Targeting Metabolism: Novel Antibacterial Hydraulic …...Targeting Metabolism: New Strategy to...
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Tsuyoshi Inoue, Ph.D. Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences てんかん患者の約３割には、既存の治療薬が奏功しません。その難治性てんかん患 者に、食事療法（ケトン食療法）が有効です。つまり、ケトン食療法には、既存の 治療薬にはない作用機序があると想定されます。我々は、ケトン食療法に基づく治 療薬の開発方法を見出しました。 Stiripentol Metabolism-targeting antiepileptic drugs A clinically-used antiepileptic drug Metabolic target (LDH) LDH is a metabolic enzyme to suppress seizures, and stiripentol is a compound to act on the LDH. Metabolism-targeting antiepileptic drugs can be developed by using LDH as the drug target and stiripentol as the lead compound. Roadmap to new antiepileptic drugs: We obtained the following three findings. 1. A metabolic pathway in the brain (astrocyte-neuron lactate shuttle) contributed to antiepileptic actions by ketogenic diets. 2. Lactate dehydrogenase (LDH) is a metabolic enzyme mediating this lactate shuttle, and its inhibition hyperpolarized neurons and suppressed seizures in a mouse model of epilepsy. 3. Stiripentol, a clinically-used antiepileptic drug for Dravet syndrome, was an LDH inhibitor. A stiripentol analog also inhibited LDH, and suppressed seizures more strongly. Our findings (Science 347, 1362-7, 2015): As epilepsy is characterized by hyperexcitation of electrical activities in nerve cells, an antiepileptic drug suppresses the hyperexcitation. Therefore, antiepileptic drugs were designed to act on the molecules regulating electrical activities in nerve cells such as an ion channel. However, these antiepileptic drugs are ineffective for one-third of epileptic patients. On the other hand, drug-resistant epilepsy can be controlled by diet treatment ( ketogenic diet ). We found a new strategy to develop a metabolism-targeting antiepileptic drug by exploring ketogenic diet treatment. Targeting Metabolism: New Strategy to Develop an Antiepileptic Drug Kazuhiro Omori, D.D.S, Ph.D., Takashi Ito, D.D.S, Ph.D. Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences 超高齢化社会を迎える先進国にとって、口腔バイオフィルム感染症は国家的な懸案 事項となります。今回、私たちは、既存の歯科用水硬セメント（Caviton®，GC 社） に殺菌成分である塩化セチルピリジニウム（CPC）を配合した抗菌セメントを作製し、 口腔バイオフィルムを形成する代表的な菌（ミュータンス菌、 カンジダ菌、 肺炎球菌） や MRSAに対する高い抗菌効果を確認しました。本抗菌セメントは、口腔バイオフィ ルム感染予防に簡便に応用できる新たな技術です。 ・High antibacterial activity was observed on oral pathogens including methicillin-resistant Staphylococcus aureus (MRSA) (Fig. 3). ・Commercially available dental hydraulic cement (Caviton®, GC corporation) is easy to use for temporary sealing of dental treatment, however, the problem is intrusion of oral pathogens during the hardening of cement. ・Our concept is very simple. Hydraulic cement is mixed with bacteriocide and cetylpyridinium chloride (CPC). ・No intrusion of oral pathogens were observed during the hardening of the cement mixed with CPC (Fig. 2). ・The cement mixture with 0.5% CPC keeps the performance of original cement including hardness. ・High antibacterial activity was observed on oral pathogens including methicillin-resistant Staphylococcus aureus (MRSA) (Fig. 3). ・It is ready to use. No mixing with powder and liquid is required. Filling with fingers provides no air turbine or dental engine for adjusting. Fig. 3 Fig. 2 Advantages of Our Antibacterial Hydraulic Cement Fig. 1 ・In developed countries, the oral health management of aging society is one of important national issues recently (Fig. 1). ・ Oral problems significantly reduce Quality of Life (QOL). ・ Oral care reduces the risk of systemic disease, like aspiration pneumonia, however, the completion of oral care is extremely limited by the number of dental professions. ・In developed countries, the oral health management of aging society is one of important national issues recently (Fig. 1). ・ Oral problems significantly reduce Quality of Life (QOL). ・ Oral care reduces the risk of systemic disease, like aspiration pneumonia, however, the completion of oral care is extremely limited by the number of dental professions. To manage oral biofilm infections is essential for QOL. To manage oral biofilm infections is essential for QOL. Oral Biofilm Infection Threatens a Life in Elderly ! Novel Antibacterial Hydraulic Cement for Oral Biofilm Infection Toshihiko Kiwa, Ph.D. in Eng. Graduate School of Natural Science and Technology 我々の研究グループでは、化学反応の分布を可視化することができる新しい顕微鏡 「テラヘルツ波ケミカル顕微鏡」の開発を行っています。これまでに、抗原抗体反応、 触媒金属の反応など様々な反応の可視化に成功してきました。 The TCM is a ‘multi-purpose’ system for various kinds of chemical reactions, e.g. immune reactions, catalytic reactions and redox reactions so far. Schematic of how to measure chemical reactions Prototype TCM Terahertz(THz) chemical microscope (TCM) measurement system for chemical reactions are proposed and developed. Pat. US8710440 and US8300223. The key component of TCM is a ‘sensing plate’ which consists of Si and SiO2 film on the substrate. When ultra-fast lasers hit the sensing plate, the THz pulses are radiated into free space. As the amplitude of THz pulses is linked to the chemical reactions on the sensing plate, the chemical reactions can be visualized by scanning the laser across the sensing plate. A Terahertz Chemical Microscope Shine on chemical reactions by terahertz pulses Sensing Plate Trigger Laser Pulse For PC antenna Excitation Laser Pulse TH ｚ Solution, Gas Sensing plate Ultrafast laser THz radiation SiO2 Film (275 nm) Si Film (150 nm) Sapphire Substrate (600 μm) Enzyme T.Kiwa et al., SPIE newsroom, (2013) K.Akimune et al., APEX, (2014) Ion Detection μ-TAS T.Kiwa et al., JJAP 46, L1052-L1054 (2007) pH Imaging T.Kiwa et al., Appl. Opt. 46, 3324-3327 (2008) T.Kiwa et al., IEEJ Trans. Sens. Micromachines, 129, 221-224 (2009) Catalytic Metal Immune Assay T.Kiwa et al., APL 96, 211114 (2010) T.Kiwa et al., Sens. Act.:B, 187, 8-11 (2013) T.Kiwa et al., Opt. Exp., 22, 1330-1335 (2014) (Selected in Virtual J. Biomed.I Opt.) T.Kiwa et al., APL 86, 261102 (2005) T.Kiwa et al., Opt. Exp. 20, 11637-11642 (2012) Pump Pump TCM 画像取得 流速制御 Immobilized Urease Membrane X-Axis (mm) Y-Axis (mm) X-axis (mm) 1 0 2 3 4 1 0 2 3 4 0 2.5 5.0 THz amplitude (mV) X-Axis (mm) Y-Axis (mm) THz amplitude (mv) Avidin Immobilized Area Y-Axis (mm) X-Axis (mm) THz amplitude (a.u.) Avatin Biotin Terahertz signal Silica Sapphire Laser 0.1500 0.1200 0.09000 0.06000 0.03000 0 0 0 1 2 3 4 5 2 4 6 8 THz amplitude (mv) 0.60 0.55 0.50 0.45 0.40 0 200 400 600 Time (s) Amplitude (mv) 3 1 0 -1 -3 2 2 4 6 8 10 12 4 6 8 10 12 -0.2 -0.1 0 0 1 2 3 4 0 1 2 3 4 1 2 3 4 0
Transcript of Targeting Metabolism: Novel Antibacterial Hydraulic …...Targeting Metabolism: New Strategy to...
Tsuyoshi Inoue, Ph.D.Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
てんかん患者の約３割には、既存の治療薬が奏功しません。その難治性てんかん患者に、食事療法（ケトン食療法）が有効です。つまり、ケトン食療法には、既存の治療薬にはない作用機序があると想定されます。我々は、ケトン食療法に基づく治療薬の開発方法を見出しました。
Stiripentol Metabolism-targetingantiepileptic drugsA clinically-used
antiepileptic drug
Metabolic target(LDH)
LDH is a metabolic enzyme to suppress seizures, and stiripentolis a compound to act on the LDH. Metabolism-targetingantiepileptic drugs can be developed by using LDH as thedrug target and stiripentol as the lead compound.
Roadmap to new antiepileptic drugs:
We obtained the following three findings.1. A metabolic pathway in the brain (astrocyte-neuron lactate shuttle) contributed to antiepileptic actions by ketogenic diets.
2. Lactate dehydrogenase (LDH) is a metabolic enzyme mediating this lactate shuttle, and its inhibition hyperpolarized neurons and suppressed seizures in a mouse model of epilepsy.
3. Stiripentol, a clinically-used antiepileptic drug for Dravet syndrome, was an LDH inhibitor. A stiripentol analog also inhibited LDH, and suppressed seizures more strongly.
Our findings (Science 347, 1362-7, 2015):
As epilepsy is characterized by hyperexcitation of electrical activitiesin nerve cells, an antiepileptic drug suppresses the hyperexcitation.Therefore, antiepileptic drugs were designed to act on the moleculesregulating electrical activities in nerve cells such as an ion channel.However, these antiepileptic drugs are ineffective for one-third ofepileptic patients. On the other hand, drug-resistant epilepsy can becontrolled by diet treatment ( ketogenic diet ). We found a newstrategy to develop a metabolism-targeting antiepileptic drug byexploring ketogenic diet treatment.
Targeting Metabolism:New Strategy to Develop an Antiepileptic Drug
Kazuhiro Omori, D.D.S, Ph.D., Takashi Ito, D.D.S, Ph.D.Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
超高齢化社会を迎える先進国にとって、口腔バイオフィルム感染症は国家的な懸案事項となります。今回、私たちは、既存の歯科用水硬セメント（Caviton®，GC 社）に殺菌成分である塩化セチルピリジニウム（CPC）を配合した抗菌セメントを作製し、口腔バイオフィルムを形成する代表的な菌（ミュータンス菌、 カンジダ菌、 肺炎球菌）や MRSA に対する高い抗菌効果を確認しました。本抗菌セメントは、口腔バイオフィルム感染予防に簡便に応用できる新たな技術です。
・ High antibacterial activity was observed on oral pathogens including methicillin-resistant Staphylococcus aureus (MRSA) (Fig. 3).
・ Commercially available dental hydraulic cement (Caviton®, GC corporation) is easy to use for temporary sealing of dental treatment, however, the problem is intrusion of oral pathogens during the hardening of cement.
・Our concept is very simple. Hydraulic cement is mixed with bacteriocide and cetylpyridinium chloride (CPC).
・ No intrusion of oral pathogens were observed during the hardening of the cement mixed with CPC (Fig. 2).
・ The cement mixture with 0.5% CPC keeps the performance of original cement including hardness.
・ High antibacterial activity was observed on oral pathogens including methicillin-resistant Staphylococcus aureus (MRSA) (Fig. 3).
・ It is ready to use. No mixing with powder and liquid is required. Filling with fingers provides no air turbine or dental engine for adjusting.
Fig. 3Fig. 2
Advantages of Our Antibacterial Hydraulic Cement
Fig. 1
・ In developed countries, the oral health management of aging society is one of important national issues recently (Fig. 1).
・ Oral problems significantly reduce Quality of Life (QOL).
・ Oral care reduces the risk of systemic disease, like aspiration p n e u m o n i a , h o w e v e r , t h e comple t ion of ora l care i s extremely limited by the number of dental professions.
・ In developed countries, the oral health management of aging society is one of important national issues recently (Fig. 1).
・ Oral problems significantly reduce Quality of Life (QOL).
・ Oral care reduces the risk of systemic disease, like aspiration p n e u m o n i a , h o w e v e r , t h e comple t ion of ora l care i s extremely limited by the number of dental professions.
To manage oral biofilm infections is essential for QOL.
To manage oral biofilm infections is essential for QOL.
Oral Biofilm Infection Threatens a Life in Elderly !
Novel Antibacterial Hydraulic Cement for Oral Biofilm Infection
Toshihiko Kiwa, Ph.D. in Eng.Graduate School of Natural Science and Technology
我々の研究グループでは、化学反応の分布を可視化することができる新しい顕微鏡「テラヘルツ波ケミカル顕微鏡」の開発を行っています。これまでに、抗原抗体反応、触媒金属の反応など様々な反応の可視化に成功してきました。
The TCM is a ‘multi-purpose’ system for various kinds of chemicalreactions, e.g. immune reactions, catalytic reactions and redoxreactions so far.
Schematic of how to measurechemical reactions
Prototype TCM
Terahertz (THz) chemical microscope(TCM) measurement systemfor chemical reactions are proposed and developed.Pat. US8710440 and US8300223. The key component of TCM is a ‘sensing plate’ which consists of Si and SiO2 film on the substrate. When ultra-fast lasers hit thesensing plate, the THz pulses are radiated into free space. As theamplitude of THz pulses is linked to the chemical reactionson the sensing plate, the chemical reactions can be visualized byscanning the laser across the sensing plate.
A Terahertz Chemical Microscope Shine on chemical reactions by terahertz pulses
Sensing Plate
Trigger Laser PulseFor PC antenna
Excitation Laser Pulse
THｚSolution, Gas
Sensing plate
Ultrafast laser THz radiation
SiO2 Film (275 nm)Si Film (150 nm)Sapphire Substrate(600 μm)
Enzyme
T.Kiwa et al., SPIE newsroom, (2013)K.Akimune et al., APEX, (2014)
Ion Detectionμ-TAS
T.Kiwa et al., JJAP 46, L1052-L1054 (2007)
pH Imaging
T.Kiwa et al., Appl. Opt. 46, 3324-3327 (2008)T.Kiwa et al., IEEJ Trans. Sens. Micromachines,129, 221-224 (2009)
Catalytic Metal
Immune Assay
T.Kiwa et al., APL 96, 211114 (2010)T.Kiwa et al., Sens. Act.:B, 187, 8-11 (2013)T.Kiwa et al., Opt. Exp., 22, 1330-1335 (2014)(Selected in Virtual J. Biomed.I Opt.)
T.Kiwa et al., APL 86, 261102 (2005)T.Kiwa et al., Opt. Exp. 20, 11637-11642 (2012)
Pump Pump
TCM 画像取得
流速制御Immobilized Urease Membrane
X-Axis (mm)
Y-Ax
is (m
m)
0 1 2 3 40
1
2
3
4
X-Axis (mm)
Y-A
xis
(m
m)
0
1.3
2.5
3.7
5.0
TH
z am
plitu
de (m
V)
X-axis (mm)
Y-a
xis (
mm
)
10
2 3 4
1
0
2
3
4
0
2.5
5.0
THz a
mpl
itude
(mV
)
X-Axis (mm)
Y-Ax
is (m
m)
THz
ampl
itude
(mv)
Avidin Immobilized Area
Y-Ax
is (m
m)
X-Axis (mm)
THz
ampl
itude
(a.u
.)
Avatin
Biotin
Terahertzsignal
SilicaSapphire
Laser
0.1500
0.1200
0.09000
0.06000
0.03000
0
00
1
2
3
4
5
2 4 6 8
THz
ampl
itude
(mv)
0.60
0.55
0.50
0.45
0.40
0 200 400 600
Time (s)
Ampl
itude
(mv)3
10
-1-3
22
4
6
8
10
12
4 6 8 10 12
-0.2
-0.1
0
0 1 2 3 40
1
2
3
4
X-Axis (mm)
Y-A
xis
(mm
)
0
1.3
2.5
3.7
5.0
THz
ampl
itude
(mV)
0 1 2 3 40
1
2
3
4
X-Axis (mm)
Y-A
xis
(m
m)
0
1.3
2.5
3.7
5.0
TH
z am
plitu
de (m
V)
X-axis (mm)
Y-a
xis (
mm
)
10
2 3 4
1
0
2
3
4
0
2.5
5.0
THz a
mpl
itude
(mV
)
