Hydrogen-Rich Water Mitigates LPS-Induced Chronic Intestinal Inflammatory Response in Rats via Nrf-2 and NF-κB Signaling Pathways

Simple Summary Our study provides substantial evidence that hydrogen-rich water can prevent intestinal damage caused by LPS-induced stimulation. Intestinal injury caused by LPS is related to the NFκB signaling pathway. LPS promotes the generation of inflammatory factors and oxygen free radicals by activating the NFκB signaling pathway in intestinal cells, causing inflammation and oxidative stress and destroying the tight-junction state of the intestine, causing intestinal damage. Hydrogen-rich water can activate the Nrf-2 signaling pathway to remove excess oxygen free radicals and relieve oxidative stress. The Nrf-2 signaling pathway, an upstream signaling pathway of NFκB, can act as a protective mechanism against inflammation by regulating NFκB. In summary, hydrogen-rich water can inhibit oxidative stress and regulate NF by activating Nrf-2 signal pathway κB signal pathway, inhibit the production of inflammatory cytokines, maintain the tight connection in the intestine, and protect the intestine from damage caused by lipopolysaccharide. Our research contributes to further understanding of the mechanism of hydrogen-rich water, as well as its value for clinical application. Abstract Long-term exposure to low-dose lipopolysaccharide can impair intestinal barriers, causing intestinal inflammation and leading to systemic inflammation. Hydrogen-rich water possesses antioxidant and anti-inflammatory functions and exerts inhibitory effects on various inflammatory diseases. In this study, we investigated whether oral hydrogen-rich water could prevent lipopolysaccharide-induced chronic intestinal inflammation. An experimental model was established by feeding hydrogen-rich water, followed by the injection of lipopolysaccharide (200 μg/kg) in the tail vein of rats after seven months. ELISA, Western blot, immunohistochemistry, and other methods were used to detect related cytokines, proteins related to the NF-κB and Nrf-2 signaling pathways, and tight-junction proteins to study the anti-inflammatory and antioxidant effects of hydrogen-rich water. The obtained results show that hydrogen-rich water significantly increased the levels of superoxide dismutase and structural proteins; activated the Nrf-2 signaling pathway; downregulated the expression of inflammatory factors cyclooxygenase-2, myeloperoxidase, and ROS; and decreased the activation of the NF-κB signaling pathway. These results suggest that hydrogen-rich water could protect against chronic intestinal inflammation in rats caused by lipopolysaccharide-induced activation of the NF-κB signaling pathway by regulating the Nrf-2 signaling pathway.

[1]  Pingzhu Wang,et al.  Hydrogen Attenuated Inflammation Response and Oxidative in Hypoxic Ischemic Encephalopathy via Nrf2 Mediated the Inhibition of NLRP3 and NF-κB , 2021, Neuroscience.

[2]  Jian-tao Zhang,et al.  The Therapeutic Effects of Oral Intake of Hydrogen Rich Water on Cutaneous Wound Healing in Dogs , 2021, Veterinary sciences.

[3]  Weiling Jiang,et al.  Intermittent hypoxia aggravates non-alcoholic fatty liver disease via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway. , 2021, Life sciences.

[4]  Ping Yang,et al.  Targeted Inhibition of FTO Demethylase Protects Mice Against LPS-Induced Septic Shock by Suppressing NLRP3 Inflammasome , 2021, Frontiers in Immunology.

[5]  Fengqin Wang,et al.  Gut Immunity and Microbiota Dysbiosis Are Associated with Altered Bile Acid Metabolism in LPS-Challenged Piglets , 2021, Oxidative medicine and cellular longevity.

[6]  Guoyao Wu,et al.  Puerarin enhances intestinal function in piglets infected with porcine epidemic diarrhea virus , 2021, Scientific Reports.

[7]  T. Zeng,et al.  Targeting macrophage polarization by Nrf2 agonists for treating various xenobiotics-induced toxic responses , 2021, Toxicology mechanisms and methods.

[8]  Qifeng Deng,et al.  Salmonella Effector SpvB Disrupts Intestinal Epithelial Barrier Integrity for Bacterial Translocation , 2020, Frontiers in Cellular and Infection Microbiology.

[9]  K. Homma,et al.  Daily inhalation of hydrogen gas has a blood pressure-lowering effect in a rat model of hypertension , 2020, Scientific Reports.

[10]  S. Hashemi,et al.  Relationship Between Vitamin D Deficiency and Disease Activity in Patients with Inflammatory Bowel Disease in Ahvaz, Iran , 2020, Clinical and experimental gastroenterology.

[11]  Jing Zhang,et al.  Purified Sika deer antler protein attenuates GM-induced nephrotoxicity by activating Nrf2 pathway and inhibiting NF-κB pathway , 2020, Scientific Reports.

[12]  S. Madhunapantula,et al.  Strategies for Targeting SARS CoV-2: Small Molecule Inhibitors—The Current Status , 2020, Frontiers in Immunology.

[13]  Liyuan Liu,et al.  Capsaicin alleviates acetaminophen-induced acute liver injury in mice. , 2020, Clinical immunology.

[14]  X. Xia,et al.  Kaempferol from Penthorum chinense Pursh suppresses HMGB1/TLR4/NF-κB signaling and NLRP3 inflammasome activation in acetaminophen-induced hepatotoxicity. , 2020, Food & function.

[15]  Wenjin Guo,et al.  Niacin Alleviates Dairy Cow Mastitis by Regulating the GPR109A/AMPK/NRF2 Signaling Pathway , 2020, International journal of molecular sciences.

[16]  Yehao Liu,et al.  The Dysbiosis of Gut Microbiota Caused by Low-Dose Cadmium Aggravate the Injury of Mice Liver through Increasing Intestinal Permeability , 2020, Microorganisms.

[17]  P. Luo,et al.  The multifaceted role of CARD9 in inflammatory bowel disease , 2019, Journal of cellular and molecular medicine.

[18]  Y. Mine,et al.  Lactobacillus pentosus S-PT84 prevents LPS-induced low-grade chronic inflammation in a C57BL/6J mouse model , 2019, Journal of Functional Foods.

[19]  Xukun Deng,et al.  γ-Oryzanol alleviates acetaminophen-induced liver injury: roles of modulating AMPK/GSK3β/Nrf2 and NF-κB signaling pathways. , 2019, Food & function.

[20]  Zhiling Yu,et al.  Dietary Supplementation with Sea Bass (Lateolabrax maculatus) Ameliorates Ulcerative Colitis and Inflammation in Macrophages through Inhibiting Toll-Like Receptor 4-Linked Pathways , 2019, International journal of molecular sciences.

[21]  Ning Zhang,et al.  Activation of HO-1 protects placental cells function in oxidative stress via regulating ZO-1/occludin. , 2019, Biochemical and biophysical research communications.

[22]  X. Terra,et al.  Protective Effect of Proanthocyanidins in a Rat Model of Mild Intestinal Inflammation and Impaired Intestinal Permeability Induced by LPS , 2019, Molecular nutrition & food research.

[23]  G. Kollias,et al.  Genetic Restoration of Heme Oxygenase-1 Expression Protects from Type 1 Diabetes in NOD Mice , 2019, International journal of molecular sciences.

[24]  T. Hibi,et al.  Hydrogen-rich solution attenuates cold ischemia-reperfusion injury in rat liver transplantation , 2019, BMC Gastroenterology.

[25]  Chengbo Yang,et al.  Thymol Improves Barrier Function and Attenuates Inflammatory Responses in Porcine Intestinal Epithelial Cells during Lipopolysaccharide (LPS)-Induced Inflammation. , 2019, Journal of agricultural and food chemistry.

[26]  Ping Liu,et al.  Rhein ameliorates lipopolysaccharide‐induced intestinal barrier injury via modulation of Nrf2 and MAPKs , 2019, Life sciences.

[27]  Xiaoming Deng,et al.  Upregulation of Heme Oxygenase-1 by Hemin Alleviates Sepsis-Induced Muscle Wasting in Mice , 2018, Oxidative medicine and cellular longevity.

[28]  N. Sharif,et al.  Prostaglandin FP receptor antagonists: discovery, pharmacological characterization and therapeutic utility , 2018, British journal of pharmacology.

[29]  Man Li,et al.  Potential Medications or Compounds Acting on Toll-like Receptors in Cerebral Ischemia , 2018, Current neuropharmacology.

[30]  Saijun Fan,et al.  Hydrogen-water ameliorates radiation-induced gastrointestinal toxicity via MyD88’s effects on the gut microbiota , 2018, Experimental & Molecular Medicine.

[31]  H. Oh,et al.  Steppogenin Isolated from Cudrania tricuspidata Shows Antineuroinflammatory Effects via NF-κB and MAPK Pathways in LPS-Stimulated BV2 and Primary Rat Microglial Cells , 2017, Molecules.

[32]  Qifan Zhang,et al.  Advanced oxidation protein products induce S-phase arrest of hepatocytes via the ROS-dependent, β-catenin-CDK2-mediated pathway , 2017, Redox biology.

[33]  Y. Mine,et al.  Intervention of Dietary Dipeptide Gamma-l-Glutamyl-l-Valine (γ-EV) Ameliorates Inflammatory Response in a Mouse Model of LPS-Induced Sepsis. , 2017, Journal of agricultural and food chemistry.

[34]  Min Chen,et al.  Protective effects of hydrogen rich water on the intestinal ischemia/reperfusion injury due to intestinal intussusception in a rat model , 2017, Medical gas research.

[35]  H. Jaeschke,et al.  Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. , 2017, Journal of hepatology.

[36]  C. Piantadosi,et al.  Mitochondrial quality-control dysregulation in conditional HO-1-/- mice. , 2017, JCI insight.

[37]  Rohit Arora,et al.  Ameliorative potential of Alstonia scholaris (Linn.) R. Br. against chronic constriction injury-induced neuropathic pain in rats , 2017, BMC Complementary and Alternative Medicine.

[38]  Meng-Chen Lu,et al.  The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update , 2016, Medicinal research reviews.

[39]  A. Józkowicz,et al.  Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism , 2016, Cellular and Molecular Life Sciences.

[40]  A. MacLeod,et al.  The Innate Immune System in Acute and Chronic Wounds , 2016, Advances in wound care.

[41]  G. Nicolson,et al.  Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine , 2016 .

[42]  Baoxue Yang,et al.  Ganoderma lucidum polysaccharide peptide prevents renal ischemia reperfusion injury via counteracting oxidative stress , 2015, Scientific Reports.

[43]  J. Duan,et al.  Frankincense and myrrh suppress inflammation via regulation of the metabolic profiling and the MAPK signaling pathway , 2015, Scientific Reports.

[44]  C. Sanderson,et al.  Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways , 2015, Biochemical Society transactions.

[45]  M. Ichihara,et al.  Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents , 2015, Molecular and Cellular Biochemistry.

[46]  A. Mukherjee,et al.  Engineered Silybin Nanoparticles Educe Efficient Control in Experimental Diabetes , 2014, PloS one.

[47]  A. Cuadrado,et al.  Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation* , 2014, The Journal of Biological Chemistry.

[48]  G. E. Fernandez,et al.  Low Doses of Celecoxib Attenuate Gut Barrier Failure During Experimental Peritonitis , 2013, Laboratory Investigation.

[49]  E. Shimizu,et al.  Monocyte chemoattractant protein‐1 is a mediator of the anabolic action of parathyroid hormone on bone , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[50]  Ashutosh Kumar,et al.  Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy☆ , 2013, Redox biology.

[51]  Caihong Hu,et al.  Early weaning increases intestinal permeability, alters expression of cytokine and tight junction proteins, and activates mitogen-activated protein kinases in pigs. , 2013, Journal of animal science.

[52]  S. Mandrup,et al.  Surfactant Protein D Deficiency in Mice Is Associated with Hyperphagia, Altered Fat Deposition, Insulin Resistance, and Increased Basal Endotoxemia , 2012, PloS one.

[53]  Jun-ji Ma,et al.  Curcumin Ameliorates Hydrogen Peroxide-Induced Epithelial Barrier Disruption by Upregulating Heme Oxygenase-1 Expression in Human Intestinal Epithelial Cells , 2012, Digestive Diseases and Sciences.

[54]  Fang Liu,et al.  Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. , 2011, Cellular signalling.

[55]  C. Ahn,et al.  Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. , 2010, Cellular signalling.

[56]  X. Xu,et al.  Hydrogen-rich saline ameliorates the severity of l-arginine-induced acute pancreatitis in rats. , 2010, Biochemical and biophysical research communications.

[57]  Yuming Guo,et al.  Supplemental zinc reduced intestinal permeability by enhancing occludin and zonula occludens protein-1 (ZO-1) expression in weaning piglets , 2009, British Journal of Nutrition.

[58]  A J Bauer,et al.  Hydrogen Inhalation Ameliorates Oxidative Stress in Transplantation Induced Intestinal Graft Injury , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[59]  E. Severson,et al.  JAM-A regulates permeability and inflammation in the intestine in vivo , 2007, The Journal of experimental medicine.

[60]  B. Chandran,et al.  Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells. , 2007, Cellular signalling.

[61]  W. Koltun,et al.  Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. , 2007, The Journal of surgical research.

[62]  Yasuo Katayama,et al.  Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals , 2007, Nature Medicine.

[63]  Si-hai Zhu,et al.  Protective roles of hydroxyethyl starch 130/0.4 in intestinal inflammatory response and survival in rats challenged with polymicrobial sepsis. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[64]  V. Nizet,et al.  Innate Immunity Gone Awry: Linking Microbial Infections to Chronic Inflammation and Cancer , 2006, Cell.

[65]  C. B. Pickett,et al.  Nrf2 Controls Constitutive and Inducible Expression of ARE-driven Genes through a Dynamic Pathway Involving Nucleocytoplasmic Shuttling by Keap1* , 2005, Journal of Biological Chemistry.

[66]  K. Wellen,et al.  Inflammation, stress, and diabetes. , 2005, The Journal of clinical investigation.

[67]  Jie Tian,et al.  The Effects of Hydroxyethyl Starch on Lung Capillary Permeability in Endotoxic Rats and Possible Mechanisms , 2004, Anesthesia and analgesia.

[68]  Shoichiro Tsukita,et al.  Multifunctional strands in tight junctions , 2001, Nature Reviews Molecular Cell Biology.

[69]  Y. Qing.  Toll-like Receptor 4 Mediates Lipopolysaccharide-induced Cell Activation in Human Endothelial Cells , 2002 .

[70]  N. Perkins.  The Rel/NF-kappa B family: friend and foe. , 2000, Trends in biochemical sciences.

[71]  R. Blumberg,et al.  First line of defense: the role of the intestinal epithelium as an active component of the mucosal immune system , 2000, Journal of Gastroenterology.