Channels, Voltage-Gated
Abstract

Background: IKs, an important repolarizing current in heart, is an antiarrhythmic drug target and is markedly increased by activation of protein kinase A (PKA; eg, by beta-adrenergic stimulation). Because beta-adrenergic stimulation is a frequent trigger of arrhythmias, we hypothesized that PKA stimulation inhibits drug block., Methods and Results: CHO cells were transfected with KCNQ1 cDNA (encoding the pore-forming subunit) with or without the ancillary subunit KCNE1. IC50 for quinidine block of basal IKs was 5.8+/-1.2 micromol/L, versus 19.9+/-3.2 micromol/L (P<0.01) for PKA-stimulated current. A similar >3-fold shift was apparent in the absence of KCNE1 and with the IKs-specific blocker chromanol 293B. The first current recorded after channels were held at rest and exposed to the drug was reduced approximately 40%, and further depolarizations increased the block with a time constant (tau) of 181+/-27 seconds. By contrast, PKA-stimulated channels displayed a <5% first-pulse block and much slower block development (tau=405+/-85 seconds). Alanine substitution at 3 potential PKA target sites (S27, S468, and T470) generated an IKs that did not increase with PKA stimulation; this mutant retained wild-type drug sensitivity that was unaffected by PKA., Conclusions: Activation of this key intracellular signaling pathway blunts drug block. The onset of block and the data with the PKA-resistant mutant support the concept that phosphorylation of the KCNQ1 subunit directly modulates drug access to a binding site on the channel. These data identify a novel mechanism for modulation of drug-channel interactions that may be especially important during beta-adrenergic stimulation.

Published
2003
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