Ionized Alkaline Water: New Strategy for Management of Metabolic Acidosis in Experimental Animals

Metabolic acidosis can occur as a result of either the accumulation of endogenous acids or loss of bicarbonate from the gastrointestinal tract or the kidney, which represent common causes of metabolic acidosis. The appropriate treatment of acute metabolic acidosis has been very controversial. Ionized alkaline water was not evaluated in such groups of patients in spite of its safety and reported benefits. So, we aimed to assess its efficacy in the management of metabolic acidosis in animal models. Two models of metabolic acidosis were created in dogs and rats. The first model of renal failure was induced by ligation of both ureters; and the second model was induced by urinary diversion to gut (gastrointestinal bicarbonate loss model). Both models were subjected to ionized alkaline water (orally and by hemodialysis). Dogs with renal failure were assigned to two groups according to the type of dialysate utilized during hemodialysis sessions, the first was utilizing alkaline water and the second was utilizing conventional water. Another two groups of animals with urinary diversion were arranged to receive oral alkaline water and tap water. In renal failure animal models, acid-base parameters improved significantly after hemodialysis with ionized alkaline water compared with the conventional water treated with reverse osmosis (RO). Similar results were observed in urinary diversion models as there was significant improvement of both the partial pressure of carbon dioxide and serum bicarbonate (P = 0.007 and 0.001 respectively) after utilizing alkaline water orally. Alkaline ionized water can be considered as a major safe strategy in the management of metabolic acidosis secondary to renal failure or dialysis or urinary diversion. Human studies are indicated in the near future to confirm this issue in humans.

Suppressive Effect of ERW on Lipid Peroxidation and Plasma Triglyceride Level

Electrolyzed reduced water (ERW) containing hydrogen molecules and Pt nanoparticles is expected as a new antioxidant. Thiobarbituric acid reactive substances (TBARS) assay revealed that ERW had an inhibitory effect on the oxidation of low-density lipoproteins (LDL). In addition, ERW significantly suppressed LDL oxidation in the medium cultured J.774.A1 macrophage like cells. ERW inhibited Cu2+ ion-catalyzed oxidation of LDL ex vivo. ERW lowered lipid peroxide level in blood red cells and plasma triglyceride in rats fed a basal diet containing 2% cholesterol. These results suggest that ERW has anti-LDL oxidation and anti-hyperlipidemia effects.

Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress

Molecular hydrogen (H(2)) is an efficient antioxidant that diffuses rapidly across cell membranes, reduces reactive oxygen species (ROS), such as hydroxyl radicals and peroxynitrite, and suppresses oxidative stress-induced injury in several organs. ROS have been implicated in radiation-induced damage to lungs. Because prompt elimination of irradiation-induced ROS should protect lung tissue from damaging effects of irradiation, we investigated the possibility that H(2) could serve as a radioprotector in the lung. Cells of the human lung epithelial cell line A549 received 10 Gy irradiation with or without H(2) treatment via H(2)-rich PBS or medium. We studied the possible radioprotective effects of H(2) by analyzing ROS and cell damage. Also, C57BL/6J female mice received 15 Gy irradiation to the thorax. Treatment groups inhaled 3% H(2) gas and drank H(2)-enriched water. We evaluated acute and late-irradiation lung damage after H(2) treatment. H(2) reduced the amount of irradiation-induced ROS in A549 cells, as shown by electron spin resonance and fluorescent indicator signals. H(2) also reduced cell damage, measured as levels of oxidative stress and apoptotic markers, and improved cell viability. Within 1 wk after whole thorax irradiation, immunohistochemistry and immunoblotting showed that H(2) treatment reduced oxidative stress and apoptosis, measures of acute damage, in the lungs of mice. At 5 mo after irradiation, chest computed tomography, Ashcroft scores, and type III collagen deposition demonstrated that H(2) treatment reduced lung fibrosis (late damage). This study thus demonstrated that H(2) treatment is valuable for protection against irradiation lung damage with no known toxicity.

Intravenous low redox potential saline attenuates FeCl3-induced vascular dysfunction via downregulation of endothelial H2O2, CX3CL1, intercellular adhesion molecule-1, and p53 expression

Exaggerated reactive oxygen species (ROS) may contribute to vascular injury by the enhancement of CX3CL1, intercellular adhesion molecule-1 (ICAM-1), and pro-apoptotic p53 expression. Reduced water with safely antioxidant activity may protect vascular tissue against oxidative injury. We established reduced water (RW) by using a modified magnesium alloy and evaluated the effects of an RW-made culture medium on TNF-α-induced endothelial damage in vitro and intravenous RW-made saline (0.9%NaCl) infusion on FeCl(3)-induced arterial injury in rats in vivo. Several oxidative stresses were evaluated by using a chemiluminescence analyzer, Western blot, and immunohistochemistry. We found that the established RW, RW-culture medium, and RW saline displayed a lower redox potential (<-150 mV) and efficient H(2)O(2) scavenging activity compared with distilled-water-made solutions. The RW-culture medium significantly depressed TNF-α-enhanced endothelial H(2)O(2) production; improved CX3CL1, ICAM-1, and p53 expression; and inhibited activated monocyte adhesion to endothelial cells as well as to the CX3CL1 or the ICAM-1 coated plate when compared with the distilled-water-culture medium. In the in vivo study, the time required for FeCl(3)-induced occlusion in the urethane anesthetized rat's carotid and femoral arteries was significantly extended by intravenous RW saline infusion compared with distilled-water saline. FeCl(3) stimulation significantly enhanced vascular NADPH oxidase activity, ROS production, as well as CX3CL1, ICAM-1, p53, 3-nitrotyrosine, and 4-hydroxynonenal expression in the damaged arteries. Intravenous RW saline significantly reduced all the FeCl(3)-enhanced oxidative parameters when compared with intravenous distilled-water-saline infusion. We conclude that the RW-culture medium and saline made from magnesium alloy confer cardiovascular protection by the antioxidant capability.

Hydrogen (H2) treatment for acute erythymatous skin disease. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers

We have treated 4 patients of acute erythematous skin diseases with fever and/or pain by H2 enriched intravenous fluid. We also added data from two volunteers for assessing the mode of H2 delivery to the skin for evaluation of feasibility of H2 treatment for this type of skin diseases. All of the four patients received intravenous administration of 500 ml of H2 enriched fluid in 30 min for more than 3 days except in one patient for only once. From two volunteers (one for intravenous H2 administration and the other for H2 inhalation), blood samples were withdrawn serially and air samples were collected from a heavy duty plastic bag covering a leg, before, during and after H2 administration. These samples were checked for H2 concentration immediately by gas chromatography. Multiple physiological parameters and blood chemistry data were collected also. Erythema of these 4 patients and associated symptoms improved significantly after the H2 treatment and did not recur. Administration of H2 did not change physiological parameters and did not cause deterioration of the blood chemistry. The H2 concentration in the blood from the volunteers rapidly increased with H2 inhalation and slowly decreased with cessation of H2 particularly in the venous blood, while H2 concentration of the air from the surface of the leg showed much slower changes even after H2 inhalation was discontinued, at least during the time of sample collection. An improvement in acute erythemtous skin diseases followed the administration of H2 enriched fluid without compromising the safety. The H2 delivery study of two volunteers suggested initial direct delivery and additional prolonged delivery possibly from a slowly desaturating reservoir in the skin to the surface.

Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats

Lactulose is a synthetic disaccharide that can be catalyzed only by intestinal bacteria in humans and rodents, and a large amount of hydrogen is produced by bacterial catalysis of lactulose. We previously reported marked effects of ad libitum administration of hydrogen water on prevention of a rat model of Parkinson’s disease (PD). End-alveolar breath hydrogen concentrations were measured in 28 healthy subjects and 37 PD patients, as well as in 9 rats after taking hydrogen water or lactulose. Six-hydroxydopamine (6-OHDA)-induced hemi-PD model was stereotactically generated in rats. We compared effects of hydrogen water and lactulose on prevention of PD. We also analyzed effects of continuous and intermittent administration of 2% hydrogen gas. Hydrogen water increased breath hydrogen concentrations from 8.6 ± 2.1 to 32.6 ± 3.3 ppm (mean and SEM, n = 8) in 10 min in healthy subjects. Lactulose increased breath hydrogen concentrations in 86% of healthy subjects and 59% of PD patients. Compared to monophasic hydrogen increases in 71% of healthy subjects, 32% and 41% of PD patients showed biphasic and no increases, respectively. Lactulose also increased breath hydrogen levels monophasically in 9 rats. Lactulose, however, marginally ameliorated 6-OHDA-induced PD in rats. Continuous administration of 2% hydrogen gas similarly had marginal effects. On the other hand, intermittent administration of 2% hydrogen gas prevented PD in 4 of 6 rats. Lack of dose responses of hydrogen and the presence of favorable effects with hydrogen water and intermittent hydrogen gas suggest that signal modulating activities of hydrogen are likely to be instrumental in exerting a protective effect against PD.

Protection of oral hydrogen water as an antioxidant on pulmonary hypertension

This study aimed to explore the protective effect of hydrogen as an antioxidant on monocrotaline (MCT)-induced pulmonary hypertension (PH). Forty-eight SD rats were equally randomized into four groups: SHAM group, MCT group, MCT+Oral-H2 group and MCT+Inj-H2 group. The results showed that the mean pulmonary arterial pressure, right ventricle weight and right ventricular hypertrophy index in MCT group were significant higher than those in SHAM group; pulmonary inflammatory response, atrial natriuretic factor, 3-nitrityrosine and intercellular adhesion molecule-1 were also increased significantly in MCT group. These indexes were decreased significantly in both MCT+Oral-H2 group and MCT+Inj-H2 group, which indicate Oral-H2 and Inj-H2 have similar effects of preventing the development of PH and mitigating RV hypertrophy. The protective effect of hydrogen is associated with its antioxidative ability and action of reducing pulmonary inflammatory response. While Oral-H2 is more convenient than Inj-H2, Oral-H2 may be ideal for clinical use in future.

Hydrogen-rich saline attenuates vascular smooth muscle cell proliferation and neointimal hyperplasia by inhibiting reactive oxygen species production and inactivating the Ras-ERK1/2-MEK1/2 and Akt pathways

Hydrogen-rich saline has been reported to prevent neointimal hyperplasia induced by carotid balloon injury. The purpose of the present study was to further investigate the molecular mechanisms underlying this phenomenon. Daily injection of a hydrogen-rich saline solution (HRSS) in rats was employed to study the effect of hydrogen on balloon injury-induced neointimal hyperplasia and the neointima/media ratio was assessed. HRSS significantly decreased the neointima area and neointima/media ratio in a dose-dependent manner. In vitro effects of hydrogen on fetal bovine serum (FBS)-induced vascular smooth muscle cell (VSMC) proliferation were also investigated. Hydrogen-rich medium (HRM) inhibited rat VSMC proliferation and migration induced by 10% FBS. FBS-induced reactive oxygen species (ROS) production and activation of intracellular Ras, MEK1/2, ERK1/2, proliferative cell nuclear antigen (PCNA), Akt were significantly inhibited by HRM. In addition, HRM blocked FBS-induced progression from the G0/G1 to the S-phase and increased the apoptosis rate of VSMCs. These results showed that hydrogen-rich saline was able to attenuate FBS-induced VSMC proliferation and neointimal hyperplasia by inhibiting ROS production and inactivating the Ras-ERK1/2-MEK1/2 and Akt pathways. Thus, HRSS may have potential therapeutic relevance for the prevention of human restenosis.

Effectiveness of Oral and Topical Hydrogen for Sports-Related Soft Tissue Injuries

Background: Because hydrogen therapy has been found beneficial for the treatment of inflammation, ischemia-reperfusion injury, and oxidative stress in humans, it seems useful to evaluate the effects of exogenously administered hydrogen as an element in the immediate management of sports-related soft tissue injuries. The main aim of this pilot study was to examine the effects of 2-week administration of hydrogen on the biochemical markers of inflammation and functional recovery in male professional athletes after acute soft tissue injury. Method: During the 2013 season (from March to May), 36 professional athletes were recruited as participants and examined by a certified sports medicine specialist in the first 24 hours after an injury was sustained. Subjects were allocated to 3 randomly assigned trials in a single-blind design. Those in the control group received a traditional treatment protocol for soft tissue injury. Subjects in the first experimental group followed the same procedures as the control group but with additional administration throughout the study of oral hydrogen-rich tablets (2 g per day). Subjects in the second experimental group also followed the procedures of the control group, with additional administration throughout the study of both oral hydrogen-rich tablets (2 g per day) and topical hydrogen-rich packs (6 times per day for 20 minutes). Participants were evaluated at the time of the injury report and at 7 and 14 days after baseline testing. Results: Oral and topical hydrogen intervention was found to augment plasma viscosity decrease as compared with the control group (P = 0.04). Differences were found for range-of-motion recovery between the 3 groups; oral and topical hydrogen intervention resulted in a faster return to normal joint range of motion for both flexion and extension of the injured limb as compared with the control intervention (P < 0.05). Conclusion: These preliminary results support the hypothesis that the addition of hydrogen to traditional treatment protocols is potentially effective in the treatment of soft tissue injuries in male professional athletes. Trial identification: Clinicaltrials.gov number NCT01759498.

Effectiveness Of Molecular Hydrogen In The Management Of Musculotendinous Injuries

Muscle and tendon strains (MTS) are often accompanied by subsequent tissue hypoxia and overproduction of reactive oxygen species; this may aggravate the initial cellular damage caused by the actual mechanism of injury. Molecular hydrogen (H2) seems to be beneficial for treating ischemia-reperfusion injury, oxidative stress, and inflammation in human diseases; however, the effects of H2 as an element of acute management of musculotendinous injuries are unclear. PURPOSE: To examine the effects of one-week oral and topical H2 administration on markers of inflammation, functional recovery and pain intensity in competitive male athletes after acute MTS. METHODS: During the 2013 competitive season (from March to May) participants (12 professional athletes) were recruited and examined by a certified sports medicine specialist in the first 24 hours after a MTS was sustained. The subjects were allocated in a double-blind design to two randomly assigned trials: control group (CON) received a traditional treatment protocol after the soft-tissue injury (first 48 h: rest, ice packs for 20 min every 2 h, compression with elastic bandage, elevation of the injured area above the level of the heart at all possible times; next 5 days: passive stretching 3 times per day for 90 sec, isometric strength exercise with 3 sets with 15 reps, 30 min of pain-free weight-bearing exercise); experimental group (HYD) followed the above procedures with additional administration of oral H2 tablets (2 g/day) and topical hydrogen-rich packs (6 times per day for 20 min). Participants were evaluated at the time of the injury report and 7 days after baseline testing. RESULTS: HYD intervention augmented the decrease in plasma viscosity as compared to the CON (20.7 ± 2.4 vs. 15.4 ± 1.9%; p = 0.002). Limb swelling was reduced in both groups at post-intervention, with the decline in limb circumference significantly higher in the HYD (8.0 ± 1.6 vs. 6.2 ± 0.7%; p = 0.04). CONCLUSION: The addition of oral and topical molecular hydrogen to traditional first-line treatment is effective in the management of musculotendinous injuries in athletes.