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Chronic ultraviolet (UV) exposure-induced oxidative stress is associated with the pathogenesis of skin damage. However, the nuclear factor erythroid‑2‑related factor 2 (Nrf2) pathway is a critical factor in protecting cells against UVB‑induced injury through inhibiting oxidative stress. Furthermore, Nrf2 activation requires the involvement of the phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) pathway, which has a major role in survival of various cell types. Molecular hydrogen exerts protective effects on UV‑induced injury, but the underlying mechanisms have remained elusive. The present study assessed the protective effects of hydrogen against oxidative stress‑induced injury caused by UVB irradiation and investigated the molecular mechanisms. In vitro, UVB‑induced HaCaT cells were collected for the detection of reactive oxygen species, 8‑iso‑prostaglandin F2α, malondialdehyde via fluorescence spectrometry and ELISA; cell activity and cytotoxicity by MTT and lactate dehydrogenase assays, respectively. Additionally, the expression level of PI3K, Akt, Nrf2 and heme oxygenase‑1 (HO‑1) were investigated using western blot, etc. All of the results indicated that hydrogen decreased the levels of reactive oxygen species, 8‑iso‑prostaglandin F2α and malondialdehyde, and promoted the UVB exposure‑induced expression of PI3K, Akt, Nrf2 and heme oxygenase‑1 in HaCaT cells. Of note, PI3K inhibition partially reversed the effects of hydrogen on UVB‑induced HaCaT cells. Therefore, hydrogen effectively protects cells from UVB radiation‑induced oxidative stress by inhibiting Nrf2/HO‑1 activation through the PI3K/Akt signaling pathway.

Hydrogen gas (H(2)) as a new medical gas exerts organ-protective effects through regulating oxidative stress, inflammation and apoptosis. In contrast to H(2), hydrogen-rich saline (HS) may be more suitable for clinical application. The present study was designed to investigate whether HS can offer a neuroprotective effect in a rat model of permanent focal cerebral ischemia and what mechanism(s) underlies the effect. Sprague-Dawley rats were subjected to permanent focal cerebral ischemia induced by permanent middle cerebral artery occlusion (pMCAO). Different doses of HS or normal saline were intraperitoneally administered at 5min after pMCAO or sham operation followed by injections at 6h, 12h and 24h. Here, we found that HS treatment significantly reduced infarct volume and improved neurobehavioral outcomes at 24h, 48h and 72h after pMCAO operation in a dose-dependent manner (P<0.05). Moreover, we found that HS treatment dose-dependently increased the activities of endogenous antioxidant enzymes (SOD and CAT) as well as decreased the levels of oxidative products (8-iso-PGF2α and MDA) and inflammatory cytokines (TNF-α and HMGB1) in injured ipsilateral brain tissues at 6h, 12h and 24h after pMCAO operation (P<0.05). Thus, hydrogen-rich saline dose-dependently exerts a neuroprotective effect against permanent focal cerebral ischemia, and its beneficial effect is at least partially mediated by reducing oxidative stress and inflammation. Molecular hydrogen may be an effective therapeutic strategy for stroke patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Hydrogen gas (H(2)) has been considered as a novel antioxidant to selectively reduce the toxic reactive oxygen species (ROS) such as hydroxyl radical (•OH) without affecting the other signal ROS. Our recent study shows that H(2) inhalation is beneficial to traumatic brain injury (TBI) via reducing oxidative stress. In contrast to H(2), hydrogen-rich saline (HS) may be more suitable for clinical application. The present study was designed to investigate whether HS has a protective effect against TBI via reducing oxidative stress in rats., Methods: TBI model was induced by controlled cortical impact injury. Different dosages of HS were intraperitoneally administered at 5 min after TBI operation. We then measured the brain edema, blood-brain barrier (BBB) breakdown, neurological dysfunction and injury volume in all animals. In addition, the oxidative products and antioxidant enzymes in brain tissues were detected., Results: TBI-challenged rats exhibited significant brain injuries characterized by the increase of BBB permeability, brain edema, and lesion volume as well as neurological dysfunction, which were dose-dependently ameliorated by HS treatment. Moreover, we found that HS treatment increased the endogenous antioxidant enzymatic activities and decreased the oxidative product levels in brain tissues of TBI-challenged rats., Conclusion: Hydrogen-rich saline can exert a protective effect against TBI via reducing oxidative stress. Molecular hydrogen may be a more effective therapeutic strategy for TBI patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Recently, hydrogen gas (H₂) is reported to be a new therapeutic agent in organ damage induced by ischemia-reperfusion (I/R). The present study was designed to investigate the beneficial effects of H₂ against spinal cord I/R injury and its associated mechanisms. Spinal cord ischemia was induced by infrarenal aortic occlusion for 20 min in male New Zealand white rabbits. Treatment with 1%, 2% or 4% H₂ inhalation was given from 10 min before reperfusion to 60 min after reperfusion (total 70 min). Here, we found that I/R-challenged animals showed significant spinal cord damage characterized by the decreased numbers of normal motor neurons and hind-limb motor dysfunction, which was significantly improved by 2% and 4 % H₂ treatment. Furthermore, we found that the beneficial effects of H₂ treatment against spinal cord I/R injury were associated with the decreased levels of oxidative products [8-iso-prostaglandin F2α (8-iso-PGF2α) and malondialdehyde (MDA)] and pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1)], as well as increased activities of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] in serum and spinal cord. In addition, H₂ treatment reduced motor neuron apoptosis in the spinal cord of this model. Thus, H₂ inhalation may be an effective therapeutic strategy for spinal cord I/R damage., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is a leading cause of mortality and disability among the young population. It has been shown that hydrogen gas (H(2)) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical (OH, the most cytotoxic ROS). Recently, we have found that H(2) inhalation significantly improved the survival rate and organ damage of septic mice. In the present study, we investigated the effectiveness of H(2) therapy on brain edema, blood-brain barrier (BBB) breakdown, neurological dysfunction and injury volume in TBI-challenged rats. In addition, we investigated the effects of H(2) treatment on the changes of oxidative products and antioxidant enzymes in brain tissue of TBI-challenged rats. Hydrogen treatment was given by exposure to 2% H(2) from 5 min to 5h after sham or TBI operation, respectively. Here, we found that TBI-challenged rats showed significant brain injuries characterized by the increase of BBB permeability, brain edema and lesion volume as well as neurological dysfunction, which was significantly attenuated by 2% H(2) treatment. In addition, we found that the decrease of oxidative products and the increase of endogenous antioxidant enzymatic activities in the brain tissue may be associated with the protective effects of H(2) treatment in TBI-challenged rats. The present study supports that H(2) inhalation may be a more effective therapeutic strategy for patients with TBI., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Despite recent advances in antibiotic therapy and intensive care, sepsis is still considered to be the most common cause of death in intensive care units. Excessive production of reactive oxygen species plays an important role in the pathogenesis of sepsis. Recently, it has been suggested that molecular hydrogen (H2) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radicals (*OH, the most cytotoxic reactive oxygen species) and effectively protects against organ damage induced by I/R. Therefore, we hypothesized that H2 treatment had a beneficial effect on sepsis. In the present study, we found that H2 inhalation starting at 1 and 6 h after cecal ligation and puncture (CLP) or sham operation significantly improved the survival rate of septic mice with moderate or severe CLP in a concentration- and time-dependent manner. Furthermore, moderate or severe CLP mice showed significant multiple organ damage characterized by the increases of lung myeloperoxidase activity, wet-to-dry weight ratio, protein concentration in bronchoalveolar lavage, serum biochemical parameters, and organ histopathologic scores at 24 h after CLP operation, which was significantly attenuated by 2% H2 treatment. In addition, we found that the beneficial effects of H2 treatment on sepsis and sepsis-associated organ damage were associated with the decreased levels of oxidative product, increased activities of antioxidant enzymes, and reduced levels of high-mobility group box 1 in serum and tissue. Thus, H2 inhalation may be an effective therapeutic strategy for patients with sepsis.

Objective: Sepsis-associated encephalopathy (SAE) is a major cause of mortality worldwide. Oxidative stress, inflammatory response and apoptosis participate in the pathogenesis of SAE. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) pathway is involved in oxidative stress and inflammatory response. We reported that hydrogen gas protected against sepsis in wild-type (WT) but not Nrf2 knockout (KO) mice. Therefore, it is vital to identify the underlying cause of hydrogen gas treatment of sepsis-associated encephalopathy. Methods: SAE was induced in WT and Nrf2 KO mice by cecal ligation and puncture (CLP). As a NLRP3 inflammasome inhibitor, MCC950 (50 mg/kg) was administered by intraperitoneal (i.p.) injection before operation. Hydrogen gas (H2)-rich saline solution (5 mL/kg) was administered by i.p. injection at 1 h and 6 h after sham and CLP operations. Brain tissue was collected to assess the NLRP3 and Nrf2 pathways by western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. Results: SAE increased NLRP3 and Nrf2 expression in microglia. MCC950 inhibited SAE-induced NLRP3 expression, interleukin (IL)-1β and IL-18 cytokine release, neuronal apoptosis and mitochondrial dysfunction. SAE increased NLRP3 and caspase-1 expression in WT mice compared to Nrf2 KO mice. Hydrogen increased Nrf2 expression and inhibited the SAE-induced expression of NLRP3, caspase-1, cytokines IL-1β and IL-18, neuronal apoptosis, and mitochondrial dysfunction in WT mice but not Nrf2 KO mice. Conclusion: SAE increased NLRP3 and Nrf2 expression in microglia. Hydrogen alleviated inflammation, neuronal apoptosis and mitochondrial dysfunction via inhibiting Nrf2-mediated NLRP3 pathway. [ABSTRACT FROM AUTHOR]

It has previously been demonstrated that hyperglycemia-induced oxidative stress and inflammation are closely associated with the development of diabetic complications, including diabetic neuropathy. Additionally, mitochondrial ATP-sensitive potassium (Mito-K-ATP) channels play a homeostatic role on blood glucose regulation in organisms. Molecular hydrogen (H2) exhibits anti-inflammatory, anti-antioxidative and anti-apoptotic properties and can be used to treat more than 71 diseases safely. In addition, the diabetes animal models which are set up using streptozotocin (STZ) injection, is a type of high long-term stability, low animal mortality rate and security method. The aim of the current study was to assess the value of hydrogen-rich saline (HS) in diabetic peripheral neuropathy (DPN) treatment and to determine its associated mechanisms in STZ-induced diabetic experimental rats. Additionally, the effects of the Mito-K-ATP channels, oxidative stress, inflammatory cytokines and apoptosis on DPN were also evaluated. From week 5 of STZ injections, HS (2.5, 5 and 10 ml/kg) was injected into the rat abdominal cavity every day for a period of 4 weeks. The results of the current study demonstrated that HS significantly reduced behavioral, biochemical and molecular effects caused by DPN. However, 5-hydroxydecanoate, a selective Mito-K-ATP channels general pathway inhibitor, partially eliminated the therapeutic effect of HS on DPN. These results indicated that the use of HS may be a novel strategy to treat DPN by activating the Mito-K-ATP pathway and reducing oxidative stress, inflammatory cytokines and apoptosis. [ABSTRACT FROM AUTHOR]

In this study, we demonstrated the effects of a high-fiber diet on intestinal lesions, oxidative stress and systemic inflammation in a murine model of endotoxemia. C57BL/6 mice were randomly assigned to four groups: the control group (CONTROL), which received a commercial normal-fiber rodent diet comprising normal fiber; a CLP group, which received a commercial normal-fiber rodent diet and underwent caecal ligation puncture (CLP); a high-fiber group (HFG), which received a commercial high-fiber rodent diet; and a high fiber + CLP group (HFCLP) which received a commercial high-fiber rodent diet and underwent CLP (30%). The sepsis model was created via CLP after 2 weeks of dietary intervention. Notably, dietary high-fiber supplementation in HFCLP group improved survival rates and reduced bacterial loads, compared with CLP alone. In the HFCLP group, dietary fiber supplementation decreased the serum concentrations of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and high-mobility group protein 1 (HMG-1) but raised the concentration of interleukin 10 (IL-10), compared with the levels in CLP mice. Meanwhile, high-fiber supplementation increased the relative proportions of Akkermansia and Lachnospiraceae. These data show that dietary high-fiber supplementation may be therapeutic for sepsis-induced lesions. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) is characterized by persistent pain, tactile allodynia, or hyperalgesia. Peripheral nerve injury contributes to rapid progress of inflammatory response and simultaneously generates neuropathic pain. Hydrogen (H) has anti-inflammation, anti-apoptosis, and anti-oxidative stress effects. Therefore, we hypothesized that H treatment could alleviate allodynic and hyperalgesic behaviors and the release of inflammatory factors in rats with neuropathic pain. Peripheral neuropathic pain was established by chronic constriction injury of sciatic nerve in rats. H was given twice through intraperitoneal injection at a daily dose of 10 mL/kg during days 1-7 after the operation. Hyperalgesia and allodynia were tested, pro-inflammatory factors of dorsal root ganglia (DRG) and the spinal cord were measured by enzyme-linked immunosorbent assay (ELISA) during days 1-14 after the operation, and heme oxygenase (HO)-1 messenger RNA (mRNA) and protein expression and activities were measured at day 14 after sciatic nerve injury in rats. After Sn (IV) protoporphyrin IX dihydrochloride (SnPP)-IX, hemin, and carbon monoxide-releasing molecule (CORM)-2 had been given for chronic constriction injury (CCI) in rats, the above indicators were assessed. We found that H clearly inhibited hyperalgesia and allodynia in neuropathic pain and also attenuated the pro-inflammatory cytokines TNF- α, IL-1β, and high-mobility group box (HMGB) 1. H improved HO-1 mRNA and protein expression and activities in the process of pain. SnPP-IX reversed the inhibitory effect of H on hyperalgesia and allodynia and on pro-inflammatory cytokines in DRG and the spinal cord. The antinociceptive and anti-inflammatory effects of H were involved in the activation of HO-1/CO signaling during neuropathic pain in rats. [ABSTRACT FROM AUTHOR]

During the development of sepsis, the complication in central nervous system (CNS), appearing early and frequently relative to other systems, can obviously increase the mortality of sepsis. Moreover, sepsis survivors also accompany long-term cognitive dysfunction, while the ultimate causes and effective therapeutic strategies of brain injury in sepsis are still not fully clear. We designed this study to investigate the effects of 2% hydrogen gas (H 2 ) on brain injury in a mouse model of sepsis. Male ICR mice were underwent cecal ligation and puncture (CLP) or sham operation. 2% H 2 was inhaled for 60 min beginning at both 1 and 6 h after sham or CLP operation, respectively. H 2 concentration in arterial blood, venous blood and brain tissue was detected after H 2 inhalation separately. The survival rate was observed and recorded within 7 days after sham or CLP operation. The histopathologic changes and neuronal apoptosis were observed in hippocampus by Nissl staining and TUNEL assay. The permeability of brain–blood barrier (BBB), brain water content, inflammatory cytokines, activities of antioxidant enzymes (SOD and CAT) and oxidative products (MDA and 8-iso-PGF2α) in serum and hippocampus were detected at 24 h after sham or CLP operation. The expressions of nucleus and total nuclear factor erythroid 2-related factor 2 (Nrf2) and cytoplasmic heme oxygenase-1(HO-1) in hippocampus were measured at 24 h after sham or CLP operation. We assessed their cognitive function via Y-maze and Fear Conditioning test on day 3, 5, 7 and 14 after operation. H 2 treatment markedly improved the survival rate and cognitive dysfunction of septic mice. CLP mice showed obvious brain injury characterized by aggravated pathological damage, BBB disruption and brain edema at 24 h after CLP operation, which was markedly alleviated by 2% H 2 treatment. Furthermore, we found that the beneficial effects of H 2 on brain injury in septic mice were linked to the decreased levels of inflammatory cytokines and oxidative products and the increased activities of antioxidant enzymes in serum and hippocampus. In addition, 2% H 2 inhalation promoted the expression and transposition of Nrf2 and the expression of HO-1 to mitigate brain injury in sepsis. Thus, the inhalation of hydrogen gas may be a promising therapeutic strategy to relieve brain injury in sepsis. [ABSTRACT FROM AUTHOR]

Abstract: Hydrogen-rich saline (HS) is reported to be a new therapeutic agent in ischemia-reperfusion (I/R)-induced organ damage. The present study was designed to investigate the beneficial effects of HS against spinal cord I/R injury and its associated mechanisms. Spinal cord ischemia was induced by infrarenal aortic occlusion for 20min in male New Zealand white rabbits. Different doses of HS were intravenously (i.v.) administered at 5min before or after the beginning of reperfusion. Moreover, the roles of mitochondrial ATP-sensitive potassium channels (mitoKATP), oxidative stress, inflammatory cytokines and apoptosis was assessed. Here, we found that I/R-challenged rabbits exhibited significant spinal cord injury characterized by the decreased numbers of normal motor neurons and hind-limb motor dysfunction, which was significantly ameliorated by 5mL/kg and 10mL/kg HS treatment before reperfusion or 10mL/kg HS treatment after reperfusion. However, the protective effects of HS treatment in spinal cord I/R injury were partially abolished by the selective mitoKATP channel blocker 5-hydroxydecanoate (5-HD). Moreover, we showed that the beneficial effects of 10mL/kg HS treatment against spinal cord I/R damage were associated with the decreased levels of oxidative products [8-iso-prostaglandin F2α (8-iso-PGF2α) and malondialdehyde (MDA)] and pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1)], as well as the increased activities of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] in serum at 6h, 12h, 24h, 48h and 72h after reperfusion and in spinal cord at 72h after reperfusion. Furthermore, HS treatment (10mL/kg) reduced caspase-3 activity in the spinal cord of this model. Thus, HS may be an effective therapeutic agent for spinal cord I/R injury via activation of mitoKATP channels as well as reduction of oxidative stress, inflammatory cytokines and apoptosis. [Copyright &y& Elsevier]

Abstract: Objective: Cisplatin, an anticancer drug used extensively to treat a broad range of tumors, has strong ototoxic side effects induced by reactive oxygen species (ROS). Recently, it has been reported that hydrogen gas (H2) is a new antioxidant by selectively reducing hydroxyl radical, the most cytotoxic ROS. The present study was designed to investigate whether H2 treatment is beneficial to cisplatin-induced ototoxicity via reducing oxidative stress. Methods: The animals were intraperitoneally given a 30min infusion of 16mg/kg cisplatin or the same volume of saline. H2 treatment was given twice with 2% H2 inhalation for 60min starting at 1h and 6h after cisplatin or saline injection, respectively. The hearing status of all animals was evaluated by auditory brainstem responses (ABR). The hair cell damage was observed by phalloidin staining. In addition, the levels of oxidative products in serum and cochlear tissue were measured. Results: We found that H2 treatment significantly attenuated cisplatin-induced hearing loss evaluated by click-evoked and tone burst ABR threshold. Furthermore, histological analysis revealed that 2% H2 treatment significantly alleviated cisplatin-induced hair cell damage in the organ of corti. In addition, cisplatin significantly increased the levels of malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α) in serum and cochlear tissue, which was attenuated by H2 treatment. Conclusion: These results demonstrate that H2 is beneficial to cisplatin-induced ototoxicity via reducing oxidative stress. Therefore, H2 has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the cisplatin ototoxicity. [Copyright &y& Elsevier]