Article

Potential ghrelin-mediated benefits and risks of hydrogen water

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  • Calytic Longevity Foundation
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Abstract

Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson's disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders. Copyright © 2015. Published by Elsevier Ltd.

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... Evidence from several studies suggests that IL-22 -through antioxidant and anti-apoptotic pathways -exerts protective effects against hepatic injury induced by concanavalin A [11] , carbon tetrachloride (CCl4) [12] and EtOH [3] . Ghrelin, a 28-amino acid peptide produced in gastric mucosa, acts in the hypothalamus to promote appetite and inhibit sympathetic activity, thus increasing food intake while lowering metabolic rate [13,14] . Recent studies suggest that ghrelin has various biological functions, including anti-oxidation, anti-inflammation, antiautoimmunity and promotion of vascular health [13][14][15][16] . ...
... Ghrelin, a 28-amino acid peptide produced in gastric mucosa, acts in the hypothalamus to promote appetite and inhibit sympathetic activity, thus increasing food intake while lowering metabolic rate [13,14] . Recent studies suggest that ghrelin has various biological functions, including anti-oxidation, anti-inflammation, antiautoimmunity and promotion of vascular health [13][14][15][16] . ...
... Acyl ghrelin acts within the hypothalamus to promote appetite and inhibit sympathetic activity, which increases food intake while lowering metabolic rate [13,14] . Our findings indicate that, as compared with a control liquid diet, an EtOH-containing liquid diet significantly decreases dietary intake and acyl ghrelin level, which suggests that EtOH affects appetite. ...
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AIM To investigate the effects of hydrogen-rich water (HRW) treatment on prevention of ethanol (EtOH)-induced early fatty liver in mice. METHODS In vitro reduction of hydrogen peroxide by HRW was determined with a chemiluminescence system. Female mice were randomly divided into five groups: control, EtOH, EtOH + silymarin, EtOH + HRW and EtOH + silymarin + HRW. Each group was fed a Lieber-DeCarli liquid diet containing EtOH or isocaloric maltose dextrin (control diet). Silymarin was used as a positive control to compare HRW efficacy against chronic EtOH-induced hepatotoxicity. HRW was freshly prepared and given at a dosage of 1.2 mL/mouse trice daily. Blood and liver tissue were collected after chronic-binge liquid-diet feeding for 12 wk. RESULTS The in vitro study showed that HRW directly scavenged hydrogen peroxide. The in vivo study showed that HRW increased expression of acyl ghrelin, which was correlated with food intake. HRW treatment significantly reduced EtOH-induced increases in serum alanine aminotransferase, aspartate aminotransferase, triglycerol and total cholesterol levels, hepatic lipid accumulation and inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. HRW attenuated malondialdehyde level, restored glutathione depletion and increased superoxide dismutase, glutathione peroxidase and catalase activities in the liver. Moreover, HRW reduced TNF-α and IL-6 levels but increased IL-10 and IL-22 levels. CONCLUSION HRW protects against chronic EtOH-induced liver injury, possibly by inducing acyl ghrelin to suppress the pro-inflammatory cytokines TNF-α and IL-6 and induce IL-10 and IL-22, thus activating antioxidant enzymes against oxidative stress.
... Some of these have been extensively reviewed by Shirahata et al. (2012) and include anti-diabetic effects, anti-ageing effects, anti-gastric mucosal injury effects, anti-arteriosclerosis effects and so on. Molecular hydrogen in ARW might be a promising agent for hormonal balance through regulation of gastrointestinal peptide like ghrelin and by improving obesity via activation of hepatic FGF21 [21,22]. There is also a clinical application of ARW during dialysis in kidney disease [19]. ...
... Active hydrogen molecule in ARW has a plethora of heath benefit such as improving obesity diabetes and metabolic syndrome by activation of hepatic growth factor FGF21 [22]. It also has positive impact on hormone regulation via ghrelin and AMH [11,21]. Thus, complex pathogenicity of PCOS can be alleviated by ARW. ...
... This active molecular hydrogen might be directly effective against the AMH-related hormonal imbalance as previously evidenced that molecular hydrogen can protect AMH-related ovulatory reserve function, which is essential to PCOS [34]. Further, molecular hydrogen in ARW would independently control ghrelin as previously documented [9,21]. These balancing effects of AMH and ghrelin might stabilize the levels of estrogen, luteinizing hormone (LH), and follicle stimulating hormone (FSH), consequently leading to ameliorating the hormonal storm incurred by PCOS [8]. ...
... Although the etiology of AD is unknown, it is thought that inflammation and oxidative stress together with genetic background and environmental factors contribute to disease pathology. [2][3][4] Hydrogen water )HW( contains dissolved molecular hydrogen, which has high potential in alleviating oxidative stress, and it has shown therapeutic effects in several pathological conditions, including AD. [5][6][7][8][9][10] Hydrogen water has been reported to enhance glutathione peroxidase activity and downregulate thymus and activation-regulated chemokine )TARC(, which is implicated in the pathogenesis of AD and used as an indicator of disease severity. 10 Thymus and activation-regulated chemokine binds to the chemokine receptor CCR4 and induces chemotaxis in T cells, thus acting as a proinflammatory factor in AD, and it is suggested that HW may have therapeutic potential in AD by reducing TARC. ...
... Hydrogen water is known to attenuate several pathological conditions, including neuropathic pain, pulmonary hypertension, and neurodegeneration. [5][6][7][8] However, the effects of HW in AD are controversial. A group from Korea found no or only slight effects on AD severity in NC/Nga mice treated with HW for 12 weeks, although changes in the redox balance and inflammation were detected. ...
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Objectives To examine the effect of hydrogen water (HW) on the severity of atopic dermatitis (AD) and elucidate the underlying pathophysiological mechanisms. Methods For this experimental study between March 2015 and December 2015, NC/Nga mice characterized by mild AD severity were given either HW (n=11) or purified water (PW) (n=9) ad libitum; specific-pathogen-free mice (n=9) were used as AD-free control. Atopic dermatitis severity score and transepidermal water loss (TEWL) were examined at baseline (0 week), and after 4 weeks of HW/PW treatment. Levels of serum thymus and activation-regulated chemokine (TARC) and cytokines in the AD lesion were measured by ELISA; and mRNA expression of TARC and aquaporin (AQP-3) genes in the skin was examined by real-time polymerase chain reaction. Results Mice treated with HW for 4 weeks demonstrated a significant decrease in the AD severity score compared with PW-treated mice (p<0.01). Hydrogen water administration also significantly reduced TEWL and serum TARC levels (p<0.01), infiltration of mast cells (p<0.05), and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-33 (p<0.05) in skin lesions compared with PW. However, no difference was observed between PW and HW groups in interferon-g secretion and expression of AQP-3 and TARC genes. Conclusion Hydrogen water suppressed inflammation in AD mice, leading to amelioration of disease severity, which suggests the therapeutic potential of HW in AD treatment.
... For instance, propionic acid and H 2 S are known to have many physiological functions that might be relevant for both intestinal and systemic immunomodulation, gene expression and cell signaling (Al-Lahham, Peppelenbosch, Roelofsen, Vonk, & Venema 2010;Blachier et al., 2010). This indirect effect might be accompanied by another possible impact of HRW that occurs after a proportion of exogenous H 2 passes through the gut mucosa wall into the circulation and being transported to various organs; this by itself may produce effects relevant to the gut microbiota that are mediated by gastrin modulation (McCarty, 2015). Besides, hydrogen from HRW may also act as a signaling agent and alter gene expression of several gut-specific metabolic genes including proliferator-activated receptor-gamma coactivator-1alpha and fibroblast growth factor 21 (Kamimura, Ichimiya, Iuchi, & Ohta, 2016), and reactome pathways related to collagen biosynthesis and heat shock response (Nishiwaki et al., 2018). ...
Article
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Hydrogen-rich water (HRW) is an innovative functional drink with many professed benefits for human health, including good intestinal viability and gut microbiota upregulation. A source of molecular hydrogen, HRW might be a convenient medium to deliver this bioactive gas to the gastrointestinal tract, and perhaps modulate the activity of both hydrogen-producing and hydrogen-consuming bacteria, abundant members of the intestinal microbiota community. This paper summarizes the findings from previous studies evaluating a response of gut microbiota to HRW intake and discusses possible mechanisms and medical consequences of this interaction. It appears that only a handful of rodent studies and one human randomized-controlled trial investigated how drinking HRW affects gut microbiota, with all studies published from 2018 onwards. HRW-induced protection of the gut barrier integrity and upregulation of butyrate-producing bacteria were seen in most studies, with HRW ameliorated clinical features of gut microbiota disturbances, including diarrhea rate, weight, and fluid loss. However, no well-powered multicentric trial evaluated the effectiveness of HRW consumption so far in common gastrointestinal diseases with gut flora scenario, including inflammatory bowel disease, irritable bowel syndrome, gastroenteritis and colitis of infectious origin. HRW might be an up-and-coming compound that might tune endogenous H2 homeostasis and modulate gut microbiota but it should still be perceived as an experimental drink and not widely recommended to the general public.
... Additionally, H 2 could alter mitochondrial energy metabolism and hormone secretion [33]. In this sense, it has been observed that HRW intake caused up-regulation of ghrelin, a peptide hormone that increases appetite, stimulates the release of growth hormone and helps to maintain lean mass [34], factors that could improve performance during exercise. ...
Article
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Hydrogen-rich water (HRW) is used as a supplement to improve performance and reduce fatigue in athletes. However, the potentially beneficial effects of HRW intake could be mediated by the training status of athletes. The purpose of the study was to analyse the ergogenic effect of intake of HRW for one week on aerobic and anaerobic performance, both in trained and untrained individuals. Thirty-seven volunteers participated in the study and were divided into two experimental groups: trained cyclists and untrained subjects. A doubleblind crossover design was performed in which all subjects took a placebo (PW) and nano-bubble HRW (pH: 7.5; hydrogen concentration: 1.9 ppm; oxidation-reduction potential (ORP): -600 mV). At the end of 7-day intake, performance was assessed by an incremental VO2max test and by a maximum anaerobic test. After HRW intake, only trained cyclists improved their performance in the anaerobic test with an increase in peak power (from 766.2 ± 125.6 to 826.5 ± 143.4 W; d = .51) and mean power (from 350.0 ± 53.5 to 380.2 ± 71.3 W; d = .51), and a decrease in the fatigue index (from 77.6 ± 5.8 to 75.1 ± 5.9%; d = .45). The findings demonstrate that the ergogenic effect of HRW is mediated by the training status, and that 7-day intake of HRW would be an effective strategy for improving anaerobic performance in trained cyclists.
... Although H 2 can't scavenge peroxynitrite, it is able to diminish the toxicity of peroxynitrite [9] . This is in accordance with previous studies, which established that H 2 or hydrogen rich water can reduce the concentration of peroxynitrite in animal models [10][11][12] . ...
... 30,31 In the present study, H 2 therapy was shown to alleviate drug-related adverse events, most of which have been reported in animal models, including lung injury caused by various factors, [18][19][20][21] hepatobiliary diseases, 32-34 maculopapular rash, 35 diarrhea and constipation, [36][37][38] nausea and vomiting, 39,40 oral mucositis, 41,42 anemia, 43 thrombocytopenia, 44 and anorexia. 45 We found that the prevalence of insomnia, dizziness and headache could be reduced significantly after H 2 inhalation, which could be related to relief of diseases of the central nervous system, such as cerebral hemorrhage, [46][47][48] Parkinson's disease 49,50 and Alzheimer's disease, 51,52 observed in animal experiments. The mechanism of action observed in animal experiments could be used as a reference for clinical research. ...
Article
Chemotherapy, targeted therapy, and immunotherapy are used against advanced non-small cell lung cancer. A clinically efficacious method for relieving the adverse events associated of such therapies is lacking. Fifty-eight adult patients were enrolled in our trial to relieve pulmonary symptoms or the adverse events of drugs. Twenty patients who refused drug treatment were assigned equally and randomly to a hydrogen (H2)-only group and a control group. According to the results of tumor-gene mutations and drug-sensitivity tests, 10, 18, and 10 patients were enrolled into chemotherapy, targeted therapy, and immunotherapy groups in which these therapies were combined with H2-therapy, respectively. Patients underwent H2 inhalation for 4-5 hours per day for 5 months or stopped when cancer recurrence. Before study initiation, the demographics (except for tumor-mutation genes) and pulmonary symptoms (except for moderate cough) of the five groups showed no significant difference. During the first 5 months of treatment, the prevalence of symptoms of the control group increased gradually, whereas that of the four treatment groups decreased gradually. After 16 months of follow-up, progression-free survival of the control group was lower than that of the H2-only group, and significantly lower than that of H2 + chemotherapy, H2 + targeted therapy, and H2 + immunotherapy groups. In the combined-therapy groups, most drug-associated adverse events decreased gradually or even disappeared. H2 inhalation was first discovered in the clinic that can be used to control tumor progression and alleviate the adverse events of medications for patients with advanced non-small cell lung cancer. This study was approved by the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval No. Fuda20181207), and was registered at ClinicalTrials.gov (Identifier: NCT03818347) on January 28, 2019.
... Serum IGF-1 appeared to drop by ~ 10% after 7-day hydrogen inhalation while serum IGF-1 remained high after placebo intervention, implying a possible down-regulation link between exogenous H 2 and the anabolic response. This disagrees with a recent paper that reported an up-regulating effect of hydrogen-rich water on the growth hormone-IGF-1 axis, with an effect mediated by ghrelin, a peptide hormone produced predominantly in the gut [22]. We found no no- [24,25], with hydrogen gas possibly exerting a regulatory role in the release of pro-and anti-inflammatory cytokines mediated by haem oxygenase-1 expression and activation [26]. ...
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In this randomized, double-blind, placebo-controlled, crossover pilot trial, we evaluated the effects of 7-day H2 inhalation on exercise performance outcomes and serum hormonal and inflammation profiles in a cohort of young men and women. All participants (age 22.9 ± 1.5 years; body mass index 23.4 ± 2.5 kg m-2; 10 women and 10 men) were allocated to receive either gaseous hydrogen (4%) or placebo (room air) by 20-min once-per-day inhalation for 7 days, with a wash-out period of 7 days to prevent the residual effects of interventions across study periods. The primary treatment outcome was the change in running time-to-exhaustion in the incremental maximal test from baseline to day 7. Additionally, assessment of other exercise performance endpoints and clinical chemistry biomarkers was performed at baseline and at 7 days after each intervention. The trial was registered at ClinicalTrials.gov (ID NCT03846141). Breathing 4% hydrogen for 20 min per day resulted in increased peak running velocity (by up to 4.2%) as compared to air inhalation (P = 0.05). Hydrogen inhalation resulted in a notable drop in serum insulin-like growth factor 1 (IGF-1) by 48.2 ng/mL at follow-up (95% confidence interval [CI]: from -186.7 to 89.3) (P < 0.05), while IGF-1 levels were elevated by 59.3 ng/mL after placebo intervention (95% CI; from -110.7 to 229.5) (P < 0.05). Inhalational hydrogen appears to show ergogenic properties in healthy men and women. Gaseous H2 should be further evaluated for its efficacy and safety in an athletic environment.
... The fasting ghrelin concentrations in patients with simple obesity were lower than those of healthy subjects with normal body weight [19], while upregulation of ghrelin secretion by H 2 intervention might positivelyaffect the regulationoffeedingbehavior andenergyhomeostasis in obesity. This is in line with a recent report suggesting ghrelin-mediated effects of H 2 may favorably impact metabolic and vascular health [20]. Overall, the present study suggests potential metabolic benefits of H 2 administration in middle-aged overweight women by ameliorating hormonal disturbances that accompany this prevalent condition. ...
Article
Background: Molecular hydrogen (H2) effectively treats obesity-related disorders in animal models, yet no studies have investigated the effectiveness and safety of H2 for improving biomarkers of obesity in humans. Aim: In this double blind, placebo-controlled, crossover pilot trial, we evaluated the effects of H2 intervention on body composition, hormonal status, and mitochondrial function in ten (n = 10) middle-aged overweight women. Methods: Volunteers received either hydrogen-generating minerals (supplying ~6 ppm of H2 per day) or placebo by oral administration of caplets for 4 weeks. The primary end-point of treatment efficacy was the change in the body fat percentage from baseline to 4 weeks. In addition, assessment of other body composition indices, screening laboratory studies, and evaluation of side effects were performed before and at follow-up. Clinical trial registration www.clinicaltrials.gov , ID number NCT02832219. Results: No significant differences were observed between treatment groups for changes in weight, body mass index, and body circumferences at 4-week follow-up (P > 0.05). H2 treatment significantly reduced body fat percentage (3.2 vs. 0.9%, P = 0.05) and arm fat index (9.7 vs. 6.0%, P = 0.01) compared to placebo administration, respectively. This was accompanied by a significant drop in serum triglycerides after H2 intervention comparing to placebo (21.3 vs. 6.5%; P = 0.04), while other blood lipids remained stable during the study (P > 0.05). Fasting serum insulin levels dropped by 5.4% after H2 administration, while placebo intervention augmented insulin response by 29.3% (P = 0.01). Conclusions: It appears that orally administered H2 as a blend of hydrogen-generating minerals might be a beneficial agent in the management of body composition and insulin resistance in obesity.
... Ghrelin is a 28-amino acid peptide produced in specialized cells within the gastric mucosa [16]. Ghrelin has many beneficial effects; it stimulates release of growth hormone (GH), promotes vascular health, promotes efficient cognition in the hippocampus [17][18][19], has a broad range of neuroprotective activities, and suppresses inflammation and autoimmunity (see review [16,20]). The neuroprotective effect of ghrelin may partly due to the benefits of calorie restriction or alternate-day fasting regimens in rodents [21]. ...
Article
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Molecular hydrogen (H2), as a new medical gas, has protective effects in neurological disorders including Parkinson’s disease (PD). In our previous report, the neuroprotective effect of drinking water with saturated H2 (H2 water) in PD mice might be due to stomach–brain interaction via release of gastric hormone, ghrelin. In the present study, we assessed the effect of H2-induced ghrelin more precisely. To confirm the contribution of ghrelin in H2 water-drinking PD model mice, ghrelin-knock out (KO) mice were used. Despite the speculation, the effect of H2 water was still observed in ghrelin-KO PD model mice. To further check the involvement of ghrelin, possible contribution of ghrelin-induced vagal afferent effect was tested by performing subdiaphragmatic vagotomy before treating with H2 water and administration of MPTP (1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine). The protective effect of H2 water was still observed in the vagotomized mice in substantia nigra, suggesting that stimulation of vagal afferent nerves is not involved in H2-induced neuroprotection. Other neuroprotective substitutes in ghrelin-KO mice were speculated because H2-induced neuroprotection was not cancelled by ghrelin receptor antagonist, D-Lys³ GHRP-6, in ghrelin-KO PD model mice, unlike in wild-type PD model mice. Our results indicate that ghrelin may not be the only factor for H2-induced neuroprotection and other factors can substitute the role of ghrelin when ghrelin is absent, raising intriguing options of research for H2-responsive factors.
... The benefit of hydrogen as a novel anti-oxidant is that it can penetrate cell membrane, diffuse into the cytosol and target organelles easily, and selectively reduce hydroxide radicals and peroxynitrite without affecting physiological reactive oxygen species (ROS) involved in normal cell signaling [10] . Moreover, hydrogen therapy has been proven to be safe and effective in many clinical trials [11,12] . With respect to intestinal diseases, previous studies have shown that hydrogen may alleviate intestinal ischemia-reperfusion injury, UC, and colon inflammation [13][14][15] . ...
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AIM To investigate the therapeutic effect of hydrogen-rich water (HRW) on inflammatory bowel disease (IBD) and to explore the potential mechanisms involved. METHODS Male mice were randomly divided into the following four groups: control group, in which the mice received equivalent volumes of normal saline (NS) intraperitoneally (ip); dextran sulfate sodium (DSS) group, in which the mice received NS ip (5 mL/kg body weight, twice per day at 8 am and 5 pm) for 7 consecutive days after IBD modeling; DSS + HRW group, in which the mice received HRW (in the same volume as the NS treatment) for 7 consecutive days after IBD modeling; and DSS + HRW + ZnPP group, in which the mice received HRW (in the same volume as the NS treatment) and ZnPP [a heme oxygenase-1 (HO-1) inhibitor, 25 mg/kg] for 7 consecutive days after IBD modeling. IBD was induced by feeding DSS to the mice, and blood and colon tissues were collected on the 7th d after IBD modeling to determine clinical symptoms, colonic inflammation and the potential mechanisms involved. RESULTS The DSS + HRW group exhibited significantly attenuated weight loss and a lower extent of disease activity index compared with the DSS group on the 7th d (P < 0.05). HRW exerted protective effects against colon shortening and colonic wall thickening in contrast to the DSS group (P < 0.05). The histological study demonstrated milder inflammation in the DSS + HRW group, which was similar to normal inflammatory levels, and the macroscopic and microcosmic damage scores were lower in this group than in the DSS group (P < 0.05). The oxidative stress parameters, including MDA and MPO in the colon, were significantly decreased in the DSS + HRW group compared with the DSS group (P < 0.05). Simultaneously, the protective indicators, superoxide dismutase and glutathione, were markedly increased with the use of HRW. Inflammatory factors were assessed, and the results showed that the DSS + HRW group exhibited significantly reduced levels of TNF-α, IL-6 and IL-1β compared with the DSS group (P < 0.05). In addition, the pivotal proteins involved in endoplasmic reticulum (ER) stress, including p-eIF2α, ATF4, XBP1s and CHOP, were dramatically reduced after HRW treatment in contrast to the control group (P < 0.05). Furthermore, HRW treatment markedly up-regulated HO-1 expression, and the use of ZnPP obviously reversed the protective role of HRW. In the DSS + HRW + ZnPP group, colon shortening and colonic wall thickening were significantly aggravated, and the macroscopic damage scores were similar to those of the DSS + HRW group (P < 0.05). The histological study also showed more serious colonic damage that was similar to the DSS group. CONCLUSION HRW has a significant therapeutic potential in IBD by inhibiting inflammatory factors, oxidative stress and ER stress and by up-regulating HO-1 expression.
Chapter
Over the last century there have been significant advances in medical procedures pertaining to geriatrics and emergency medicine, resulting in significant average life span extensions in most developed nations. Although the life span has been significantly extended, the rate of chronic non-communicable diseases (NCDs) has risen, largely owing to the increased prevalence of sedentary lifestyles and ease of access to foods that are high in both sugar and fat. Solutions to mitigate the rising NCD rates are desperately needed in order to improve the health span, to protect against NCD-driven declines in average life span, and as strategies to reduce the financial burden of rising healthcare costs. Molecular hydrogen has shown great potential in the amelioration of many physiological distresses that contribute to NCD development. Research trends have developed demonstrating the ability of molecular hydrogen to mitigate both the development and side effects of many NCDs, including metabolic disturbances, neurodegenerative issues, cancer, and acute traumatic events. These trends also suggest that using high-concentration hydrogen water, such as that produced from DrinkHRW hydrogen-producing tablets, increases the breadth and efficacy of hydrogen therapy. Importantly, molecular hydrogen has a high safety profile with no known contraindications. As a safe and potentially effective strategy to stave off and mitigate a wide array of NCDs, large-scale clinical trials investigating the therapeutic benefits of molecular hydrogen are warranted.
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The central ghrelin signaling system engages key pathways of importance for feeding control, recently shown to include those engaged in anxiety-like behavior in rodents. Here we sought to determine whether ghrelin impacts on the central serotonin system, which has an important role in anxiety. We focused on two brain areas, the amygdala (of importance for the mediation of fear and anxiety) and the dorsal raphe (i.e. the site of origin of major afferent serotonin pathways, including those that project to the amygdala). In these brain areas, we measured serotonergic turnover (using HPLC) and the mRNA expression of a number of serotonin-related genes (using real-time PCR). We found that acute central administration of ghrelin to mice increased the serotonergic turnover in the amygdala. It also increased the mRNA expression of a number of serotonin receptors, both in the amygdala and in the dorsal raphe. Studies in ghrelin receptor (GHS-R1A) knock-out mice showed a decreased mRNA expression of serotonergic receptors in both the amygdala and the dorsal raphe, relative to their wild-type littermates. We conclude that the central serotonin system is a target for ghrelin, providing a candidate neurochemical substrate of importance for ghrelin's effects on mood.
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Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognition-enhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning.
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The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.
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Hippocampus, Amygdale and dorsal raphe nucleus are the cerebral main structures involved in learning, memory and anxiety. Ghrelin increases the level of several hormones in these structures and affects learning, memory and anxiety-like behaviors. This study was performed to investigate the effect of ghrelin agonist on passive avoidance learning and anxiety in adult female rats in the presence and absence of ovary hormones. Five groups of rats, including control group with no injections, ovariectomized groups; one group receiving normal saline and other group receiving ghrelin agonist solution, surgery shocked (sham operated) groups; one group receiving saline and other group ghrelin agonist solution, were tested. Inside stereotaxis apparatus, two sided CA1 cannulae were used and 1 microL of saline or ghrelin agonist solution, at 3 nmol microL(-1) concentration, was injected into each cannula. Passive avoidance learning was measured by using shuttle box and anxiety by elevated plus- maze. Ghrelin agonist increased the level of learning in surgery shocked group in comparison with control group. Anxiety-like behavior was seen in both ovariectomized and surgery shocked groups. Ghrelin agonist binds its own receptors in the hippocampus, thereby increases learning capability and induces anxiety-like behaviors. Proper management of these behaviors might be useful in controlling some forms of nervous system diseases in humans.
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The therapeutic potential of molecular hydrogen (H2) is emerging in a number of human diseases and in their animal models, including in particular Parkinson's disease (PD). H2 supplementation of drinking water has been shown to exert disease-modifying effects in PD patients and neuroprotective effects in experimental PD model mice. However, H2 supplementation does not result in detectable changes in striatal H2 levels, indicating an indirect effect. Here we show that H2 supplementation increases gastric expression of mRNA encoding ghrelin, a growth hormone secretagogue, and ghrelin secretion, which are antagonized by the β1-adrenoceptor blocker, atenolol. Strikingly, the neuroprotective effect of H2 water was abolished by either administration of the ghrelin receptor-antagonist, D-Lys(3) GHRP-6, or atenolol. Thus, the neuroprotective effect of H2 in PD is mediated by enhanced production of ghrelin. Our findings point to potential, novel strategies for ameliorating pathophysiology in which a protective effect of H2 supplementation has been demonstrated.
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Background: Oxidative stress is involved in the progression of Parkinson's disease (PD). Recent studies have confirmed that molecular hydrogen (H₂) functions as a highly effective antioxidant in cultured cells and animal models. Drinking H₂-dissolved water (H₂-water) reduced oxidative stress and improved Parkinson's features in model animals. Methods: In this a placebo-controlled, randomized, double-blind, parallel-group clinical pilot study, the authors assessed the efficacy of H₂ -water in Japanese patients with levodopa-medicated PD. Participants drank 1,000 mL/day of H₂-water or pseudo water for 48 weeks. Results: Total Unified Parkinson's Disease Rating Scale (UPDRS) scores in the H₂-water group (n=9) improved (median, -1.0; mean ± standard deviation, -5.7 ± 8.4), whereas UPDRS scores in the placebo group (n=8) worsened (median, 4.5; mean ± standard deviation, 4.1 ± 9.2). Despite the minimal number of patients and the short duration of the trial, the difference was significant (P<0.05). Conclusions: The results indicated that drinking H₂-water was safe and well tolerated, and a significant improvement in total UPDRS scores for patients in the H₂-water group was demonstrated.
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To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules must therefore be able to circumvent the tightly sealed vasculature of the blood-brain barrier to rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed to central hypothalamic neurons remains largely unexplored. Using in vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate that circulating ghrelin, a versatile regulator of energy expenditure and feeding behavior, rapidly binds neurons in the vicinity of fenestrated capillaries, and that the number of labeled cell bodies varies with feeding status. Thus, by virtue of its vascular connections, the hypothalamus is able to directly sense peripheral signals, modifying energy status accordingly.
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Ghrelin is an orexigenic peptide hormone secreted into the systemic circulation predominantly by the X/A-like cells in the mucosa of the stomach. In addiction to central effects on food intake and growth hormone release, ghrelin has also important vascular and metabolic actions. Our laboratory has shown that administration of exogenous ghrelin acutely improves endothelial function by increasing nitric oxide bioavailability and normalizing the alterate balance between endothelin 1/nitric oxide (ET-1/NO) within the vasculature of individuals with metabolic syndrome. Additionally, in endothelial cell cultures, it has been shown that ghrelin directly stimulates NO production using a signaling pathway that involves GHSR-1a, PI 3-kinase, Akt, and eNOS. Other cardiovascular effects of ghrelin include lowering of peripheral resistance, improvement of contractility and cardiac output. In addition ghrelin plays a significant role in the regulation of glucose homeostasis, lipid profiles and body composition. Importantly, ghrelin has antiinflammatory and antiapoptotic effects both in vivo and in vitro. This review focuses on the physiological roles of ghrelin in regulating metabolic and endothelial function and on the potential of ghrelin as the therapeutic target to treat metabolic and cardiovascular disorders.
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Background Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of bone and cartilage. Although its etiology is unknown, the hydroxyl radical has been suggested to be involved in the pathogenesis of RA. Recently, molecular hydrogen (H2) was demonstrated to be a selective scavenger for the hydroxyl radical. Also, the method to prepare water containing extremely high concentration of H2 has been developed. We hypothesized that H2 in the water could complement conventional therapy by reducing the oxidative stress in RA. Methods Twenty patients with rheumatoid arthritis (RA) drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (high H2 water) every day for 4 weeks. After a 4-week wash-out period, the patients drank the high H2 water for another 4 weeks. Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) was estimated at the end of each 4-week period. Results Drinking high H2 water seems to raise the concentration of H2 more than the H2 saturated (1.6 ppm) water in vivo. Urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01) on average. DAS28 also decreased from 3.83 to 3.02 (p < 0.01) during the same period. After the wash-out period, both the urinary 8-OHdG and the mean DAS28 decreased, compared to the end of the drinking period. During the second drinking period, the mean DAS28 was reduced from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG was not further reduced but remained below the baseline value. All the 5 patients with early RA (duration < 12 months) who did not show antibodies against cyclic citrullinated peptides (ACPAs) achieved remission, and 4 of them became symptom-free at the end of the study. Conclusions The results suggest that the hydroxyl radical scavenger H2 effectively reduces oxidative stress in patients with this condition. The symptoms of RA were significantly improved with high H2 water.
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Vascular calcification results from osteoblastic differentiation of vascular smooth muscle cells (VSMCs) and is a major risk factor for cardiovascular events. Ghrelin is a newly discovered bioactive peptide that acts as a natural endogenous ligand of the growth hormone secretagog receptor (GHSR). Several studies have identified the protective effects of ghrelin on the cardiovascular system, however research on the effects and mechanisms of ghrelin on vascular calcification is still quite rare. In this study, we determined the effect of ghrelin on osteoblastic differentiation of VSMCs and investigated the mechanism involved using the two universally accepted calcifying models of calcifying vascular smooth muscle cells (CVSMCs) and beta-glycerophosphate (beta-GP)-induced VSMCs. Our data demonstrated that ghrelin inhibits osteoblastic differentiation and mineralization of VSMCs due to decreased alkaline phosphatase (ALP) activity, Runx2 expression, bone morphogenetic protein-2 (BMP-2) expression and calcium content. Further study demonstrated that ghrelin exerted this suppression effect via an extracellular signal-related kinase (ERK)-dependent pathway and that the suppression effect of ghrelin was time dependent and dose dependent. Furthermore, inhibition of the growth hormone secretagog receptor (GHSR), the ghrelin receptor, by siRNA significantly reversed the activation of ERK by ghrelin. In conclusion, our study suggests that ghrelin may inhibit osteoblastic differentiation of VSMCs through the GHSR/ERK pathway.
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Background: Acyl-ghrelin is thought to have both orexigenic effects and to stimulate GH release. A possible cause of the anorexia of aging is an age-dependent decrease in circulating acyl-ghrelin levels. Objectives: The purpose of the study was to compare acyl-ghrelin and GH concentrations between healthy old and young adults and to examine the relationship of acyl-ghrelin and GH secretion in both age groups. Methods: Six healthy older adults (age 62-74 y, body mass index range 20.9-29 kg/m(2)) and eight healthy young men (aged 18-28 y, body mass index range 20.6-26.2 kg/m(2)) had frequent blood samples drawn for hormone measurements every 10 minutes for 24 hours. Ghrelin was measured in an in-house, two-site sandwich ELISA specific for full-length acyl-ghrelin. GH was measured in a sensitive assay (Immulite 2000), and GH peaks were determined by deconvolution analysis. The acyl-ghrelin/GH association was estimated from correlations between amplitudes of individual GH secretory events and the average acyl-ghrelin concentration in the 60-minute interval preceding each GH burst. Results: Twenty-four-hour mean (±SEM) GH (0.48 ± 0.14 vs 2.2 ± 0.3 μg/L, P < .005) and acyl-ghrelin (14.7 ± 2.3 vs 27.8 ± 3.9 pg/mL, P < .05) levels were significantly lower in older adults compared with young adults. Twenty-four-hour cortisol concentrations were higher in the old than the young adults (15.1 ± 1.0 vs 10.6 ± 0.9 μg/dL, respectively, P < .01). The ghrelin/GH association was more than 3-fold lower in the older group compared with the young adults (0.16 ± 0.12 vs 0.69 ± 0.04, P < .001). Conclusions: These results provide further evidence of an age-dependent decline in circulating acyl-ghrelin levels, which might play a role both in the decline of GH and in the anorexia of aging. Our data also suggest that with normal aging, endogenous acyl-ghrelin levels are less tightly linked to GH regulation.
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Cachexia is a devastating complication of cancer for which there is no approved treatment. Here we review the clinical development of ghrelin and ghrelin mimetics (also known as growth hormone secretagogues or GHS) for cancer cachexia treatment. Ghrelin, a novel hormone known to increase appetite, lean and fat mass, and growth hormone secretion, is being developed as a therapeutic option for cancer anorexia-cachexia syndrome (CACS). Recent animal studies suggest that it may also decrease inflammation and that some of its effects may be independent of its only known receptor, the GHS receptor-1a.Clinical studies recently have shown that administration of ghrelin or GHS improves appetite and quality of life as assessed by questionnaires. Weight gain, increased food intake and better tolerance to chemotherapy have also been reported. This treatment appears to be safe and well tolerated. Ghrelin and GHS have the potential to effectively prevent or reverse CACS. Preliminary studies show improvements in weight stabilization and appetite with short-term usage. Further studies are required to fully characterize the role of ghrelin and GHS for the treatment of CACS and to establish the safety of this approach.
Article
To investigate effects of hydrogen-rich water (HRW) on oxidative stress, liver function and HBV DNA in patients with chronic hepatitis B (CHB). Sixty patients with CHB were randomly assigned into routine treatment group or hydrogen treatment group in which patients received routine treatment alone or additional oral HRW (1200-1800 mL/day, twice daily), respectively, for 6 consecutive weeks. Serum oxidative stress, liver function, and HBV DNA level were detected before and after treatment. Thirty healthy subjects served as controls. When compared with controls, oxidative stress was obvious in CHB patients, and the liver function also significantly impaired. After treatment, the oxidative stress remained unchanged in routine treatment group, but markedly improved in hydrogen treatment group. The liver function was improved significantly and the HBV DNA reduced markedly after corresponding treatments. Although a significant difference was noted in the oxidative stress between two groups after treatment, the liver function and HBV DNA level were comparable after treatment and both had improved tendencies. HRW significantly attenuates oxidative stress in CHB patients, but further study with long-term treatment is required to confirm the effect of HRW on liver function and HBV DNA level. Clin Trans Sci 2013; Volume #: 1-4.
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Ghrelin, a gut hormone with pleiotropic effects, may act as a protective signal in parenchymal cells. We investigated the protective effects of ghrelin on hepatocytes after ischaemia/reperfusion (I/R). Hepatic injury was assessed by measurement of plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), histological analysis, and TUNEL assay. Effects of exogenous ghrelin and ghrelin receptor gene deletion on I/R induced injury of liver were evaluated. Ischaemia/reperfusion induced a profound injury to hepatocytes. This was accompanied by elevations in plasma ALT and LDH. Pretreatment with ghrelin significantly reduced elevations in plasma ALT and LDH, and attenuated tissue damage induced by hepatic I/R in mice. Hepatic injury induced by I/R was more pronounced in ghrelin receptor gene null mice. Ghrelin administration blocked the up-regulation of AMP-activated protein kinase (AMPK) activity induced by hepatic I/R. This study demonstrates that ghrelin contributes to the cytoprotection during hepatic I/R.
Article
Ghrelin, which has been shown to improve memory retention, is an endogenous ligand for the growth hormone secretagogue receptor. Recombination activating gene 1 (Rag1), which plays a critical role in the development and maturation of lymphocytes in the immune system, is also expressed in the central nervous system, particularly in the hippocampus, and has been implicated in memory formation. In the current study, the effects of ghrelin on Rag1 expression in the hippocampus and spatial memory performance in wild-type and Rag1 knockout (KO) mice were examined. The Morris water maze test was used to compare the spatial memory performance of wild-type and Rag1-KO mice. Transmission electron microscopy was used to assess morphological changes in synaptic shape and numbers in hippocampal areas after peripheral administration of ghrelin to wild-type and Rag1-KO mice. In wild-type mice, ghrelin increased synaptic vesicles and postsynaptic membrane deposits in the hippocampal CA3 region, shortened water maze escape latencies, and increased platform spans. In Rag1-KO mice, the escape latencies were significantly increased compared with the group of normal mice. Compared with wild-type mice, Rag1-KO mice showed decreasing platform spans. A tendency toward a shortening of the escape latency times and an increase in the platform spans in Rag1-KO mice was observed after ghrelin injection, but this difference was not statistically significant compared with control mice. After the administration of ghrelin, the expression of Rag1 in the hippocampus was significantly increased compared with control mice. Our results suggest that ghrelin potentiates learning and memory in mice, which may be, at least partly, through the regulation of hippocampal Rag1.
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Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia reperfusion (I-R) injury. However, reactive nitrogen species (RNS) produced by NO causes myocardial dysfunction and injury. Since H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO (80 ppm), H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 hrs, left ventricular function, the infarct size and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. While nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I-R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I-R injury.
Article
Aim: Liver fibrosis is the universal consequence of chronic liver diseases. Sustained hepatocyte injury initiates an inflammatory response, thereby activating hepatic stellate cells, the principal fibrogenic cells in the liver. Reactive oxygen species are involved in liver injury and are a promising target for treating liver fibrosis. Hydrogen water is reported to have potential as a therapeutic tool for reactive oxygen species-associated disorders. This study aimed to investigate the effects of hydrogen water on liver fibrogenesis and the mechanisms underlying these effects. Methods: C57BL/6 mice were fed with hydrogen water or control water, and subjected to carbon tetrachloride, thioacetamide and bile duct ligation treatments to induce liver fibrosis. Hepatocytes and hepatic stellate cells were isolated from mice and cultured with or without hydrogen to test the effects of hydrogen on reactive oxygen species-induced hepatocyte injuries or hepatic stellate cell activation. Results: Oral intake of hydrogen water significantly suppressed liver fibrogenesis in the carbon tetrachloride and thioacetamide models, but these effects were not seen in the bile duct ligation model. Treatment of isolated hepatocyte with 1 μg/mL antimycin A generated hydroxyl radicals. Culturing in the hydrogen-rich medium selectively suppressed the generation of hydroxyl radicals in hepatocytes and significantly suppressed hepatocyte death induced by antimycin A; however, it did not suppress hepatic stellate cell activation. Conclusion: We conclude that hydrogen water protects hepatocytes from injury by scavenging hydroxyl radicals and thereby suppresses liver fibrogenesis in mice.
Article
Since the original discovery of ghrelin and, subsequently, obestatin (the alternative product of the ghrelin gene), a major interest has been devoted to the investigation of their central and peripheral activities in physiological conditions as well as on their role in metabolic diseases. However, several studies with different methodological approaches variably identified ghrelin and obestatin synthesis and secretion in several neoplastic conditions, including neuroendocrine and non-neuroendocrine cancers of various sites. Moreover, in vitro studies showed the capability of ghrelin to modulate tumor cell functions such as cell proliferation, apoptosis and invasiveness, although with variable and even paradoxical effects in different cell models. Interestingly, in most studies, it was demonstrated that ghrelin exerts its pro- or antineoplastic properties by means of receptors other than GHSR1a, that still need to be identified. However, the possible usefulness of the modulation of the ghrelin/obestatin axis in neoplastic conditions using either synthetic agonists or antagonists, though interesting in perspective, is still far from clinical applicability, and probably more related to the regulation of specific metabolic pathways in tumor cells, including lipid and carbohydrate use, than to the specific modulation of cell proliferation.
Article
Objective: Obesity commonly causes hepatic lipid accumulation that may favor oxidative stress and inflammation with negative clinical impact. Acylated ghrelin (A-Ghr) modulates body lipid distribution and metabolism, and it may exert antioxidant effects in vitro as well as systemic anti-inflammatory effects in vivo. The impact of A-Ghr on liver triglyceride content, redox state and inflammation markers in diet-induced obesity was investigated. Design and methods: A-Ghr (200-μg/injection: HFG) or saline (HF) were administered subcutaneously twice-daily for 4 days to 12-week-old male rats fed a high-fat diet for 1 month (n = 8-10/group). Results: Compared to lean animals, liver triglyceride accumulation occurred in HF despite enhanced phosphorylation of the lipid oxidation regulator AMPK and preserved mitochondrial enzyme activities. High triglycerides were accompanied by pro-oxidant changes in redox state and proinflammatory changes in NF-kB and TNF-alpha. A-Ghr limited liver triglyceride excess (P < 0.05 HF > HFG > Control) with concomitant activation of glutathione peroxidase and normalized redox state and cytokines. A-Ghr-induced liver changes were associated with higher plasma adiponectin and lower circulating fatty acids (P < 0.05 HFG vs. Hf) conclusions: A-Ghr limits liver triglyceride accumulation and normalizes tissue redox state and inflammation markers in diet-induced obese rats. These results suggest a favorable impact of A-Ghr on hepatic complications of diet-induced obesity.
Article
Adult hippocampal neurogenesis is important in mediating hippocampal-dependent learning and memory. Exogenous ghrelin is known to stimulate progenitor cell proliferation in the dentate gyrus of adult hippocampus. The aim of this study was to investigate the role of endogenous ghrelin in regulating the in vivo proliferation and differentiation of the newly generating cells in the adult hippocampus using ghrelin knockout (GKO) mice. Targeted deletion of ghrelin gene resulted in reduced numbers of progenitor cells in the subgranular zone (SGZ) of the hippocampus, while ghrelin treatment restored progenitor cell numbers to those of wild-type controls. We also found that not only the number of BrdU-positive cells but also the fraction of immature neurons and newly generated neurons were decreased in the GKO mice, which were increased by ghrelin replacement. Additionally, in the GKO mice, we observed impairment of memory performance in Y-maze task and novel object recognition test. However, these functional deficiencies were attenuated by ghrelin administration. These results suggest that ghrelin directly induces proliferation and differentiation of adult neural progenitor cells in the SGZ. Our data suggest ghrelin may be a plausible therapeutic potential to enhance learning and memory processes.
Article
Ghrelin is an acylated peptide discovered in gastric extracts as an endogenous ligand for the growth hormone secretagogue (GHS) receptor. This peptide increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. Our study investigated the pharmacological effect of ghrelin in the prevention of polyneuropathy in streptozotocin-induced diabetes mellitus in C57BL/6N mice, GHS receptor-deficient mice, and growth hormone-deficient rats. Ghrelin or desacyl-ghrelin was administered daily for four weeks immediately after disease onset. The effects of ghrelin on food intake, body weight, blood glucose and plasma insulin levels, nerve conduction velocities, temperature sensation, and 8-isoprostaglandin F2α (8-iso-PGF2α) levels were examined. We found that ghrelin administration did not change food intake, body weight gain, blood glucose levels, or plasma insulin levels in C57BL/6N mice in comparison with mice treated with saline or desacyl-ghrelin administration. Ghrelin administration, but not desacyl-ghrelin, prevented motor and sensory polyneuropathy and reduced the plasma concentrations of 8-iso-PGF2α in C57BL/6N mice. Ghrelin also prevented the reduction in nerve conduction velocities in growth hormone-deficient rats, but not in GHS receptor-knockout mice. In conclusion, ghrelin administration in a rodent model of diabetes prevented polyneuropathy, and this effect was mediated through the GHS receptor and was independent of growth hormone. The protection against the development of experimental diabetic polyneuropathy by ghrelin could be key in preventing this otherwise intractable disorder.
Article
Ghrelin is an important gastrointestinal hormone that regulates feeding and metabolism. Moreover, ghrelin is produced by immune cells and shows potent anti-inflammatory activities. Here, we investigated its effect in two models of experimental autoimmune encephalomyelitis (EAE) that mirror chronic and relapsing-remitting multiple sclerosis. A short systemic treatment with ghrelin after the disease onset reduced clinical severity and incidence of both forms of EAE, which was associated with a decrease in inflammatory infiltrates in spinal cord and in the subsequent demyelination. This therapeutic effect was exerted through the reduction of the autoimmune and inflammatory components of the disease. Ghrelin decreased the presence/activation of encephalitogenic Th1 and Th17 cells in periphery and nervous system, down-regulated various inflammatory mediators, and induced regulatory T cells. In summary, our findings provide a powerful rationale for the assessment of the efficacy of ghrelin as a novel therapeutic approach for treating multiple sclerosis through distinct immunomodulatory mechanisms and further support the concept that the neuroendocrine and immune systems crosstalk to finely tune the final immune response of our body.
Article
Objective: The purpose of this research was to investigate the effects of ghrelin on circulating endothelial progenitor cells (EPC) directional migration and its underlying molecular mechanisms involved in this process. Materials/methods: EPC were isolated from bone marrow of SD rats by using Percoll density gradient centrifugation, and characterized by double positive for acLDL-Dil uptake and FITC-UEA-1 binding and immunocytochemistry for CD34, CD133, vWF and Flk-1. EPC were treated with different concentrations of ghrelin (10(-9)~10(-6)M) with or without GHSR1a inhibitor [D-Lys3]-GHRP-6, PI3K inhibitor LY294002 and endothelial nitric oxide synthase (eNOS) inhibitor L-NAME, migration of EPC was detected by transwell assay, levels of phosphorylated and total Akt and eNOS were determined by Western-blot analysis and Nitric Oxide (NO) production was measured by Griess assay, respectively. Results: EPC were successfully obtained by Percoll density gradient centrifugation and ghrelin at 10(-8)M~10(-7)M promoted EPC migration. Ghrelin-induced EPC migration was accompanied by phosphorylation of Akt and eNOS, as well as an increase in NO production. These biochemical events and EPC directional migration induced by ghrelin were completely inhibited by GHSR-1a blocker [D-Lys3]-GHRP-6. PI3K inhibitor LY294002 attenuated ghrelin-induced EPC migration, phosphorylation of Akt and eNOS, and NO production. eNOS inhibitor L-NAME blocked ghrelin-induced EPC migration, phosphorylation of eNOS, and NO production, but had no effect on Akt phosphorylation. Conclusions: These findings suggest that ghrelin stimulates EPC directional migration via GHSR1a-mediated PI3K/Akt/eNOS/NO signal pathway. It indicates that ghrelin may be used as a therapeutic strategy to treat ischemic diseases by promoting EPC directional migration.
Article
Background: The risk of different cancers seems to be associated with obesity. Moreover, low ghrelin levels observed in obese people may be implicated in cancer development and progression. The aim of this study was to examine the direct effects of both forms of ghrelin (acylated and unacylated) and ghrelin receptor type 1a antagonist (D-Lys-GHRP-6) on the growth of murine colon cancer MC38 and human prostate cancer DU145 cell lines in vitro. Methods: The cells were cultured for 72 h in the presence of rat or human acylated ghrelin (rG, hG), human unacylated ghrelin (hUAG), D-Lys-GHRP-6 (GHS-RA) applied either alone or jointly. The cell line growth was assessed by the colorimetric Mosmann method. Results: hUAG (10(-6), 10(-7) and 10(-10) M) inhibited MC38 cancer cell growth and, at some concentrations (10(-8), 10(-9), 10(-10) M), enhanced the antineoplastic effect of GHS-RA(10(-4) M). In turn, GHS-RA evoked a biphasic effect on MC38 cancer growth: inhibitory at 10(-4) M and stimulatory at 10(-5) and 10(-6) M. Moreover, GHS-RA at the highest examined concentration (10(-4) M) enhanced the cytostatic effect of FU. Human acylated and unacylated ghrelin and GHS-RA inhibited DU145 cancer growth with moderate and different potencies. A dose-response effect was observed for the inhibitory action of hG together with the synergistic effect of hUAG and GHS-RA. Conclusion: The obtained results indicate an involvement of the ghrelin axis in the growth regulation of colon and prostate cancers and may suggest new therapeutic options for these neoplasms.
Article
We aim to investigate the preventive and therapeutic effects of ghrelin on a rat NAFLD model and possible underlying mechanism. Sprague-Dawley rats were fed with high-fat diet for 8 weeks to induce NAFLD. A group of rats were also treated with ghrelin throughout the NAFLD induction. After 8 weeks, rats were sacrificed for liver injury measurements. Rats with NAFLD showed obvious histological changes including necrosis and inflammation foci, elevated serum enzyme (ALT and AST) levels, dysregulated hepatic lipid metabolism, increased formation of oxidative stress, and lipid peroxidation markers, up-regulated levels of pro-inflammatory cytokines and apoptotic cells in the liver. Treatment of ghrelin improved liver injury through counter-acting those events. The improvement of ghrelin was accompanied with a restoration of LKB1/AMPK and PI3 K/Akt pathways. Ghrelin treatment alone did not influence the healthy rat liver. In addition, "therapeutic" ghrelin administration (2 weeks) after the establishment of early NAFLD symptoms (4 weeks) in rats further proved the beneficial effects of ghrelin. In conclusion, administration of ghrelin could attenuate NAFLD-induced liver injury, oxidative stress, inflammation, and apoptosis partly through the action of LKB1/AMPK and PI3 K/Akt pathways.
Article
Introduction: Central neurochemical systems including the monoamine, opioid, and cannabinoid systems have been promising targets for antiobesity drugs that modify behavioral components of obesity. In addition to modulating eating behavior, centrally acting antiobesity drugs are also likely to alter emotional behavior and cognitive function due to the high expression of receptors for the neurochemical systems targeted by these drugs within the fronto-striatal and limbic circuitry. Methods: This paper reviewed the neuropsychiatric adverse effects of past and current antiobesity drugs, with a central mechanism of action, linking the adverse effects to their underlying neural substrates and neurochemistry. Results: Antiobesity drugs were found to have varying neuropsychiatric adverse event profiles. Insomnia was the most common adverse effect with drugs targeting monoamine systems (sibutramine, bupropion and tesofensine). These drugs had some positive effects on mood and anxiety and may have added therapeutic benefits in obese patients with comorbid depression and anxiety symptoms. Sedation and tiredness were the most common adverse effects reported with drugs targeting the m-opioid receptors (i.e., naltrexone) and combination therapies targeting the opioid and monoamine systems (i.e., Contrave™). Cognitive impairments were most frequently associated with the antiepileptic drugs, topiramate and zonisamide, consistent with their sedative properties. Drugs targeting the cannabinoid system (rimonabant and taranabant) were consistently associated with symptoms of anxiety and depression, including reports of suicidal ideation. Similar adverse events have also been noted for the D₁/D₅ antagonist ecopipam. Conclusion: These findings highlight the need to assess neuropsychiatric adverse events comprehensively using sensitive and validated methods early in the clinical development of candidate antiobesity drugs with a central mechanism of action.
Article
Weight loss is a characteristic finding of patients with Alzheimer's disease (AD). It seems that precedes cognitive impairment by some years, but the underlying causes are not fully understood. Ghrelin and leptin are involved in energy homeostasis, and may be implicated in weight losing observed in these patients. To examine the potential relationship between ghrelin and leptin levels and weight loss in patients with AD. The study included 27 patients (10 men and 17 women) with AD of moderate severity, and 23 controls (10 males and 13 females), matched for age and BMI. Body fat and lean mass content were assessed using a portable apparatus. Cognitive function was assessed with the Mini-Mental State Examination. Basal serum samples for the measurement of leptin, ghrelin, insulin and glucose were obtained, and serum ghrelin, insulin and glucose were measured after a 75-gr glucose load in both groups. Patients with Alzheimer Disease (AD) have lower lean mass content compared to controls. Basal ghrelin and leptin is similar in patients with AD and controls. The area-under-the-curve for ghrelin (AUC) is lower in male patients with AD compared to control males, while no difference was observed between females AD and controls. Male patients with AD, in contrast with female patients, fail to maintain a normal energy homeostasis even in the early stages of the disease, as shown by the decreased lean mass content in males AD compared to controls. Disruption of the normal compensatory modulation of ghrelin secretion might contribute to the metabolic changes observed in male patients with AD.
Article
Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation, and recent evidence suggests ghrelin prevents excessive anxiety under conditions of chronic stress. We used ghrelin knockout (ghr-/-) mice to examine the role of endogenous ghrelin in anxious behavior and hypothalamic-pituitary-adrenal axis (HPA) responses to acute stress. Ghr-/- mice are more anxious after acute restraint stress, compared with wild-type (WT) mice, with three independent behavioral tests. Acute restraint stress exacerbated neuronal activation in the hypothalamic paraventricular nucleus and medial nucleus of the amygdala in ghr-/- mice compared with WT, and exogenous ghrelin reversed this effect. Acute stress increased neuronal activation in the centrally projecting Edinger-Westphal nucleus in WT but not ghr-/- mice. Ghr-/- mice exhibited a lower corticosterone response after stress, suggesting dysfunctional glucocorticoid negative feedback in the absence of ghrelin. We found no differences in dexamethasone-induced Fos expression between ghr-/- and WT mice, suggesting central feedback was not impaired. Adrenocorticotropic hormone replacement elevated plasma corticosterone in ghr-/-, compared with WT mice, indicating increased adrenal sensitivity. The adrenocorticotropic hormone response to acute stress was significantly reduced in ghr-/- mice, compared with control subjects. Pro-opiomelanocortin anterior pituitary cells express significant growth hormone secretagogue receptor. Ghrelin reduces anxiety after acute stress by stimulating the HPA axis at the level of the anterior pituitary. A novel neuronal growth hormone secretagogue receptor circuit involving urocortin 1 neurons in the centrally projecting Edinger-Westphal nucleus promotes an appropriate stress response. Thus, ghrelin regulates acute stress and offers potential therapeutic efficacy in human mood and stress disorders.
Article
Unlabelled: Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-choline-deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-α, interleukin-6, fatty acid synthesis-related genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-α expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis.
Article
Oxidative stress is implicated in atherogenesis; however most clinical trials with dietary antioxidants failed to show marked success in preventing atherosclerotic diseases. We have found that hydrogen (dihydrogen; H2) acts as an effective antioxidant to reduce oxidative stress [I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. Katayama, S, Asoh, S. Ohta, Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat. Med. 13 (2007) 688–694]. Here, we investigated whether drinking H2-dissolved water at a saturated level (H2–water) ad libitum prevents arteriosclerosis using an apolipoprotein E knockout mouse (apoE−/−), a model of the spontaneous development of atherosclerosis. ApoE−/− mice drank H2–water ad libitum from 2 to 6 month old throughout the whole period. Atherosclerotic lesions were significantly reduced by ad libitum drinking of H2–water (p = 0.0069) as judged by Oil-Red-O staining series of sections of aorta. The oxidative stress level of aorta was decreased. Accumulation of macrophages in atherosclerotic lesions was confirmed. Thus, consumption of H2-dissolved water has the potential to prevent arteriosclerosis.
Article
Global cerebral ischemia and reperfusion (I/R) often result in high mortality. Free radicals have been reported to play an important role in global cerebral I/R, and therefore, reduction of these might improve the outcome. Here, we investigated the effect of hydrogen gas (H2) (a strong free radical scavenger) on the survival rate of mice following global cerebral I/R. We further examined the histopathological outcome and also the brain water content (as a possible determinant of mortality). Male C57BL/6J mice were subjected to global cerebral I/R by means of 45-min bilateral common carotid artery occlusion (BCCAO). A total of 160 mice were divided into three groups: sham surgery (sham group), BCCAO without H2 (BCCAO group), and BCCAO treated with 1.3% H2 (BCCAO + H2 group). We observed that H2 treatment significantly (P = 0.0232) improved the 7-day survival rate of mice, from 8.3% (BCCAO group, n = 12) to 50% (BCCAO + H2 group, n = 10). Histopathological analysis revealed that H2 treatment significantly attenuated neuronal injury and autophagy in the hippocampal cornu ammonis 1 sector and also brain edema, after 24 h of reperfusion. The beneficial effects of H2 treatment on brain injury were associated with significantly lower levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde) in the brain tissue. Thus, we believe that H2 may be an effective treatment for global cerebral I/R.
Article
Low plasma ghrelin level was found to be associated with diabetes, and ghrelin was shown to inhibit pro-atherogenic changes in experimental models of atherosclerosis. The aim of this study was to investigate the relationship between plasma ghrelin levels and coronary atherosclerotic lesions in Chinese patients with diabetes. Plasma ghrelin levels were measured using an ELISA kit. The severity of coronary artery disease (CAD) was determined via angiography. Composition of atherosclerotic plaques was detected via coronary CT angiography. A total of 178 patients with diabetes were recruited. Among the patients, 70 were diagnosed with acute coronary syndrome (ACS), 82 with stable angina pectoris (SAP) and 26 without coronary angiographic finding (controls). A negative correlation was found between ghrelin levels and the severity of the CAD, as determined via the Gensini score (r=-0.2434; P=0.0217). In diabetic patients with CAD and a complex lesion, the plasma ghrelin levels were significantly lower than in those with a simple lesion (ACS group: 3.81 ± 0.49 ng/mL vs 4.72 ± 0.50 ng/mL, P<0.0001; SAP group: 4.21 ± 0.52 ng/mL vs 4.76 ± 0.59 ng/mL, P=0.0397). Angiographically-detected complex lesion was an independent factor associated with ghrelin levels (adjusted beta coefficient=-0.67, 95% CI -0.97 to -0.37, P<0.0001). Low plasma ghrelin level is closely related to angiographically-detected severity and the complex lesion morphology in Chinese diabetic patients with CAD.
Article
Hydrogen gas has been demonstrated to neutralize free radicals and reduce oxidative stress recently. Our objective was to determine the therapeutic effect of H2 inhalation and its antioxidative activity on early brain injury after subarachnoid hemorrhage. Controlled in vivo laboratory study. Animal research laboratory. One hundred thirty-seven adult male Sprague-Dawley rats weighing 280-350 g. Subarachnoid hemorrhage was induced by endovascular perforation method in rats. Subarachnoid hemorrhage rats were treated with 2.9% hydrogen gas inhaled for 2 hrs after perforation. At 24 and 72 hrs, mortality, body weight, neurologic deficits, and brain water content were assessed. Blood-brain barrier permeability and apoptosis were also measured at 24 hrs. To investigate the antioxidative activity of hydrogen gas, the expression of malondialdehyde, nitrotyrosine, and 8-hydroxyguanosine, which are oxidative markers of lipid, protein, and DNA damage, respectively, were measured at 24 hrs. Hydrogen gas significantly alleviated brain edema and blood-brain barrier disruption, reduced apoptosis, and improved neurologic function at 24 hrs but not 72 hrs after subarachnoid hemorrhage. These effects were associated with the amelioration of oxidative injury of lipid, protein, and DNA. Hydrogen gas could exert its neuroprotective effect against early brain injury after subarachnoid hemorrhage by its antioxidative activity.
Article
Arterialized vein grafts often fail due to intimal hyperplasia. Hydrogen potently protects organs and cells from many insults via its anti-inflammatory and antioxidant properties. We investigated the efficacy of oral administration of hydrogen-rich water (HW) for prevention of intimal hyperplasia. The inferior vena cava was excised, stored in cold Ringer solution for 2 h, and placed as an interposition graft in the abdominal aorta of syngeneic Lewis rats. HW was generated by immersing a magnesium stick in tap water (Mg + 2H(2)O → Mg (OH)(2) + H(2)). Beginning on the day of graft implantation, recipients were given tap water [regular water (RW)], HW or HW that had been subsequently degassed water (DW). Six weeks after grafting, the grafts in the rats given RW or DW had developed intimal hyperplasia, accompanied by increased oxidative injury. HW significantly suppressed intimal hyperplasia. One week after grafting, the grafts in HW-treated rats exhibited improved endothelial integrity with less platelet and white blood cell aggregation. Up-regulation of the mRNAs for intracellular adhesion molecules was attenuated in the vein grafts of the rats receiving HW. Activation of p38 mitogen-activated protein kinase, matrix metalloproteinase (MMP)-2, and MMP-9 was also significantly inhibited in grafts receiving HW. In rat smooth muscle cell (A7r5) cultures, hydrogen treatment for 24 h reduced smooth muscle cell migration. Drinking HW significantly reduced neointima formation after vein grafting in rats. Drinking HW may have therapeutic value as a novel therapy for intimal hyperplasia and could easily be incorporated into daily life.