Suppressive Effect of Tetrahydrocurcumin on Pseudomonas aeruginosa Lipopolysaccharide-Induced Inflammation by Suppressing JAK/STAT and Nrf2/HO-1 Pathways in Microglial Cells

Brain inflammation, a pathological feature of neurodegenerative disorders, exhibits elevated microglial activity and increased levels of inflammatory factors. The present study was aimed at assessing the anti-inflammatory response of tetrahydrocurcumin (THC), the primary hydrogenated metabolite of curcumin, which was applied to treat Pseudomonas aeruginosa (P.a.) lipopolysaccharide- (LPS-) stimulated BV2 microglial cells. THC reduced P.a. LPS–induced mortality and the production of inflammatory mediators IL-6, TNF-α, MIP-2, IP-10, and nitrite. A further investigation revealed that THC decreased these inflammatory cytokines synergistically with JAK/STAT signaling inhibitors. THC also increased Nrf2/HO-1 signaling transduction which inhibits iNOS/COX-2/pNFκB cascades. Additionally, the presence of the HO-1 inhibitor Snpp increased the levels of IP-10, IL-6, and nitrite while THC treatment reduced those inflammatory factors in P.a. LPS–stimulated BV2 cells. In summary, we demonstrated that THC exhibits anti-inflammatory activities in P.a. LPS-induced inflammation in brain microglial cells by inhibiting STAT1/3-dependent NF-κB activation and inducing Nrf2-mediated HO-1 expression.

[1]  Seungmin Lee,et al.  Trichosanthis Semen Suppresses Lipopolysaccharide-Induced Neuroinflammation by Regulating the NF-κB Signaling Pathway and HO-1 Expression in Microglia , 2021, Toxins.

[2]  F. Geng,et al.  Tetrahydrocurcumin ameliorates Alzheimer's pathological phenotypes by inhibition of microglial cell cycle arrest and apoptosis via Ras/ERK signaling. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[3]  Yingchun Su,et al.  Camptothecin Regulates Microglia Polarization and Exerts Neuroprotective Effects via Activating AKT/Nrf2/HO-1 and Inhibiting NF-κB Pathways In Vivo and In Vitro , 2021, Frontiers in Immunology.

[4]  Meryem Temiz-Reşitoğlu,et al.  Suppression of TLR4/MyD88/TAK1/NF-κB/COX-2 Signaling Pathway in the Central Nervous System by Bexarotene, a Selective RXR Agonist, Prevents Hyperalgesia in the Lipopolysaccharide-Induced Pain Mouse Model , 2021, Neurochemical Research.

[5]  Guoping Lin,et al.  Comparation of Anti-Inflammatory and Antioxidantactivities of Curcumin, Tetrahydrocurcuminand Octahydrocurcuminin LPS-Stimulated RAW264.7 Macrophages , 2020, Evidence-based complementary and alternative medicine : eCAM.

[6]  E. Kavanagh,et al.  Microglia: Agents of the CNS Pro-Inflammatory Response , 2020, Cells.

[7]  A. Ramírez,et al.  Neuroimmune Connections in Aging and Neurodegenerative Diseases. , 2020, Trends in immunology.

[8]  H. Hoe,et al.  Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling , 2019, Journal of Neuroinflammation.

[9]  M. Leboyer,et al.  Immunoneuropsychiatry — novel perspectives on brain disorders , 2019, Nature Reviews Neurology.

[10]  Samreen Soomro.  Oxidative Stress and Inflammation , 2019, Open Journal of Immunology.

[11]  T. Deierborg,et al.  Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response , 2018, Front. Cell. Neurosci..

[12]  H. Ren,et al.  P7C3 Inhibits LPS-Induced Microglial Activation to Protect Dopaminergic Neurons Against Inflammatory Factor-Induced Cell Death in vitro and in vivo , 2018, Front. Cell. Neurosci..

[13]  Jianhui Xie,et al.  Curcumin’s Metabolites, Tetrahydrocurcumin and Octahydrocurcumin, Possess Superior Anti-inflammatory Effects in vivo Through Suppression of TAK1-NF-κB Pathway , 2018, Front. Pharmacol..

[14]  Ying Xie,et al.  Activation of Nrf2/HO-1 Pathway by Nardochinoid C Inhibits Inflammation and Oxidative Stress in Lipopolysaccharide-Stimulated Macrophages , 2018, Front. Pharmacol..

[15]  Qing Zhang,et al.  Aloin suppresses lipopolysaccharide-induced inflammation by inhibiting JAK1-STAT1/3 activation and ROS production in RAW264.7 cells , 2018, International journal of molecular medicine.

[16]  S. Amor,et al.  Inflammation in CNS neurodegenerative diseases , 2018, Immunology.

[17]  D. Kalman,et al.  Curcumin: A Review of Its’ Effects on Human Health , 2017, Foods.

[18]  L. Luo,et al.  Bergapten prevents lipopolysaccharide‐induced inflammation in RAW264.7 cells through suppressing JAK/STAT activation and ROS production and increases the survival rate of mice after LPS challenge , 2017, International immunopharmacology.

[19]  S. Salim,et al.  Oxidative Stress and the Central Nervous System , 2017, The Journal of Pharmacology and Experimental Therapeutics.

[20]  Y. Panahi,et al.  Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[21]  Shih-Yin Chen,et al.  Luteolin inhibits viral-induced inflammatory response in RAW264.7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1. , 2016, Free radical biology & medicine.

[22]  M. Kim,et al.  Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/NFκB signaling pathway , 2016, Scientific Reports.

[23]  B. Aggarwal,et al.  Curcumin Differs from Tetrahydrocurcumin for Molecular Targets, Signaling Pathways and Cellular Responses , 2014, Molecules.

[24]  GuoLin Wang,et al.  Heme oxygenase-1 mediates the anti-inflammatory effect of molecular hydrogen in LPS-stimulated RAW 264.7 macrophages. , 2013, International journal of surgery.

[25]  M. Berk,et al.  A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[26]  P. Seth,et al.  Tetrahydrocurcumin confers protection against amyloid &bgr;-induced toxicity , 2011, Neuroreport.

[27]  Serge Eifes,et al.  Curcumin―The Paradigm of a Multi-Target Natural Compound with Applications in Cancer Prevention and Treatment , 2010, Toxins.

[28]  M. Hüll,et al.  Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia , 2010, Journal of Neuroinflammation.

[29]  B. Aggarwal,et al.  Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. , 2009, The international journal of biochemistry & cell biology.

[30]  B. Aggarwal,et al.  Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. , 2007, Carcinogenesis.

[31]  M. Hüll,et al.  Signal transduction pathways regulating cyclooxygenase‐2 in lipopolysaccharide‐activated primary rat microglia , 2005, Glia.

[32]  S. Toyokuni,et al.  Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. , 2001, The Journal of nutrition.