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https://www.readbyqxmd.com/read/28919040/heme-binding-biguanides-target-cytochrome-p450-dependent-cancer-cell-mitochondria
#1
Zhijun Guo, Irina F Sevrioukova, Ilia G Denisov, Xia Zhang, Ting-Lan Chiu, Dafydd G Thomas, Eric A Hanse, Rebecca A D Cuellar, Yelena V Grinkova, Vanessa Wankhede Langenfeld, Daniel S Swedien, Justin D Stamschror, Juan Alvarez, Fernando Luna, Adela Galván, Young Kyung Bae, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Beverly Norris, Craig M Flory, Robert J Schumacher, M Gerard O'Sullivan, Qing Cao, Haitao Chu, John D Lipscomb, William M Atkins, Kalpna Gupta, Ameeta Kelekar, Ian A Blair, Jorge H Capdevila, John R Falck, Stephen G Sligar, Thomas L Poulos, Gunda I Georg, Elizabeth Ambrose, David A Potter
The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs...
August 29, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28906258/early-tumor-shrinkage-indicates-a-favorable-response-to-bevacizumab-based-first-line-chemotherapy-for-metastatic-colorectal-cancer
#2
Mamoru Ito, Hitoshi Kusaba, Satomi Mukaide, Junji Kishimoto, Hozumi Shimokawa, Shingo Tamura, Akitaka Makiyama, Gen Hirano, Hisanobu Oda, Tsuyoshi Shirakawa, Masato Komoda, Keita Uchino, Risa Tanaka, Kenji Mitsugi, Taito Esaki, Shuji Arita, Hiroshi Ariyama, Koichi Akashi, Eishi Baba
A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined...
September 12, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28899749/cyp4a-cyp2c-modulation-of-the-interaction-of-calcium-channel-blockers-with-cyclosporine-on-edhf-mediated-renal-vasodilations-in-rats
#3
Safaa H Hammoud, Amal G Omar, Assaad A Eid, Mahmoud M El-Mas
The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days...
September 9, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28890385/reduced-coronary-reactive-hyperemia-in-mice-was-reversed-by-the-soluble-epoxide-hydrolase-inhibitor-t-aucb-role-of-adenosine-a2a-receptor-and-plasma-oxylipins
#4
Ahmad Hanif, Matthew L Edin, Darryl C Zeldin, Christophe Morisseau, John R Falck, Catherine Ledent, Stephen L Tilley, Mohammed A Nayeem
Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A2AAR-deficient (A2AAR(-/-)) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). sEH-inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A2AAR(-/-) and wild type (WT) mice. We hypothesized that the attenuated CRH in A2AAR(-/-) mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH- or ω-hydroxylases-inhibition...
September 7, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28884118/the-role-of-adenosine-a2a-receptor-cyp450s-and-ppars-in-the-regulation-of-vascular-tone
#5
REVIEW
Maan T Khayat, Mohammed A Nayeem
Adenosine is an endogenous mediator involved in a myriad of physiologic functions, including vascular tone regulation. It is also implicated in some pathologic conditions. Four distinct receptor subtypes mediate the effects of adenosine, such as its role in the regulation of the vascular tone. Vascular tone regulation is a complex and continuous process which involves many mechanisms and mediators that are not fully disclosed. The vascular endothelium plays a pivotal role in regulating blood flow to and from all body organs...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28881620/eets-reduces-lps-induced-hyperpermeability-by-targeting-grp78-mediated-src-activation-and-subsequent-rho-rock-signaling-pathway
#6
Ruolan Dong, Danli Hu, Yan Yang, Zhihui Chen, Menglu Fu, Dao Wen Wang, Xizhen Xu, Ling Tu
Integrity of endothelial barrier is a determinant of the prognosis in the acute lung injury caused by sepsis. The epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, exhibit protective effects in various pathogenic states, however, whether EETs play a role in endothelial barrier enhancement and the involved mechanisms remain to be investigated. Here, we show that increased EETs level by endothelial specific cytochrome P450 epoxygenase 2J2 over-expression and soluble epoxide hydrolase (sEH) inhibitor TPPU reduced lipopolysaccharide-induced endothelial hyper-permeability in vivo, accompanied by improved survival of septic mice...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28879086/emotion-detection-deficits-and-changes-in-personality-traits-linked-to-loss-of-white-matter-integrity-in-primary-progressive-aphasia
#7
Namita Multani, Sebastiano Galantucci, Stephen M Wilson, Tal Shany-Ur, Pardis Poorzand, Matthew E Growdon, Jung Yun Jang, Joel H Kramer, Bruce L Miller, Katherine P Rankin, Maria Luisa Gorno-Tempini, Maria Carmela Tartaglia
Non-cognitive features including personality changes are increasingly recognized in the three PPA variants (semantic-svPPA, non fluent-nfvPPA, and logopenic-lvPPA). However, differences in emotion processing among the PPA variants and its association with white matter tracts are unknown. We compared emotion detection across the three PPA variants and healthy controls (HC), and related them to white matter tract integrity and cortical degeneration. Personality traits in the PPA group were also examined in relation to white matter tracts...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28874838/structural-determinants-of-5-6-epoxyeicosatrienoic-acid-binding-to-and-activation-of-trpv4-channel
#8
Alejandro Berna-Erro, Mercè Izquierdo-Serra, Romina V Sepúlveda, Fanny Rubio-Moscardo, Pau Doñate-Macián, Selma A Serra, Julia Carrillo-Garcia, Alex Perálvarez-Marín, Fernando González-Nilo, José M Fernández-Fernández, Miguel A Valverde
TRPV4 cation channel activation by cytochrome P450-mediated derivatives of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs), constitute a major mechanisms of endothelium-derived vasodilatation. Besides, TRPV4 mechano/osmosensitivity depends on phospholipase A2 (PLA2) activation and subsequent production of AA and EETs. However, the lack of evidence for a direct interaction of EETs with TRPV4 together with claims of EET-independent mechanical activation of TRPV4 has cast doubts on the validity of this mechanism...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28871245/comparative-genomic-analysis-of-neutrophilic-iron-ii-oxidizer-genomes-for-candidate-genes-in-extracellular-electron-transfer
#9
Shaomei He, Roman A Barco, David Emerson, Eric E Roden
Extracellular electron transfer (EET) is recognized as a key biochemical process in circumneutral pH Fe(II)-oxidizing bacteria (FeOB). In this study, we searched for candidate EET genes in 73 neutrophilic FeOB genomes, among which 43 genomes are complete or close-to-complete and the rest have estimated genome completeness ranging from 5 to 91%. These neutrophilic FeOB span members of the microaerophilic, anaerobic phototrophic, and anaerobic nitrate-reducing FeOB groups. We found that many microaerophilic and several anaerobic FeOB possess homologs of Cyc2, an outer membrane cytochrome c originally identified in Acidithiobacillus ferrooxidans...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28867723/the-inhibitory-effect-of-telmisartan-on-the-metabolism-of-arachidonic-acid-by-cyp2c9-and-cyp2c8-an-in-vitro-study
#10
Yuka Kato, Yuji Mukai, Anders Rane, Nobuo Inotsume, Takaki Toda
Epoxyeicosatorienoic acids (EETs) are generated from arachidonic acid (AA) by CYPs. EETs comprise four regioisomers (14,15-, 11,12-, 8,9-, and 5,6-EET). EETs show potent physiological effects, including vasodilation, anti-inflammation, myocardial preconditioning, and anti-platelet aggregation effects. We recently demonstrated that telmisartan, one of angiotensin II receptor blockers, inhibits AA metabolism by CYP enzymes, including CYP2C8, CYP2C9, and CYP2J2. We conducted studies of AA metabolism using recombinant CYP enzymes to estimate the inhibition constant and the type of inhibition by telmisartan of CYP2C9 and CYP2C8...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28863368/postprandial-effect-to-decrease-soluble-epoxide-hydrolase-activity-roles-of-insulin-and-gut-microbiota
#11
Jun Yang, Young Taek Oh, Debin Wan, Richard M Watanabe, Bruce D Hammock, Jang H Youn
Epoxides of free fatty acids (FFAs), especially epoxyeicosatrienoic acids (EETs), are lipid mediators with beneficial effects in metabolic and cardiovascular (CV) health. FFA epoxides are quickly metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EET levels, improves glucose homeostasis and CV health and is proposed as an effective strategy for the treatment of diabetes and CV diseases. Here, we show evidence that sEH activity is profoundly reduced in postprandial states in rats; plasma levels of 17 sEH products (i...
July 21, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28839898/endoscopic-management-of-barrett-s-and-early-oesophageal-neoplasia
#12
REVIEW
G Lipman, R J Haidry
Barrett's oesophagus (BO) is the only known precursor to oesophageal adenocarcinoma (OAC). Dysplasia and intramucosal cancer arising in BO can safely be treated with endoscopic eradication therapy (EET) due to the low risk of subsequent lymph node metastasis. Treatment at an early stage is paramount due to the ongoing poor prognosis and outcomes of patients with advanced OAC. The mainstay of treatment is endoscopic resection of visible lesions for accurate staging followed by ablation therapy to all remaining columnar-lined epithelium, most commonly with radiofrequency ablation...
April 2017: Frontline Gastroenterology
https://www.readbyqxmd.com/read/28839250/pharmacological-profile-and-efficiency-in-vivo-of-diflapolin-the-first-dual-inhibitor-of-5-lipoxygenase-activating-protein-and-soluble-epoxide-hydrolase
#13
Ulrike Garscha, Erik Romp, Simona Pace, Antonietta Rossi, Veronika Temml, Daniela Schuster, Stefanie König, Jana Gerstmeier, Stefanie Liening, Markus Werner, Heiner Atze, Sandra Wittmann, Christina Weinigel, Silke Rummler, Gerhard K Scriba, Lidia Sautebin, Oliver Werz
Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28835580/epoxyeicosatrienoic-acids-are-mediated-by-ephx2-variants-and-may-be-a-predictor-of-early-neurological-deterioration-in-acute-minor-ischemic-stroke
#14
Xingyang Yi, Jing Lin, Jie Li, Qiang Zhou, Zhao Han
AIM: To investigatethe association of plasma epoxyeicosatrienoic acids (EETs) with early neurologic deterioration (END), and whether EETs are mediated by EPHX2 variants in patients with minor ischemic stroke (MIS). METHOD: This was a prospective, multi-center observational study in patients with acute MIS in the Chinese population.Plasma EETs levels were measured on admission. Single nucleotide polymorphisms (SNPs) of EPHX2 rs751141 were genotyped using mass spectrometry...
August 24, 2017: Journal of Atherosclerosis and Thrombosis
https://www.readbyqxmd.com/read/28827137/a-novel-mechanism-of-ascorbate-direct-modulation-of-soluble-epoxide-hydrolase
#15
Bin Zhang, Sharath Kandhi, Yang-Ming Yang, Yicong Le, Wensheng Deng, Jun Qin, Houli Jiang, Ghezal Froogh, Dong Sun, An Huang
To test the hypothesis that VitC downregulates soluble epoxide hydrolase (sEH, responsible for converting EETs to DHETs) to stabilize tissue EETs, the heart, lung, liver, kidney, and mesenteric arteries isolated from normal rats were incubated with VitC (1000μM) for 72h, and tissue sEH expression, along with EET and DHET profiles were assessed. VitC caused significant reductions in sEH mRNA and protein content in the liver, heart and vessels, but had no effect on renal and pulmonary sEH expression, revealing a tissue-specific regulatory mechanism...
August 18, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28826711/surgical-management-of-rathke-s-cleft-cysts
#16
Vishwaraj Ratha, Subodh Patil, Vikram S Karmarkar, Nishit J Shah, Chandrashekhar E Deopujari
BACKGROUND: The diagnosis of Rathke's Cleft cysts (RCC) have increased in recent times due to improvements in imaging techniques; however symptomatic cases are uncommon and accurate preoperative diagnosis may sometimes be difficult. The indications of surgical management protocol are evolving. We aim to provide a comprehensive review of clinical, imaging, and histopathological features with operative management strategies along with outcome and prognosis in RCC. METHODS: A retrospective analysis (2003-2015)of 58 consecutive cases of RCC seen in a surgical unit...
August 4, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28822809/inhibition-of-soluble-epoxide-hydrolase-lowers-portal-hypertension-in-cirrhotic-rats-by-ameliorating-endothelial-dysfunction-and-liver-fibrosis
#17
Wensheng Deng, Yiming Zhu, Jiayun Lin, Lei Zheng, Chihao Zhang, Meng Luo
Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d...
August 16, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28822080/soluble-epoxide-hydrolase-inhibition-attenuates-mptp-induced-neurotoxicity-in-the-nigrostriatal-dopaminergic-system-involvement-of-%C3%AE-synuclein-aggregation-and-er-stress
#18
Hui-Ju Huang, Yi-Ting Wang, Hui-Ching Lin, Yi-Hsuan Lee, Anya Maan-Yuh Lin
Soluble epoxide hydrolase (sEH) is widely expressed in the mammalian brain and possesses dual enzymatic activities, including C-terminal epoxide hydrolase (C-EH) which degrades epoxyeicosatrienoic acid (EET), a beneficial arachidonic acid metabolite. In the present study, the neuroprotective effect of sEH inhibition on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using genetic and pharmacological approaches. MPTP (15 mg/kg) was intraperitoneally injected in sEH knockout (KO) mice and C57BL/6J mice as wild-type (WT) mice...
August 18, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28817716/endothelial-dysfunction-in-renal-arcuate-arteries-of-obese-zucker-rats-the-roles-of-nitric-oxide-endothelium-derived-hyperpolarizing-factors-and-calcium-activated-k-channels
#19
Dandan Yin, Qianchen Wang, Xun Zhou, Ying Li
The roles of nitric oxide (NO), endothelium-derived hyperpolarizing factors (EDHF), and calcium-activated K+ (KCa) channels in diabetes-associated endothelial dysfunction of small renal arteries are not clear. The present study investigated acetylcholine (ACh)-induced vasorelaxation of renal arcuate arteries from obese Zucker (OZ) rats at different diabetes durations, and the relative contribution of NO, EDHF, and KCa channels to the endothelial dysfunction. OZ rats of 7 weeks (prediabetic stage), 12 weeks (early diabetic stage), and 20 weeks (late diabetic stage), and time-matched lean control rats, were studied...
2017: PloS One
https://www.readbyqxmd.com/read/28808031/changes-in-aggregation-states-of-light-harvesting-complexes-as-a-mechanism-for-modulating-energy-transfer-in-desert-crust-cyanobacteria
#20
Leeat Bar Eyal, Reza Ranjbar Choubeh, Eyal Cohen, Ido Eisenberg, Carmen Tamburu, Márta Dorogi, Renata Ünnep, Marie-Sousai Appavou, Reinat Nevo, Uri Raviv, Ziv Reich, Győző Garab, Herbert van Amerongen, Yossi Paltiel, Nir Keren
In this paper we propose an energy dissipation mechanism that is completely reliant on changes in the aggregation state of the phycobilisome light-harvesting antenna components. All photosynthetic organisms regulate the efficiency of excitation energy transfer (EET) to fit light energy supply to biochemical demands. Not many do this to the extent required of desert crust cyanobacteria. Following predawn dew deposition, they harvest light energy with maximum efficiency until desiccating in the early morning hours...
August 29, 2017: Proceedings of the National Academy of Sciences of the United States of America
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