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A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: Protocol and baseline characteristics

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Background: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. Methods: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (89 women, 89 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. Discussion: This study will confirm whether H2 water can improve PD symptoms. Trial registration: UMIN000010014 (February, 13, 2013).
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S T U D Y P R O T O C O L Open Access
A randomized double-blind multi-center
trial of hydrogen water for Parkinsons
disease: protocol and baseline
characteristics
Asako Yoritaka
1,2*
, Takashi Abe
3
, Chigumi Ohtsuka
4
, Tetsuya Maeda
5
, Masaaki Hirayama
6
, Hirohisa Watanabe
7
,
Hidemoto Saiki
8
, Genko Oyama
2
, Jiro Fukae
9
, Yasushi Shimo
2
, Taku Hatano
2
, Sumihiro Kawajiri
10
,
Yasuyuki Okuma
10
, Yutaka Machida
11
, Hideto Miwa
11
, Chikako Suzuki
12
, Asuka Kazama
13
, Masahiko Tomiyama
14
,
Takeshi Kihara
15
, Motoyuki Hirasawa
16
, Hideki Shimura
17
and Nobutaka Hattori
2
Abstract
Background: Our previous randomized double-blind study showed that drinking hydrogen (H
2
) water for 48 weeks
significantly improved the total Unified Parkinsons Disease Rating Scale (UPDRS) score of Parkinsons disease (PD)
patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled
multi-center trial.
Methods: Changes in the total UPDRS scores from baseline to the 8
th
,24
th
,48
th
, and 72
nd
weeks, and after the
8
th
week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total
UPDRS score from baseline to the 72
nd
week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD
Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the
duration until the protocol is finished because additional levodopa is required or until the disease progresses, will
also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the
hydrogen water group will drink 1000 mL/day of H
2
water, and those in the placebo water group will drink normal
water. One-hundred-and-seventy-eight participants with PD (89 women, 89 men; mean age: 64.2 [SD 9.2] years,
total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants;
daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14
hospitals and were randomized.
Discussion: This study will confirm whether H
2
water can improve PD symptoms.
Trial registration: UMIN000010014 (February, 13, 2013)
Keywords: Hydrogen, oxidative stress, Parkinsons disease, randomized double-blind placebo-controlled multicenter
trial
* Correspondence: ayori@juntendo.ac.jp
1
Department of Neurology, Juntendo University Koshigaya Hospital,
Fukuroyama 560, Koshigayashi, Saitama 343-0032, Japan
2
Department of Neurology, Juntendo University School of Medicine, Tokyo,
Japan
Full list of author information is available at the end of the article
© 2016 Yoritaka et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Yoritaka et al. BMC Neurology (2016) 16:66
DOI 10.1186/s12883-016-0589-0
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Background
In patients with Parkinsons disease (PD), the pharmaco-
logic replacement of dopamine and other antiparkinsonian
drugs has been used for symptomatic therapy. However,
none of these drugs stop or lessen the dopaminergic neur-
onal degeneration or the progression of the disease. Find-
ings of increased iron and lipid peroxidation and decreased
levels of reduced glutathione in the substantia nigra
strongly suggest that enhanced oxidative stress is involved
in the pathogenesis of PD [1, 2]. Thus, antioxidant therapies
might slow the progression of PD. Molecular hydrogen
(H
2
) has recently been highlighted as a therapeutic and pre-
ventive antioxidant. Since the first publication [3], more
than 150 papers have confirmed the efficacy of H
2
in vari-
ous animal models [4]. H
2
-water reduced dopaminergic
neuronal cell loss in a 1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine (MPTP) mouse model [5] as well as 6-
hydroxydopamine did [6]. Our previous randomized
double-blind study has shown that drinking 1,000 mL of
H
2
-water for 48 weeks significantly improved (p<0.05) the
total Unified Parkinsons Disease Rating Scale (UPDRS)
scores of patients with PD who were being treated with
levodopa [7]. In the present study, we aimed to confirm
these results by conducting a longer and more large-scale
trial that also included patients who were not being treated
with levodopa. Here, we present the design and the baseline
characteristics of participants already enrolled in this study.
Methods
A placebo-controlled, randomized, double-blind, parallel-
group (1:1) clinical multi-center trial was organized by the
Department of Neurology of Juntendo University School
of Medicine in accordance with Consolidated Standards of
Reporting Trials (CONSORT) guideline. Fourteen hospi-
tals are involved as trial centers. This trial was advertised
in posters and on homepages of our clinic, and partici-
pants had to declare their intentions to participate volun-
tarily. The inclusion criteria required that the participants
have a diagnosis of PD according to the United Kingdom
Brain Bank criteria [8]. All the participants should have a
modified Hoehn and Yahr staging (H & Y stage) in the on-
phase between 1 and 4. For 8 weeks prior to establishing
the baseline, the participantsantiparkinsonian drugs were
not changed. None of the participants have dementia
(MMSE < 25) or dysphagia for water. Outpatients are pre-
ferred over admitted patients. The participants are to be
older than 20 years. The exclusion criteria included the
following: parkinsonism due to diseases other than PD,
the presence of other serious diseases, malignant tumor(s),
or adverse events caused by drugs.
The clinical study is registered at UMIN clinical trial
registry (UMIN-CTR) UMIN000010014 (February 13,
2013). The Ethics Committee of the Juntendo University
School of Medicine approved this study in February
2013, as did the ethics committees of other centers, and
all participants provided signed informed consent forms.
Randomization and blinding
The enrolled participants have been assigned using a
stratified randomization method according to their age
and if they were receiving levodopa. The assignments
were made by C.S. The participants and those assessing
outcomes will remain blinded until all the participants
have finished the protocol.
Procedures
On a daily basis, the participants will drink 1,000 mL of
saturated H
2
-water containing 5 mM of dissolved H
2
(using Hydrogen 7.0, supplied by Ecomo International
Co., Ltd. [Fukuoka, Japan]; patent No: PCT/JP2011/
063601) for 72 weeks. The placebo water is saturated
with N
2
. The water is contained in a 500-mL plastic bot-
tle, and the participants will drink 2 bottles per day. The
participants will drink the water within 3 h of opening
the cap, because H
2
evaporates. The bottles of H
2
-water
or placebo water will be sent to the participantshome
every week.
The schedule of the study is shown in Fig. 1. Changes
in the total UPDRS scores from baseline to the 8
th
,24
th
,
48
th
, and 72
nd
weeks, and after the 8
th
week, are evalu-
ated. The primary endpoint of the efficacy of this treat-
ment in PD is the change in the total UPDRS score from
baseline to the 72
nd
week.
The changes in UPDRS part II, UPDRS part III, each
UPDRS score, PD Questionnaire-39 (PDQ-39), and the
H & Y stage at these same time-points, as well as the
duration until the protocol is finished because additional
levodopa is required or until the disease progresses, will
also be analyzed. Adverse events and screening labora-
tory parameters (total protein, albumin, alkaline phos-
phatase, aspartate transaminase, alanine transaminase,
serum urea nitrogen, calcium, chloride, creatinine, glu-
cose, lactate dehydrogenase, potassium, sodium, creatin-
ine kinase, uric acid, choline esterase, LDL-cholesterol,
HDL-cholesterol, and triglyceride levels) will also be
examined.
Statistical analysis
We calculated that a minimum of 95.4 participants need
to be enrolled to detect a 5-point difference in the
UPDRS scores between the 2 groups, with a standard
deviation of the mean difference of 10, and a 2-sided
alpha level of 0.05 and 80 %. Assuming a 35 % dropout,
96 participants will be required in total. A period of
72 weeksfollow-up is a relatively long-term clinical trial
in PD; hence, we assumed a 35 % dropout rate.
Yoritaka et al. BMC Neurology (2016) 16:66 Page 2 of 4
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Variations in the endpoints between the baseline value
and treatment assessment points will be compared be-
tween the groups, using a t-test or a MannWhitney U-
test. The statistical tests are 2-sided, and the significance
level is set at 0.05. The number of participants in the
treatment and placebo groups who drop out due to dis-
ease progression will be analyzed using Kaplan Meier
curves and the log-rank test. Subgroup analysis (sex, and
treatment with or without levodopa) will be performed.
Enrollment and data collection
One-hundred-and-seventy-eight Japanese participants
with PD have already been enrolled in 14 hospitals and
have been randomized, between April 1, 2013 and Sep-
tember 30, 2015, at their baseline visit. The participants
will be followed-up for 80 weeks. The baseline character-
istics are shown in Table 1. Despite extensive efforts to
enroll more participants, the expected number of partic-
ipants was not met, as it is difficult for some patients to
consume 1000 mL water daily.
Discussion
Fujita et al. have indicated that the intake of H
2
-water,
even after MPTP administration, reduces neurotoxic
damage [5]. The findings of our previous study [7] on
PD patients are in agreement with the previous results
that were obtained in animal models.
Antioxidant supplements that are considered medicinal
products should undergo sufficient evaluation before mar-
keting, as they might be harmful at high doses [9]. H
2
se-
lectively reduces OH radicals, but not O
2
,H
2
O
2
,orNO
[4]. It is expected that prolonged application of H
2
will have
no or little adverse effects in chronic diseases. The effects
of H
2
couldbemediatedbymodulating activities and ex-
pression of various molecules, such as Lyn, ERK, p38, JNK,
ASK1, Akt, GTP-Rac1, iNOS, Nox1, NF-κB, p65, Iκba,
STST3, NFATc1, c-Fos, and ghrelin [10]. Iuchi et al. pro-
posed a hypothetical model in which H
2
is linked to the
Study period
Time point Enrolment Allocation Baseline/
0th week 1st day 8th week 24th week 48th week 72nd week After the
8th week
Enrolment
Eligibility screening
Informed consent
Allocation
Intervention
Drinking water
Assessment
UPDRS*1
Hoehn and Yahr
stage
PDQ-39*2
Blood test
Hydrogen water
Placebo water
Fig. 1 Schedule of enrolment, intervention, and assessment. Study period of enrolment, allocation, and baseline may coincide. It is approximately
1 week to 10 days from allocation to the first day to start shipping the water. *1: Unified Parkinsons Disease Rating Scale. *2: Parkinsons
Disease Questionnaire-39
Table 1 The baseline characteristics of the study participants
Mean Std. Deviation
Age 64.2 9.2
Disease duration 6.8 4.5
Sex (male/female) n 89 89
Wearing off (+/-) n 58 120
Dyskinesia (+/-) n 42 136
Levodopa mg 344.1 202.8
Levodopa (+/-) n 154 24
Dopamine agonist levodopa equivalent
dose (mg) [12]
166.3 121.1
Total levodopa equivalent dose (mg) [12]
a
592.0 317.6
Unified Parkinsons Disease Rating Scale
Part I 0.7 1.2
Part II 5.6 3.9
Part III 15.7 8.4
Part IV 1.7 2.2
Total 23.7 11.8
Modified Hoehn and Yahr stage 2.1 0.6
Parkinsons disease Questionnaire-39
Mobility 10.4 9.1
Activities of daily living 5.2 5.1
Emotional well-being 6.0 4.4
Stigma 3.2 2.8
Social support 1.4 1.9
Cognitions 4.0 3.0
Communication 1.7 2.2
Body discomfort 2.5 2.6
Total 34.4 24.2
a
: not including istradefylline and zonisamide
Yoritaka et al. BMC Neurology (2016) 16:66 Page 3 of 4
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
modulation of Ca
2+
signal transduction and the nuclear fac-
tor of activated T cells (NFAT) pathway via oxidized
phospholipid species [11].
Our previous trial was the first randomized double-blind
study of H
2
-water in patients with PD [7]. H
2
-water exhib-
ited no adverse effects at a dose of 1000 mL/day in PD sub-
jects receiving levodopa treatment. The results of the
previous study will be confirmed in this longer and larger-
scale study that includes patients who are not medicated
with levodopa. This study will confirm the safety and toler-
ability of H
2
-water and if H
2
-water can improve PD
symptoms.
Ethics approval
A randomized double-blind multi-center trial of hydro-
gen water for Parkinsons disease was approved by the
Ethics Committee of the Juntendo University School of
Medicine, and the ethics committees of other centers.
Consent for publication
Not applicable.
Availability of data and material
Not applicable.
Abbreviations
CONSORT: Consolidated Standards of Reporting Trials; H
2
: hydrogen; H &
Y: modified Hoehn and Yahr staging; MPTP: 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine; NFAT: nuclear factor of activated T cells; PD: Parkinsons
disease; PDQ-39: Parkinsons disease Questionnaire-39; UPDRS: Unified
Parkinsons Disease Rating Scale.
Competing interests
N. Hattori has served as an advisory board member for Boehringer Ingelheim
and FP Pharmaceutical Company (PC) and he has consulted for Ohtsuka PC,
Kyowa Hakko Kirin PC, GlaxoSmithKline, Novartis, Abbot, Hisamitsu, and
Schering-Plough (MSD); he also received personal compensation for attend-
ing these advisory board meetings. Other authors: None
Authorscontributions
AY conceived and designed the study, acquired data, performed statistical
analysis, and drafted and revised the manuscript. TA, CO, TM, HW, MH, SK,
YO, HS, GO, JF, YS, TH, YM, HM, MT, MH, and HS acquired the data. CS
performed randomization. AK helped in checking the data. TK acquired the
data and revised the manuscript. NH conceived the study and revised the
manuscript. All authors read and approved the final manuscript.
Acknowledgements
We thank MiZ Co. Ltd. and Ecomointernational Co., Ltd. for supplying the
Suisosui 7.0 (H
2
-water) and placebo water.
Funding
This work is supported by a grant from Japan Society for the Promotion of
Science KAKENHI (Grant Number 15 K09360).
Author details
1
Department of Neurology, Juntendo University Koshigaya Hospital,
Fukuroyama 560, Koshigayashi, Saitama 343-0032, Japan.
2
Department of
Neurology, Juntendo University School of Medicine, Tokyo, Japan.
3
Department of Neurology, Abe Neurological Clinic, Iwate, Japan.
4
Department of Neurology and Gerontology, Iwate Medical University, Iwate,
Japan.
5
Department of Neurology, Research Institute for Brain and Blood
Vessels-Akita Hospital, Akita, Japan.
6
Department of Pathophysiological
Laboratory Sciences, Nagoya University Graduate School of Medicine, Aichi,
Japan.
7
Brain and Mind Research Center, Nagoya University Graduate School
of Medicine, Aichi, Japan.
8
Department of Neurology, Kitano Hospital, The
Tazuke Kofukai Medical Research Institute, Osaka, Japan.
9
Department of
Neurology, Fukuoka University, Fukuoka, Japan.
10
Department of Neurology,
Juntendo University Shizuoka Hospital, Shizuoka, Japan.
11
Department of
Neurology, Juntendo University Nerima Hospital, Tokyo, Japan.
12
Department
of Diagnostic Radiology, Department of Molecular Medicine and Surgery,
Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
13
Nozomi Hospital, Saitama, Japan.
14
Department of Neurology, Aomori
Prefectural Central Hospital, Aomori, Japan.
15
Department of Neurology,
Rakuwakai Otowa Rehabilitation Hospital, Kyoto, Japan.
16
Department of
Neurology, Tokyo Rinkai Hospital, Tokyo, Japan.
17
Department of Neurology,
Juntendo University Urayasu Hospital, Chiba, Japan.
Received: 21 March 2016 Accepted: 5 May 2016
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To reveal the biomedical effects and mechanisms of hydrogen molecules urgently needs hydrogen molecular imaging probes as an imperative tool, but the development of these probes is extremely challenging. In this work, a catalytic hydrogenation strategy is proposed to design and synthesize a ratiometric fluorescent probe by encapsulating Pd nanoparticles and conjugating azido-/coumarin-modified fluorophore into mesoporous silica nanoparticles, realizing in vitro and in vivo fluorescence imaging of hydrogen molecules. The developed hydrogen probe exhibits high sensitivity, rapid responsivity, high selectivity and low detection limit, enabling rapid and real-time detection of hydrogen molecules both in cells and in the body of animal and plant. By application of the developed fluorescent probe, we have directly observed superhigh transmembrane and ultrafast transport abilities of hydrogen molecules in cell, animal and plant, and discovered in vivo high diffusion of hydrogen molecules.
... It is worth noting that this is the first direct evidence of hydrogen molecules crossing the BBB, which explains why hydrogen inhalation can effectively treat neurodegenerative diseases, as concluded by many clinical reports. [27][28][29][30][31] In addition, the presented results imply that continuous and long-term supply of hydrogen molecules is necessary to maintain high hydrogen dosage in the brain for efficient treatment of these diseases, [4] possibly owing to high dispersion and low solubility of hydrogen molecules. ...
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To reveal the biomedical effects and mechanisms of hydrogen molecules urgently needs hydrogen molecular imaging probes as an imperative tool, but the development of these probes is extremely challenging. In this work, a catalytic hydrogenation strategy is proposed to design and synthesize a ratiometric fluorescent probe by encapsulating Pd nanoparticles and conjugating azido-/coumarin-modified fluorophore into mesoporous silica nanoparticles, realizing in vitro and in vivo fluorescence imaging of hydrogen molecules. The developed hydrogen probe exhibits high sensitivity, rapid responsivity, high selectivity and low detection limit, enabling rapid and real-time detection of hydrogen molecules both in cells and in the body of animal and plant. By application of the developed fluorescent probe, we have directly observed superhigh transmembrane and ultrafast transport abilities of hydrogen molecules in cell, animal and plant, and discovered in vivo high diffusion of hydrogen molecules.
... Initially, the hydrogen element used in the clinical trials was mainly in a non-gaseous form. Clinical studies have shown that drinking HRW is safe and well-tolerated and HRW containing 0.8 or 5 mM dissolved H 2 improves the clinical symptoms in the patients with Parkinson's disease (20)(21)(22). HRW containing 7 ppm H 2 (3.5 mg H 2 in 500 ml water) could protect the vascular endothelium from ROS (23). Healthy adults drink 4 weeks of HRW at 1.5 L per week, which can reduce cell death and inflammation by regulating the Toll-like receptor-nuclear factorkappa B (TLR-NF-κB) signaling and enhance the antioxidant capacity of the body. ...
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Coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has no specific and effective treatment. The pathophysiological process of the COVID-19 is an excessive inflammatory response after an organism infects with a virus. Inflammatory storms play an important role in the development of the COVID-19. A large number of studies have confirmed that hydrogen has a therapeutic effect on many diseases via inhibiting excessive inflammatory cells and factors. Recently, a study led by the Academician Zhong Nanshan in China on the treatment of the patients with the COVID-19 by inhalation of a mixed gas composed of hydrogen and oxygen has attracted widespread international attention and hydrogen therapy has also been included in a new treatment plan for the COVID-19 in China. This study mainly describes the mechanism of occurrence of the COVID-19, summarizes the therapeutic effects and underlying mechanisms of hydrogen on the critical disease, and analyzes the feasibility and potential therapeutic targets of hydrogen for the treatment of the COVID-19.
... 30 Furthermore, HW administration for 48 weeks was shown to improve the total scores in the unified Parkinson's disease rating scale in individuals with Parkinson's disease. 31 These findings suggest the potential utility of oral HW intake for the management of oxidative stress-induced pathologies. ...
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... Several substitute pathways are currently being studied as main components of the energy moderating characteristics of H 2 , including: (1) ghrelin-linked upregulation of ghrelin receptor (GHS-R1α); (2) ghrelinlinked motivation of glucose transporter 1; (3) non-ghrelin linked stimulation of glucose transporter 4; and (4) non-ghrelin linked improved expression of fibroblast growth factor 21 (FGF21), a regulator of energy expenses [57,58]. HRW has shown neuroprotective properties in a murine MTTP-induced PD model [45,59,60]. Lin and colleagues reported that HRW reduces OS in patients with chronic hepatitis B and metabolic syndrome [61]. ...
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Oxidative stress (OS) and neuroinflammatory stress affect many neurological disorders. Despite the clinical significance of oxidative damage in neurological disorders, still, no effective and safe treatment methods for neuro diseases are available. With this, molecular hydrogen (H2) has been recently reported as an antioxidant and anti-inflammatory agent to treat several oxidative stress-related diseases. In animal and human clinical trials, the routes for H2 administration are mainly categorized into three types: H2 gas inhalation, H2 water dissolving, and H2-dissolved saline injection. This review explores some significant progress in research on H2 use in neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, neonatal disorders of the brain, and other NDs (retinal ischemia and traumatic brain injury). Even though most neurological problems are not currently curable, these studies have shown the therapeutic potential for prevention, treatment, and mitigation of H2 administration. Several possible H2-effectors, including cell signal-ing molecules and hormones, which prevent OS and inflammation, will also be addressed. However , more clinical and other related studies are required to evaluate the direct H2 target molecule.
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We previously showed that H2 acts as a novel antioxidant to protect cells against oxidative stress. Subsequently, numerous studies have indicated the potential applications of H2 in therapeutic and preventive medicine. Moreover, H2 regulates various signal transduction pathways and the expression of many genes. However, the primary targets of H2 in the signal transduction pathways are unknown. Here, we attempted to determine how H2 regulates gene expression. In a pure chemical system, H2 gas (approximately 1%, v/v) suppressed the autoxidation of linoleic acid that proceeds by a free radical chain reaction, and pure 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC), one of the major phospholipids, was autoxidized in the presence or absence of H2. H2 modified the chemical production of the autoxidized phospholipid species in the cell-free system. Exposure of cultured cells to the H2-dependently autoxidized phospholipid species reduced Ca2+ signal transduction and mediated the expression of various genes as revealed by comprehensive microarray analysis. In the cultured cells, H2 suppressed free radical chain reaction-dependent peroxidation and recovered the increased cellular Ca2+, resulting in the regulation of Ca2+-dependent gene expression. Thus, H2 might regulate gene expression via the Ca2+ signal transduction pathway by modifying the free radical-dependent generation of oxidized phospholipid mediators.
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Therapeutic effects of molecular hydrogen for a wide range of disease models and human diseases have been investigated since 2007. A total of 321 original articles have been published from 2007 to June 2015. Most studies have been conducted in Japan, China, and the USA. About three-quarters of the articles show the effects in mice and rats. The number of clinical trials is increasing every year. In most diseases, the effect of hydrogen has been reported with hydrogen water or hydrogen gas, which was followed by confirmation of the effect with hydrogen-rich saline. Hydrogen water is mostly given ad libitum. Hydrogen gas of less than 4 % is given by inhalation. The effects have been reported in essentially all organs covering 31 disease categories that can be subdivided into 166 disease models, human diseases, treatment-associated pathologies, and pathophysiological conditions of plants with a predominance of oxidative stress-mediated diseases and inflammatory diseases. Specific extinctions of hydroxyl radical and peroxynitrite were initially presented, but the radical-scavenging effect of hydrogen cannot be held solely accountable for its drastic effects. We and others have shown that the effects can be mediated by modulating activities and expressions of various molecules such as Lyn, ERK, p38, JNK, ASK1, Akt, GTP-Rac1, iNOS, Nox1, NF-κB p65, IκBα, STAT3, NFATc1, c-Fos, and ghrelin. Master regulator(s) that drive these modifications, however, remain to be elucidated and are currently being extensively investigated.
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It has been shown that molecular hydrogen (H(2)) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H(2)-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H(2) showed that H(2) as low as 0.08 ppm had almost the same effect as saturated H(2) water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H(2)-containing water, whereas production of superoxide (O(2)*(-)) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H(2) in drinking water can reduce oxidative stress in the brain. Thus, drinking H(2)-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration.
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Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.
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On page 845 in the first paragraph of the “All Randomized Trials” subsection, the sentence that read “Heterogeneity was not significant (I²=18.6%, P=.10)” should have read “Heterogeneity was significant (I²=18.9%, P=.10).” In the following sentence that begins “Adjusted-rank correlation test (P=.08), but not the regression asymmetry test (P=.26), suggested the bias among trials,” the respective P values should have read “(P=.09)” and “(P=.24).” In the second paragraph of the same subsection, the portion of the sentence that begins on page 845: “Univariate meta-regression analyses revealed significant influences of dose of beta carotene (RR, 1.004; 95% CI, 1.001-1.007; P=.012),” the P value should have been equal to “.014.” In the latter part of the same sentence that falls on page 847, the P value for the dose of selenium that read “P=.002” should have read “P=.001.” In the following part of the sentence, the upper confidence limit that read “1.29” should have read “1.30.” In the third paragraph of the same subsection, on page 847, the P value for the “multivariate meta-regression” for dose of selenium that read “P=.005” should have read “P=.004,” the lower confidence limit for low-bias risk trials that read “1.05” should have read “1.04,” and the P value for the low-bias risk trials in the same sentence that read “P=.005” should have read “P=.006.” In Table 5 on page 853, the RR (95% CI) in the “Beta carotene given singly” row that read “1.06 (1.01-1.11)” should have read “1.05 (1.00-1.11)” and the I² value that read “5.4” should have read “11.8.” In the “Beta carotene given in combination with other antioxidant supplements” row, the I² value that read “55.6” should have read “55.5.” In the “Beta carotene given singly or in combination with other antioxidant supplements” row, the CI range that read “(0.96-1.08)” should have read “(0.95-1.07)” and the I2 value that read “52.2” should have read “52.5.” In the “Beta carotene given singly or in combination with other antioxidant supplements after exclusion of high-bias risk and selenium trials” row, the I² value that read 36.8” should have read “34.4” In the “Vitamin E given singly” row, the number of study participants that read “47 007” should have read “41 341.” In the “Vitamin E given in combination with other antioxidant supplements” row, the RR that read “1.01” should have read “1.00” and the I² value that read “17.2” should have read “16.9.” In the “Vitamin E given singly or in combination with other antioxidant supplements” row, the I²value that read “2.8” should have read “2.4.” In the “Vitamin E given singly or in combination with other antioxidant supplements after exclusion of high-bias risk and selenium trials” row, the list of references should have included reference 87 and excluded 95.
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Mitochondria are the major source of oxidative stress. Acute oxidative stress causes serious damage to tissues, and persistent oxidative stress is one of the causes of many common diseases, cancer and the aging process; however, there has been little success in developing an effective antioxidant with no side effect. We have reported that molecular hydrogen has potential as an effective antioxidant for medical applications [Ohsawa et al., Nat. Med. 13 (2007) 688-694]. We review the recent progress toward therapeutic and preventive applications of hydrogen. Since we published the first paper in Nature Medicine, effects of hydrogen have been reported in more than 38 diseases, physiological states and clinical tests in leading biological/medical journals. Based on this cumulative knowledge, the beneficial biological effects of hydrogen have been confirmed. There are several ways to intake or consume hydrogen, including inhaling hydrogen gas, drinking hydrogen-dissolved water, taking a hydrogen bath, injecting hydrogen-dissolved saline, dropping hydrogen-dissolved saline into the eyes, and increasing the production of intestinal hydrogen by bacteria. Hydrogen has many advantages for therapeutic and preventive applications, and shows not only anti-oxidative stress effects, but also has various anti-inflammatory and anti-allergic effects. Preliminary clinical trials show that drinking hydrogen-dissolved water seems to improve the pathology of mitochondrial disorders. Hydrogen has biological benefits toward preventive and therapeutic applications; however, the molecular mechanisms underlying the marked effects of small amounts of hydrogen remain elusive. Hydrogen is a novel antioxidant with great potential for actual medical applications. This article is part of a Special Issue entitled Biochemistry of Mitochondria.
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Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.
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Molecular hydrogen serves as an antioxidant that reduces hydroxyl radicals, but not the other reactive oxygen and nitrogen species. In the past year, molecular hydrogen has been reported to prevent or ameliorate eight diseases in rodents and one in human associated with oxidative stress. In Parkinson's disease, mitochondrial dysfunction and the associated oxidative stress are major causes of dopaminergic cell loss in the substantia nigra. We examined effects of approximately 50%-saturated molecular hydrogen in drinking water before or after the stereotactic surgery on 6-hydroxydopamine-induced nigrostrital degeneration in a rat model of Parkinson's disease. Methamphetamine-induced behavioral analysis showed that molecular hydrogen prevented both the development and progression of the nigrostrital degeneration. Tyrosine hydroxylase staining of the substantia nigra and striatum also demonstrated that pre- and post-treatment with hydrogen prevented the dopaminergic cell loss. Our studies suggest that hydrogen water is likely able to retard the development and progression of Parkinson's disease.
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Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.