The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
Bruce D Hammock - One of the best experts on this subject based on the ideXlab platform.
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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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Vascular Lipidomic Profiling of Potential Endogenous Fatty Acid PPAR Ligands Reveals the Coronary Artery as Major Producer of CYP450-Derived Epoxy Fatty Acids
Cells, 2020Co-Authors: Matthew L. Edin, Bruce D Hammock, Darryl C. Zeldin, Fred B. Lih, Scott Thomson, David Bishop-baileyAbstract:A number of oxylipins have been described as endogenous PPAR ligands. The very short biological half-lives of oxylipins suggest roles as autocrine or paracrine signaling molecules. While coronary arterial atherosclerosis is the root of myocardial infarction, aortic atherosclerotic plaque formation is a common readout of in vivo atherosclerosis studies in mice. Improved understanding of the compartmentalized sources of oxylipin PPAR ligands will increase our knowledge of the roles of PPAR signaling in diverse vascular tissues. Here, we performed a targeted lipidomic analysis of ex vivo-generated oxylipins from porcine aorta, coronary artery, pulmonary artery and perivascular adipose. Cyclooxygenase (COX)-derived prostanoids were the most abundant detectable oxylipin from all tissues. By contrast, the coronary artery produced significantly higher levels of oxylipins from CYP450 pathways than other tissues. The TLR4 ligand LPS induced prostanoid formation in all vascular tissue tested. The 11-HETE, 15-HETE, and 9-HODE were also induced by LPS from the aorta and pulmonary artery but not coronary artery. Epoxy Fatty Acid (EpFA) formation was largely unaffected by LPS. The pig CYP2J homologue CYP2J34 was expressed in porcine vascular tissue and primary coronary artery smooth muscle cells (pCASMCs) in culture. Treatment of pCASMCs with LPS induced a robust profile of pro-inflammatory target genes: TNFα, ICAM-1, VCAM-1, MCP-1 and CD40L. The soluble epoxide hydrolase inhibitor TPPU, which prevents the breakdown of endogenous CYP-derived EpFAs, significantly suppressed LPS-induced inflammatory target genes. In conclusion, PPAR-activating oxylipins are produced and regulated in a vascular site-specific manner. The CYP450 pathway is highly active in the coronary artery and capable of providing anti-inflammatory oxylipins that prevent processes of inflammatory vascular disease progression.
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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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toxicity of Epoxy Fatty Acids and related compounds to cells expressing human soluble epoxide hydrolase
Chemical Research in Toxicology, 2000Co-Authors: Jessica F Greene, John W Newman, Kristin C Williamson, Bruce D HammockAbstract:Soluble epoxide hydrolase (sEH) is suggested to alter the mode of action and increase the toxic potency of Fatty Acid epoxides. To characterize the structural features necessary for sEH-dependent Epoxy Fatty Acid toxicity, 75 aliphatic compounds were assayed for cytotoxicity in the presence and absence of sEH. Three groups of aliphatic epoxide−diol pairs were described by their observed differential toxicity. Group I compounds were typified by terminal epoxides whose toxicity was reduced in the presence of sEH. Group II compounds were toxic in either their epoxide or diol form, but toxicity was unaffected by sEH. Group III compounds exhibited sEH-dependent toxicity and were therefore used to investigate the structural elements required for cytotoxicity in this study. The optimal structure for group III compounds appeared to be a Fatty Acid 18−20 atoms long (e.g., a carbon backbone plus a terminal heteroatom) with an epoxide positioned between C-7 and C-12. In the absence of sEH, replacement of epoxides wi...
Johan Meijer - One of the best experts on this subject based on the ideXlab platform.
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Brassica napus soluble epoxide hydrolase (BNSEH1)
European journal of biochemistry, 2002Co-Authors: Stefan Bellevik, Jiaming Zhang, Johan MeijerAbstract:Epoxide hydrolase (EC 3.3.2.3) in plants is involved in the metabolism of Epoxy Fatty Acids and in mediating defence responses. We report the cloning of a full-length epoxide hydrolase cDNA (BNSEH1) from oilseed rape (Brassica napus) obtained by screening of a cDNA library prepared from methyl jasmonate induced leaf tissue, and the 5′-RACE technique. The cDNA encodes a soluble protein containing 318 amino Acid residues. The identity on the protein level is 85% to an Arabidopsis soluble epoxide hydrolase (sEH) and 50–60% to sEHs cloned from other plants. A 5 × His tag was added to the N-terminus of the BNSEH1 and the construct was over-expressed in the yeast Pichia pastoris. The recombinant protein was recovered at high levels after Ni-agarose chromatography of lysed cell extracts, had a molecular mass of 37 kDa on SDS/PAGE and cross-reacted on Western blots with antibodies raised to a sEH from Arabidopsis thaliana. BNSEH1 was shown to be a monomer by gel filtration analysis. The activity was low towards cis-stilbene oxide but much higher using trans-stilbene oxide as substrate with Vmax of 0.47 µmol·min·mg−1, Km of 11 µm and kcat of 0.3 s−1. The optimum temperature of the recombinant enzyme was 55 °C and the optimum pH 6–7 for trans-stilbene oxide hydrolysis. The isolation of BNSEH1 will facilitate metabolic engineering of Epoxy Fatty Acid metabolism for functional studies of resistance and seed oil modification in this important oilcrop.
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Brassica napus soluble epoxide hydrolase (BNSEH1)
European journal of biochemistry, 2002Co-Authors: Stefan Bellevik, Jiaming Zhang, Johan MeijerAbstract:Epoxide hydrolase (EC 3.3.2.3) in plants is involved in the metabolism of Epoxy Fatty Acids and in mediating defence responses. We report the cloning of a full-length epoxide hydrolase cDNA (BNSEH1) from oilseed rape (Brassica napus) obtained by screening of a cDNA library prepared from methyl jasmonate induced leaf tissue, and the 5'-RACE technique. The cDNA encodes a soluble protein containing 318 amino Acid residues. The identity on the protein level is 85% to an Arabidopsis soluble epoxide hydrolase (sEH) and 50-60% to sEHs cloned from other plants. A 5 x His tag was added to the N-terminus of the BNSEH1 and the construct was over-expressed in the yeast Pichia pastoris. The recombinant protein was recovered at high levels after Ni-agarose chromatography of lysed cell extracts, had a molecular mass of 37 kDa on SDS/PAGE and cross-reacted on Western blots with antibodies raised to a sEH from Arabidopsis thaliana. BNSEH1 was shown to be a monomer by gel filtration analysis. The activity was low towards cis-stilbene oxide but much higher using trans-stilbene oxide as substrate with Vmax of 0.47 micro mol.min.mg-1, Km of 11 micro m and kcat of 0.3 s-1. The optimum temperature of the recombinant enzyme was 55 degrees C and the optimum pH 6-7 for trans-stilbene oxide hydrolysis. The isolation of BNSEH1 will facilitate metabolic engineering of Epoxy Fatty Acid metabolism for functional studies of resistance and seed oil modification in this important oilcrop.
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Cloning and characterization of the recombinant enzyme expressed in Pichia pastoris
2002Co-Authors: Stefan Bellevik, Jiaming Zhang, Johan MeijerAbstract:Epoxide hydrolase (EC 3.3.2.3) in plants is involved in the metabolism of Epoxy Fatty Acids and in mediating defence responses. We report the cloning of a full-length epoxide hydrolase cDNA (BNSEH1) from oilseed rape (Brassica napus) obtained by screening of a cDNA library prepared from methyl jasmonate induced leaf tissue, and the 5¢-RACE technique. The cDNA encodes a soluble protein containing 318 amino Acid residues. The identity on the protein level is 85% to an Arabidopsis soluble epoxide hydrolase (sEH) and 50–60% to sEHs cloned from other plants. A 5 · His tag was added to the N-terminus of the BNSEH1 and the construct was over-expressed in the yeast Pichia pastoris. The recombinant protein was recovered at high levels after Ni-agarose chromatography of lysed cell extracts, had a molecular mass of 37 kDa on SDS/PAGE and cross-reacted on Western blots with antibodies raised to a sEH from Arabidopsis thaliana. BNSEH1 was shown to be a monomer by gel filtration analysis. The activity was low towards cisstilbene oxide but much higher using trans-stilbene oxide as substrate with Vmax of 0.47 lmolAEminAEmg )1 , Km of 11 lM and kcat of 0.3 s )1 . The optimum temperature of the recombinant enzyme was 55 � C and the optimum pH 6–7 for trans-stilbene oxide hydrolysis. The isolation of BNSEH1 will facilitate metabolic engineering of Epoxy Fatty Acid metabolism for functional studies of resistance and seed oil modification in this important oilcrop.
Xuejun Liu - One of the best experts on this subject based on the ideXlab platform.
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solvent free oxidative cleavage of Epoxy Fatty Acid methyl esters by a release and capture catalytic system
Green Chemistry, 2019Co-Authors: Libo Peng, Hailun Jin, Ni Yang, Yong Nie, Qinglong Xie, Xuejun LiuAbstract:The creation of a catalytic method that possesses high activity and effective reusability for the oxidative cleavage of vegetable oils and their derivatives to prepare bio-based oxo-chemicals is a challenge. This work introduces a “release and capture” catalytic system consisting of H2O2, WO3 and mesoporous SnO2. This system was intended to promote catalyst reusability in the oxidative cleavage of methyl 9,10-Epoxystearate (ME) to the corresponding aldehydes. No organic solvent was used in the reaction. The reaction temperature, molar ratio of ME/WO3/H2O2, and reaction time were optimized to 70 °C, 1/0.017/1.3, and 20 min, respectively. Under these conditions, complete ME conversion and 80% aldehyde yield were obtained. The hot filtration experiment and ICP-MS analysis confirmed the leaching of tungsten. Mesoporous SnO2 did not affect the ME conversion and aldehyde yield, but effectively adsorbed the leached tungsten. The catalyst in this system showed no significant decrease in activity after being reused ten times.
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Solvent-free oxidative cleavage of Epoxy Fatty Acid methyl esters by a “release and capture” catalytic system
Green Chemistry, 2019Co-Authors: Meizhen Lu, Hailun Jin, Xianghong Lu, Libo Peng, Zhenyu Wu, Ni Yang, Yong Nie, Xuejun Liu, Qinglong Xie, Jianbing JiAbstract:The creation of a catalytic method that possesses high activity and effective reusability for the oxidative cleavage of vegetable oils and their derivatives to prepare bio-based oxo-chemicals is a challenge. This work introduces a “release and capture” catalytic system consisting of H2O2, WO3 and mesoporous SnO2. This system was intended to promote catalyst reusability in the oxidative cleavage of methyl 9,10-Epoxystearate (ME) to the corresponding aldehydes. No organic solvent was used in the reaction. The reaction temperature, molar ratio of ME/WO3/H2O2, and reaction time were optimized to 70 °C, 1/0.017/1.3, and 20 min, respectively. Under these conditions, complete ME conversion and 80% aldehyde yield were obtained. The hot filtration experiment and ICP-MS analysis confirmed the leaching of tungsten. Mesoporous SnO2 did not affect the ME conversion and aldehyde yield, but effectively adsorbed the leached tungsten. The catalyst in this system showed no significant decrease in activity after being reused ten times.
Guang Yu Yang - One of the best experts on this subject based on the ideXlab platform.
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Proinflammatory enzyme soluble epoxide hydrolase bridges obesity to colonic inflammation and potential carcinogenesis.
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Guang Yu YangAbstract:Obesity and chronic inflammation are two well-recognized risk factors for the development of colorectal cancer (CRC). In PNAS, Wang et al. (1) use lipidomic profiling analysis to identify a significant mechanistic link between obesity and colonic inflammation via enhancing the proinflammatory enzyme soluble epoxide hydrolase (sEH). The aberrant metabolism of polyunsaturated Fatty Acids, and particularly arachidonic Acid, is thought to be a key inflammatory mediator contributing to colorectal carcinogenesis. The role of cytochrome P450 Epoxygenase in this metabolism, though, and the role of its Epoxy Fatty Acid metabolites in obesity and CRC are not … [↵][1]1Email: g-yang{at}northwestern.edu. [1]: #xref-corresp-1-1
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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.
Libo Peng - One of the best experts on this subject based on the ideXlab platform.
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solvent free oxidative cleavage of Epoxy Fatty Acid methyl esters by a release and capture catalytic system
Green Chemistry, 2019Co-Authors: Libo Peng, Hailun Jin, Ni Yang, Yong Nie, Qinglong Xie, Xuejun LiuAbstract:The creation of a catalytic method that possesses high activity and effective reusability for the oxidative cleavage of vegetable oils and their derivatives to prepare bio-based oxo-chemicals is a challenge. This work introduces a “release and capture” catalytic system consisting of H2O2, WO3 and mesoporous SnO2. This system was intended to promote catalyst reusability in the oxidative cleavage of methyl 9,10-Epoxystearate (ME) to the corresponding aldehydes. No organic solvent was used in the reaction. The reaction temperature, molar ratio of ME/WO3/H2O2, and reaction time were optimized to 70 °C, 1/0.017/1.3, and 20 min, respectively. Under these conditions, complete ME conversion and 80% aldehyde yield were obtained. The hot filtration experiment and ICP-MS analysis confirmed the leaching of tungsten. Mesoporous SnO2 did not affect the ME conversion and aldehyde yield, but effectively adsorbed the leached tungsten. The catalyst in this system showed no significant decrease in activity after being reused ten times.
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Solvent-free oxidative cleavage of Epoxy Fatty Acid methyl esters by a “release and capture” catalytic system
Green Chemistry, 2019Co-Authors: Meizhen Lu, Hailun Jin, Xianghong Lu, Libo Peng, Zhenyu Wu, Ni Yang, Yong Nie, Xuejun Liu, Qinglong Xie, Jianbing JiAbstract:The creation of a catalytic method that possesses high activity and effective reusability for the oxidative cleavage of vegetable oils and their derivatives to prepare bio-based oxo-chemicals is a challenge. This work introduces a “release and capture” catalytic system consisting of H2O2, WO3 and mesoporous SnO2. This system was intended to promote catalyst reusability in the oxidative cleavage of methyl 9,10-Epoxystearate (ME) to the corresponding aldehydes. No organic solvent was used in the reaction. The reaction temperature, molar ratio of ME/WO3/H2O2, and reaction time were optimized to 70 °C, 1/0.017/1.3, and 20 min, respectively. Under these conditions, complete ME conversion and 80% aldehyde yield were obtained. The hot filtration experiment and ICP-MS analysis confirmed the leaching of tungsten. Mesoporous SnO2 did not affect the ME conversion and aldehyde yield, but effectively adsorbed the leached tungsten. The catalyst in this system showed no significant decrease in activity after being reused ten times.