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Bruce D Hammock - One of the best experts on this subject based on the ideXlab platform.
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an epoxide Hydrolase Inhibitor reduces neuroinflammation in a mouse model of alzheimer s disease
Science Translational Medicine, 2020Co-Authors: Anamitra Ghosh, Bruce D Hammock, Debin Wan, Sung Hee Hwang, Michele M Comerota, Fading Chen, Nicholas E Propson, Hui ZhengAbstract:Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer's disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited because of their rapid hydrolysis by the soluble epoxide Hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and is elevated in postmortem brain tissue from patients with AD and in the 5xFAD β amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small-molecule sEH Inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected wild-type mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement of this small molecule. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.
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lack of rewarding effects of a soluble epoxide Hydrolase Inhibitor tppu in mice comparison with morphine
Neuropsychopharmacology Reports, 2020Co-Authors: Xiayun Wan, Bruce D Hammock, Yuko Fujita, Lijia Chang, Yan Wei, Gerile Wuyun, Kenji HashimotoAbstract:Aim Although opioids have been used as treatment of neuropathic pain, opioids have abuse potential in humans. Since soluble epoxide Hydrolase (sEH) in the metabolism of polyunsaturated fatty acids plays a key role in the pain, sEH Inhibitors would be promising new therapeutic drugs for neuropathic pain. In this study, we examined the effect of the sEH Inhibitor TPPU on rewarding effects in mice using the conditioned place preference (CPP) paradigm. Methods The rewarding effects of morphine (10 mg/kg) and TPPU (3, 10, or 30 mg/kg) in mice were examined using CPP paradigm. Furthermore, the effect of TPPU (30 mg/kg) on morphine-induced rewarding effects was examined. Results TPPU (3, 10, or 30 mg/kg) did not increase CPP scores in the mice whereas morphine significantly increased CPP scores in the mice. Furthermore, pretreatment with TPPU did not block the rewarding effects of morphine in the mice, suggesting that sEH does not play a role in the rewarding effect of morphine. Conclusion This study suggests that TPPU did not have rewarding effects in rodents. This would make sEH Inhibitors potential therapeutic drugs without abuse potential for neuropathic pain.
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epoxy fatty acid dysregulation and neuroinflammation in alzheimer s disease is resolved by a soluble epoxide Hydrolase Inhibitor
bioRxiv, 2020Co-Authors: Anamitra Ghosh, Bruce D Hammock, Debin Wan, Sung Hee Hwang, Michele M Comerota, Fading Chen, Nicholas E Propson, Hui ZhengAbstract:Abstract Neuroinflammation has been increasingly recognized to play critical roles in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide Hydrolase (sEH). We found that sEH is predominantly expressed in astrocytes where its levels are significantly elevated in postmortem human AD brains and in β-amyloid mouse models, and the latter is correlated with drastic reductions of brain EpFA levels. Using a highly potent and specific small molecule sEH Inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report here that TPPU treatment potently protected against LPS-induced inflammation in vitro and in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation, and this is associated with reduced β–amyloid pathology and improved synaptic integrity and cognitive function. Importantly, TPPU treatment reinstated and positively correlated EpFA levels in the 5xFAD mouse brain, demonstrating its brain penetration and target engagement. These findings support TPPU as a novel therapeutic target for the treatment of AD and related disorders. One Sentence Summary We show that soluble epoxide Hydrolase is upregulated in AD patients and mouse models, and that inhibition of this lipid metabolic pathway using an orally bioavailable small molecule Inhibitor is effective in restoring brain epoxy fatty acids, ameliorating AD neuropathology and improving synaptic and cognitive function.
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soluble epoxide Hydrolase Inhibitor tppu increases regulatory t cells pathway in an arthritis model
The FASEB Journal, 2020Co-Authors: Carlos Antonio Trindadedasilva, Christophe Morisseau, Bruce D Hammock, Henrique Ballassini Abdalla, Juliana Trindade Clementenapimoga, Sergio Marcolino Rosa, Carlos Ueiravieira, Waldiceu A Verri, Victor Angelo Martins Montalli, Marcelo Henrique NapimogaAbstract:Epoxyeicosatrienoic acids (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds, which are converted by the soluble epoxide Hydrolase (sEH) to dihydroxylethersatrienoic acids (DHETs) with lessened biological effects. Inhibition of sEH is used as a strategy to increase EET levels leading to lower inflammation. Rheumatoid arthritis is a chronic autoimmune disease that leads to destruction of joint tissues. This pathogenesis involves a complex interplay between the immune system, and environmental factors. Here, we investigate the effects of inhibiting sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) on a collagen-induced arthritis model. The treatment with TPPU ameliorates hyperalgesia, edema, and decreases the expression of important pro-inflammatory cytokines of Th1 and Th17 profiles, while increasing Treg cells. Considering the challenges to control RA, this study provides robust data supporting that inhibition of the sEH is a promising target to treat arthritis.
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soluble epoxide Hydrolase Inhibitor mediated analgesia lacks tolerance in rat models
Brain Research, 2020Co-Authors: Karen Wagner, Jogen Atone, Bruce D HammockAbstract:Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble epoxide Hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety of sEH inhibition in addition to this demonstrated efficacy is a critical step to the further development of sEH Inhibitors (sEHI) as analgesics. Here we describe a comparison of the sEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. The sEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.
Christophe Morisseau - One of the best experts on this subject based on the ideXlab platform.
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soluble epoxide Hydrolase Inhibitor tppu increases regulatory t cells pathway in an arthritis model
The FASEB Journal, 2020Co-Authors: Carlos Antonio Trindadedasilva, Christophe Morisseau, Bruce D Hammock, Henrique Ballassini Abdalla, Juliana Trindade Clementenapimoga, Sergio Marcolino Rosa, Carlos Ueiravieira, Waldiceu A Verri, Victor Angelo Martins Montalli, Marcelo Henrique NapimogaAbstract:Epoxyeicosatrienoic acids (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds, which are converted by the soluble epoxide Hydrolase (sEH) to dihydroxylethersatrienoic acids (DHETs) with lessened biological effects. Inhibition of sEH is used as a strategy to increase EET levels leading to lower inflammation. Rheumatoid arthritis is a chronic autoimmune disease that leads to destruction of joint tissues. This pathogenesis involves a complex interplay between the immune system, and environmental factors. Here, we investigate the effects of inhibiting sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) on a collagen-induced arthritis model. The treatment with TPPU ameliorates hyperalgesia, edema, and decreases the expression of important pro-inflammatory cytokines of Th1 and Th17 profiles, while increasing Treg cells. Considering the challenges to control RA, this study provides robust data supporting that inhibition of the sEH is a promising target to treat arthritis.
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Impact of the acute local inhibition of soluble epoxide Hydrolase on diabetic skin microcirculatory dysfunction
Diabetes and Vascular Disease Research, 2019Co-Authors: Yann Savina, Thomas Duflot, Frédéric Bounoure, Sylvain Kotzki, Pierre-alain Thiébaut, Pierre-alex Serreau, Mohamed Skiba, Jean-michel Picquenot, Marie Cornic, Christophe MorisseauAbstract:The impact of the local inhibition of soluble epoxide Hydrolase, which metabolizes vasodilator and anti-inflammatory epoxyeicosanoids, on diabetic skin microvascular dysfunction was assessed. In diabetic db/db mice, basal skin blood flow assessed using laser Doppler imaging was similar to that of control mice, but thermal hyperemia was markedly reduced. At 2 h after the topical administration of an aqueous gel containing the soluble epoxide Hydrolase Inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB: 400 mg/L), the peak concentration of t-AUCB was detected in the skin of diabetic mice, which quickly decreased thereafter. In parallel, 2 h after application of t-AUCB treatment, thermal hyperemia was increased compared to the control gel. Quantification of t-AUCB in plasma of treated animals showed no or low systemic diffusion. Furthermore, haematoxylin and eosin histological staining of skin biopsies showed that skin integrity was preserved in t-AUCB-treated mice. Finally, for pig ear skin, a surrogate for human skin, using Franz diffusion cells, we observed a continuous diffusion of t-AUCB from 2 h after application to beyond 24 h. A single topical administration of a soluble epoxide Hydrolase Inhibitor improves microcirculatory function in the skin of db/db mice and might represent a new therapeutic approach for preventing the development of skin complications in diabetic patients.
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effects of adamantane alterations on soluble epoxide Hydrolase inhibition potency physical properties and metabolic stability
Bioorganic Chemistry, 2018Co-Authors: V V Burmistrov, Christophe Morisseau, Todd R Harris, G M Butov, Bruce D HammockAbstract:Abstract Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide Hydrolase Inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor Inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good Inhibitors suggesting that the active site of sEH opens to capture the substrate or Inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds.
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Ingestion of the epoxide Hydrolase Inhibitor AUDA modulates immune responses of the mosquito, Culex quinquefasciatus during blood feeding.
Insect biochemistry and molecular biology, 2016Co-Authors: Christophe Morisseau, Jun Yang, Kin Sing Stephen Lee, Shizuo G. Kamita, Bruce D HammockAbstract:Epoxide Hydrolases (EHs) are enzymes that play roles in metabolizing xenobiotic epoxides from the environment, and in regulating lipid signaling molecules, such as juvenile hormones in insects and epoxy fatty acids in mammals. In this study we fed mosquitoes with an epoxide Hydrolase Inhibitor AUDA during artificial blood feeding, and we found the Inhibitor increased the concentration of epoxy fatty acids in the midgut of female mosquitoes. We also observed ingestion of AUDA triggered early expression of defensin A, cecropin A and cecropin B2 at 6 h after blood feeding. The expression of cecropin B1 and gambicin were not changed more than two fold compared to controls. The changes in gene expression were transient possibly because more than 99% of the Inhibitor was metabolized or excreted at 42 h after being ingested. The ingestion of AUDA also affected the growth of bacteria colonizing in the midgut, but did not affect mosquito longevity, fecundity and fertility in our laboratory conditions. When spiked into the blood, EpOMEs and DiHOMEs were as effective as the Inhibitor AUDA in reducing the bacterial load in the midgut, while EETs rescued the effects of AUDA. Our data suggest that epoxy fatty acids from host blood are immune response regulators metabolized by epoxide Hydrolases in the midgut of female mosquitoes, inhibition of which causes transient changes in immune responses, and affects growth of microbes in the midgut.
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Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers
The Journal of pharmacology and experimental therapeutics, 2016Co-Authors: Sumanta Kumar Goswami, Christophe Morisseau, Debin Wan, Jun Yang, Carlos A. Trindade Da Silva, Sean D. Kodani, Guang Yu Yang, Bora Inceoglu, Bruce D HammockAbstract:Proton pump Inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide Hydrolase Inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose- [10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-α (TNF-α) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P < 0.05) loss of Hb and an increase in the level of MPO and TNF-α, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P < 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-α Thus sEHI might be useful in the management of NSAID-induced ulcers.
Jian Hai - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide Hydrolase Inhibitor URB597 ameliorate neuroinflammatory responses in chronic cerebral hypoperfusion model by blocking NF-κB pathways
Naunyn-Schmiedeberg's Archives of Pharmacology, 2017Co-Authors: Shao-hua Su, Qi Lin, Yi-fang Wu, Jian HaiAbstract:The present study explored the protective effects of cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide Hydrolase Inhibitor URB597 (URB) against neuroinflammation in rats with chronic cerebral hypoperfusion (CCH). Activated microglia, astrocytes, and nuclear factor kappa B (NF-κB) p65-positive cells were measured by immunofluorescence. Reactive oxygen species (ROS) was assessed by dihydroethidium staining. The protein levels of cluster of differentiation molecule 11b (OX-42), glial fibrillary acidic protein (GFAP), NF-κB p65, Inhibitor of kappa B alpha (IκB-a), IκB kinase a/β (IKK a/β), phosphorylated IKK a/β (p-IKK a/β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and interleukin-1β (IL-1β) were examined by western blotting or enzyme-linked immunosorbent assay. All the protein levels of OX-42, GFAP, TNF-a, IL-1β, COX-2, and iNOS are increased in CCH rats. WIN and URB downregulated the levels of OX-42, GFAP, TNF-α, IL-1β, COX-2 and iNOS and inhibited CCH-induced ROS accumulation in CCH rats, indicating that WIN and URB might exert their neuroprotective effects by inhibiting the neuroinflammatory response. In addition, the NF-κB signaling pathway was activated by CCH in frontal cortex and hippocampus, while the aforementioned changes were reversed by WIN and URB treatment. These findings suggest that WIN and URB treatment ameliorated CCH-induced neuroinflammation through inhibition of the classical pathway of NF-κB activation, resulting in mitigation of chronic ischemic injury.
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cannabinoid receptor agonist win55 212 2 and fatty acid amide Hydrolase Inhibitor urb597 suppress chronic cerebral hypoperfusion induced neuronal apoptosis by inhibiting c jun n terminal kinase signaling
Neuroscience, 2015Co-Authors: Qi Lin, Jian HaiAbstract:Abstract The endocannabinoid system (ECS) has therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced cerebral diseases. This study investigated the protective effects of two ECS compounds, cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide Hydrolase Inhibitor URB597 (URB) on CCH-induced neuronal apoptosis in vivo . CCH was induced in male Sprague–Dawley rats by bilateral common carotid artery occlusion (BCCAo); the rats were then treated with WIN or URB for 12 weeks and their spatial learning and memory abilities were assessed using the Morris water maze. Changes in neuronal number were examined by labeling neurons with an antibody against the neuronal nuclei antigen, and apoptosis of cortical and hippocampal CA1 neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. The expression of B cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), and activated caspase-3 as well as mitogen-activated protein kinases including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, phosphorylated (p-)ERK, p-JNK, and p-P38 was examined by Western blotting. Rats treated with WIN or URB showed better learning and memory performance than controls. The neuroprotective effects of URB were greater than those of WIN, and co-administration of WIN and URB had a synergistic effect. In addition, WIN and URB blocked JNK phosphorylation as well as the decrease in Bcl-2/Bax ratio and caspase-3 activation induced by CCH, implying that these agents modulate neuronal survival. Moreover, the selective JNK Inhibitor SP600125 improved mitochondrial membrane dysfunction and blocked neuronal apoptosis induced by JNK-dependent Bcl-2 signaling. WIN and URB enhanced the effects of SP600125, implying that they may exert anti-apoptotic effects in part by inhibiting a non-nuclear JNK pathway. These findings indicate that WIN and URB promote neuronal survival and may potentially be used to protect neurons against chronic ischemic insults.
Jun Yang - One of the best experts on this subject based on the ideXlab platform.
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Anti-inflammatory treatment with a soluble epoxide Hydrolase Inhibitor attenuates seizures and epilepsy-associated depression in the LiCl-pilocarpine post-status epilepticus rat model
Brain behavior and immunity, 2019Co-Authors: Yijun Shen, Bruce D Hammock, Jun Yang, Wei-feng Peng, Qing-lan Chen, Jun-yan Liu, Jing Ding, Xin WangAbstract:Abstract Purpose This study aimed to investigate whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide Hydrolase Inhibitor with anti-inflammatory effects, could alleviate spontaneous recurrent seizures (SRS) and epilepsy-associated depressive behaviours in the lithium chloride (LiCl)-pilocarpine-induced post-status epilepticus (SE) rat model. Methods The rats were intraperitoneally (IP) injected with LiCl (127 mg/kg) and pilocarpine (40 mg/kg) to induce SE. A video surveillance system was used to monitor SRS in the post-SE model for 6 weeks (from the onset of the 2nd week to the end of the 7th week after SE induction). TPPU (0.1 mg/kg/d) was intragastrically given for 4 weeks from the 21st day after SE induction in the SRS + 0.1 TPPU group. The SRS + PEG 400 group was given the vehicle (40% polyethylene glycol 400) instead, and the control group was given LiCl and PEG 400 but not pilocarpine. The sucrose preference test (SPT) and forced swim test (FST) were conducted to evaluate the depression-like behaviours of rats. Immunofluorescent staining, enzyme-linked immunosorbent assay, and western blot analysis were performed to measure astrocytic and microglial gliosis, neuronal loss, and levels of soluble epoxide Hydrolase (sEH), cytokines [tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6], and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB). Results The frequency of SRS was significantly decreased at 6 weeks and 7 weeks after SE induction in the 0.1TPP U group compared with the SRS + PEG 400 group. The immobility time (IMT) evaluated by FST was significantly decreased, whereas the climbing time (CMT) was increased, and the sucrose preference rate (SPR) evaluated by SPT was in an increasing trend. The levels of sEH, TNF-α, IL-1β, and IL-6 in the hippocampus (Hip) and prefrontal cortex (PFC) were all significantly increased in the SRS + PEG 400 group compared with the control group; neuronal loss, astrogliosis, and microglial activation were also observed. The astrocytic and microglial activation and levels of the pro-inflammatory cytokines in the Hip and PFC were significantly attenuated in the TPPU group compared with the SRS + PEG 400 group; moreover, neuronal loss and the decreased CREB expression were significantly alleviated as well. Conclusion TPPU treatment after SE attenuates SRS and epilepsy-associated depressive behaviours in the LiCl-pilocarpine induced post-SE rat model, and it also exerts anti-inflammatory effects in the brain. Our findings suggest a new therapeutic approach for epilepsy and its comorbidities, especially depression.
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Abstract LB-299: Enhanced Inhibitory effects on mutant KrasG12D-initiated murine pancreatic carcinoma growth in Fat-1 transgenic mice treated with soluble epoxide Hydrolase Inhibitor t-AUCB
Prevention Research, 2016Co-Authors: Jie Liao, Bruce D Hammock, Jun Yang, Rong Xia, Xueyan Wang, Xiaoming You, Sung Hee Hwang, Guang Yu YangAbstract:Anti-carcinogenic effects of ω-3 polyunsaturated fatty acid (PUFAs) are well known; but the mechanism/s remains unclear. Of the three metabolic pathways (COX, LOX, and CYP), ω-3 PUFAs are predominantly metabolized by cyto-p450 epoxygenase/s, leading to an accumulation of ω-3 epoxy fatty acid (ω-3 epoxides), and ω-3 PUFAs are poor substrates of COX and LOX. Functional studies indicate that ω-3 epoxides are highly potential metabolites responsible for anti-inflammatory/carcinogenic actions. However, under physiologic conditions, these ω-3 epoxides are quickly inactivated by soluble epoxide Hydrolase (sEH) to the diol products, and a sEH Inhibitor appears crucial to stabilizing/enhancing the actions of these ω-3 epoxides. Fat1 transgenic mouse constitutively converts ω-6 to ω-3 PUFAs in all organs and are an efficient model to study ω-3 PUFAs. Herein, we have determined if a potent sEH Inhibitor t-AUCB enhanced the Inhibitory effect on mutant KrasG12D-initiated pancreatic cancer growth in Fat-1 mice and further determined the metabolic profile of ω-3 PUFAs, particularly on epoxide metabolites. Using an implanted mouse pancreatic carcinoma model (PK03 cell line, obtained from LSL-KrasG12D/Pdx1-Cre mice), a significant reduction of in vivo implanted PK03 pancreatic carcinoma growth was observed in Fat1 mice compared to wild type mice (Tumor volume: 355 ± 50 vs 519 ± 61 mm3, P Citation Format: Jie Liao, Rong Xia, Jun Yang, Haonan Li, Dandan Xu, Xueyan Wang, Xiaoming You, Sung Hee Hwang, Bruce Hammock, Guang-Yu Yang. Enhanced Inhibitory effects on mutant KrasG12D-initiated murine pancreatic carcinoma growth in Fat-1 transgenic mice treated with soluble epoxide Hydrolase Inhibitor t-AUCB. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-299.
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Ingestion of the epoxide Hydrolase Inhibitor AUDA modulates immune responses of the mosquito, Culex quinquefasciatus during blood feeding.
Insect biochemistry and molecular biology, 2016Co-Authors: Christophe Morisseau, Jun Yang, Kin Sing Stephen Lee, Shizuo G. Kamita, Bruce D HammockAbstract:Epoxide Hydrolases (EHs) are enzymes that play roles in metabolizing xenobiotic epoxides from the environment, and in regulating lipid signaling molecules, such as juvenile hormones in insects and epoxy fatty acids in mammals. In this study we fed mosquitoes with an epoxide Hydrolase Inhibitor AUDA during artificial blood feeding, and we found the Inhibitor increased the concentration of epoxy fatty acids in the midgut of female mosquitoes. We also observed ingestion of AUDA triggered early expression of defensin A, cecropin A and cecropin B2 at 6 h after blood feeding. The expression of cecropin B1 and gambicin were not changed more than two fold compared to controls. The changes in gene expression were transient possibly because more than 99% of the Inhibitor was metabolized or excreted at 42 h after being ingested. The ingestion of AUDA also affected the growth of bacteria colonizing in the midgut, but did not affect mosquito longevity, fecundity and fertility in our laboratory conditions. When spiked into the blood, EpOMEs and DiHOMEs were as effective as the Inhibitor AUDA in reducing the bacterial load in the midgut, while EETs rescued the effects of AUDA. Our data suggest that epoxy fatty acids from host blood are immune response regulators metabolized by epoxide Hydrolases in the midgut of female mosquitoes, inhibition of which causes transient changes in immune responses, and affects growth of microbes in the midgut.
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Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers
The Journal of pharmacology and experimental therapeutics, 2016Co-Authors: Sumanta Kumar Goswami, Christophe Morisseau, Debin Wan, Jun Yang, Carlos A. Trindade Da Silva, Sean D. Kodani, Guang Yu Yang, Bora Inceoglu, Bruce D HammockAbstract:Proton pump Inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide Hydrolase Inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose- [10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-α (TNF-α) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P < 0.05) loss of Hb and an increase in the level of MPO and TNF-α, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P < 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-α Thus sEHI might be useful in the management of NSAID-induced ulcers.
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effect of a soluble epoxide Hydrolase Inhibitor uc1728 on lps induced uveitis in the rabbit
Journal of ocular biology, 2016Co-Authors: Gillian J Mclellan, Jun Yang, Sung Hee Hwang, Zeynep Aktas, Elizabeth A Hennesbeean, Aaron W Kolb, Inna V Larsen, Emily Schmitz, Hilary R Clausius, Christophe MorisseauAbstract:Cytochrome P450 epoxygenase isozymes convert free arachidonic acid into eicosanoids named epoxyeicosatrienoic acids (EETs) that have roles in regulating inflammation. EETs are rapidly converted to dihydroxyeicosatrienoic acids (DiHETs) by soluble epoxide Hydrolase (sEH). Little is known about the potential role of these metabolites in uveitis, but conversion of EETs to DiHETs could contribute to the inflammation. We tested a potent and orally available Inhibitor of sEH for its ability to reduce ocular inflammation in a rabbit LPS-induced model of uveitis. Rabbits were treated by subcutaneous injection with the sEH Inhibitor (UC1728, 3 mg/kg), or the vehicle control (PEG400) and uveitis was assessed at 6, 24 and 48 h post-intracameral LPS injection using a modified Hackett-McDonald scoring system. Eyes treated by intra-cameral injection of PBS, or by aseptic preparation served as further controls. Signs of inflammation in this model were mild and transient. Treatment with UC1728 did not significantly reduce inflammation compared to animals treated with the PEG400 vehicle. Blood levels of UC1728 were a thousand fold higher than the in vitro determined Inhibitory potency (IC50) of the compound suggesting a significant degree of inhibition of sEH in the rabbit. The lack of efficacy suggests that sEH or its substrates the EETs may not be involved in mediating inflammation in this model of uveitis.
You Lu - One of the best experts on this subject based on the ideXlab platform.
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The Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates Radiation-Induced Lung Injury in a Mouse Model
Inflammation, 2017Co-Authors: Rui Li, Ruizhan Tong, Jianxin Xue, Jie Lan, Lei Deng, He Xu, Lin Zhou, Guo Chen, Fei Tang, You LuAbstract:Radiation-induced lung injury (RILI) is a potentially life-threatening complication of radiotherapy. In the current study, we examined the potential protective effects of URB937, an Inhibitor of fatty acid amide Hydrolase using a mouse model of RILI. Briefly, male C57BL/6 mice received 16Gy irradiation to the thoracic region and then intraperitoneal injection of either URB937 (1 mg/kg) or vehicle every 2 days for 30 days. The extent of the lung injury was evaluated histologically at the end of the drug treatment as well as 3 months after the cessation of the treatment. The data showed URB937 attenuated radiation-induced lung injury and increased endocannabinoid concentration in lung tissue. Treatment with URB937 decreased leukocyte migration and inflammatory cytokines in bronchoalveolar lavage fluid and plasma at day 30. Histopathological examination revealed URB937 could restore lung structure and restrain inflammatory cell and fibroblast accumulation caused by irradiation in lung tissue. URB937 also decreased radiation-induced pro-inflammatory (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α) and pro-fibrotic cytokines (e.g., transforming growth factor-β1) level in lung tissue, as well as lipid peroxidation in the lungs. Mouse survival examined in a separate group of experimental subjects indicated that URB937 could prolong animal survival. Experiments using a mouse bearing Lewis lung carcinoma cells showed that URB937 does not affect irradiation-induced inhibition of tumor growth. These results suggest that inhibiting fatty acid amide Hydrolase could ameliorate RILI without compromising the efficacy of irradiation on tumor control.
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Abstract 2233: The fatty acid amide Hydrolase Inhibitor URB937 ameliorates radiation-induced lung injury in a mouse model
Cancer Research, 2017Co-Authors: Rui Li, You LuAbstract:Radiation-induced lung injury (RILI) is a common and potentially serious complication from radiotherapy to the thoracic region. In the current study, we examined the potential protective effects of URB937, an Inhibitor of fatty acid amide Hydrolase in a mouse model of RILI. Here we challenged male C57BL/6 mice with irradiation (16Gy to the thoracic region), and then injected intraperitonealy either URB937 (1 mg/kg) or vehicle three times a week for 30 days. Mice were sacrificed at either the end of treatment or120 days from irradiation to evaluate the extent of RILI and mice survival. Potential effects of URB937 on irradiation induced tumor growth inhibition were also evaluated. We found URB937 increased endocannabinoids in the lungs, attenuated the extent of RILI, prolonged the survival,inhibited mice developed pathological alterations of pneumonitis and lung fibrosis. Irradiation-induced increases of proinflammatory and profibrotic cytokines were decreased, including interleukin-1β, interleukin-6, tumor necrosis factor-α, transforming growth factor-β1 in plasma and lung tissue. Moreover, malondialdehyde in plasma and inflammation cells in bronchoalveolar lavage fluid were lower in mice treated with irradiation plus URB937. URB937 did not affect tumor growth inhibition caused by irradiation. These results suggested that inhibiting fatty acid amide Hydrolase through URB937 could ameliorate the RILI, without affecting the efficacy of irradiation on tumor control. Note: This abstract was not presented at the meeting. Citation Format: Rui Li, Jianxin Xue, You Lu. The fatty acid amide Hydrolase Inhibitor URB937 ameliorates radiation-induced lung injury in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2233. doi:10.1158/1538-7445.AM2017-2233
