Pomegranate Phytoconstituents Blunt The Inflammatory Cascade In A Chemically Induced Rodent Model Of Hepatocellular Carcinogenesis
Biochemistry & Molecular Biology; cancer chemoprevention; Chemoprevention; cyclooxygenase-2; cyclooxygenase-2; factor-kappa-b; gene-expression; heat-shock proteins; hepatocarcinogenesis; human-disease; Inflammation; inhibitors; molecular chaperones; nitric-oxide synthase; Nuclear factor-kappaB; Nutrition & Dietetics; oxidative stress; Pomegranate; punica-granatum l.
Liver cancer, predominantly hepatocellular carcinoma (HCC), represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation. Due to dismal prognosis and limited therapeutic intervention, chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC. Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties. We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant mechanisms. Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB (NF-kappa B)-regulated inflammatory pathway, our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion (PE) during DENA-induced rat hepatocarcinogenesis. Rats were administered with PE (1 or 10 g/kg) 4 weeks before and 18 weeks following DENA initiation. There was a significant increase in hepatic expressions of inducible nitric oxide synthase, 3-nitrotyrosine, heat shock protein 70 and 90, cyclooxygenase-2 and NF-kappa B in DENA-exposed rat livers. PE dose-dependently suppressed all aforementioned elevated inflammatory markers. A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography. Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-kappa B signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis. Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits, namely, Nrf2-mediated redox signaling and NF-kappa B-regulated inflammatory pathway, by pomegranate phytoconstituents to achieve chemoprevention of HCC. (C) 2013 Elsevier Inc. All rights reserved.
Bishayee A; Thoppil R J; Darvesh A S; Ohanyan V; Meszaros J G; Bhatia D
Journal of Nutritional Biochemistry
2013
2013-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.jnutbio.2012.04.009" target="_blank" rel="noreferrer noopener">10.1016/j.jnutbio.2012.04.009</a>
Chronic Exposure To Nicotine And Saquinavir Decreases Endothelial Notch-4 Expression And Disrupts Blood-brain Barrier Integrity
acetylcholine-receptors; Biochemistry & Molecular Biology; choline transporter; cigarette-smoke condensate; electron-spin-resonance; endothelial cell toxicity; gene-expression; in-vitro; inhibitors; Neurosciences & Neurology; nicotine; Notch-4; osmotic pumps; parkinsons-disease; perfusion technique; protease; protease inhibitors; proteins; ritonaivir; ROS; saquinqavir; tight junction
Manda V K; Mittapalli R K; Geldenhuys W J; Lockman P R
Journal of Neurochemistry
2010
2010-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1111/j.1471-4159.2010.06948.x" target="_blank" rel="noreferrer noopener">10.1111/j.1471-4159.2010.06948.x</a>
Pomegranate Phytoconstituents Blunt The Inflammatory Cascade In A Chemically Induced Rodent Model Of Hepatocellular Carcinogenesis
Biochemistry & Molecular Biology; cancer chemoprevention; chemoprevention; cyclooxygenase-2; cyclooxygenase-2; factor-kappa-b; gene-expression; heat-shock proteins; hepatocarcinogenesis; human-disease; inflammation; inhibitors; molecular chaperones; nitric-oxide synthase; Nuclear factor-kappaB; Nutrition & Dietetics; oxidative stress; Pomegranate; punica-granatum l.
Bishayee A; Thoppil R J; Darvesh A S; Ohanyan V; Meszaros J G; Bhatia D
Journal of Nutritional Biochemistry
2013
2013-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.jnutbio.2012.04.009" target="_blank" rel="noreferrer noopener">10.1016/j.jnutbio.2012.04.009</a>
Role of angiotensin II in sympathetic nervous system induced left ventricular dysfunction
contractility; Physiology; myocardium; Pharmacology & Pharmacy; nitric-oxide; catecholamines; inhibitors; mechanisms; hearts; rabbits; bradykinin; attenuation; calcium channel opener-blocker; captopril; converting-enzyme inhibitor; myocardial; nifedipine; ramiprilat
Experiments were undertaken to determine whether angiotensin (Ang) II concentration increases during massive sympathetic nervous system (SNS) activation and whether such an increase plays a role in the pathogenesis of SNS-induced left ventricular (LV) dysfunction. We also sought to determine whether excessive Ca2+ uptake through L-type channels due to intense adrenoceptor activation is responsible for the LV dysfunction. AngII concentration was measured in the plasma and myocardium before and after massively activating the SNS with an intracisternal injection of veratrine. In separate experiments, rabbits were given losartan, enalaprilat, enalaprilat plus HOE-140, nifedipine, betaBay K 4866, or saline before massively activating the SNS. LV function was evaluated 2.5 h later. The intense SNS activity caused plasma and myocardial AngII to increase by 400 and 437%, respectively. AngII receptor blockade did not prevent LV dysfunction. In contrast, enalaprilat reduced the degree of dysfunction, but its cardioprotection was abolished by HOE-140. Although nifedipine prevented SNS-induced LV dysfunction, administration of the Ca2+ channel opener, betaBay K 4866, did not increase its severity. Our results indicate that AngII is not involved in the pathogenesis of SNS-induced LV dysfunction and that the cardioprotection provided by angiotensin converting enzyme (ACE) inhibition is due to activation of a bradykinin pathway. Furthermore, the finding that the magnitude of the LV dysfunction was reduced by enalaprilat, and not increased by betaBay K 4866, suggests that intense adrenoceptor activation of L-type Ca2+ channels is not the primary pathogenetic mechanism.
Bosso F J; Jarjoura D G; Pilati C F
Canadian Journal of Physiology and Pharmacology
1999
1999-10
Journal Article or Conference Abstract Publication
n/a
Novel role of aminopeptidase-A in angiotensin-(1-7) metabolism post myocardial infarction
ace2; Aminopeptidase A; angiotensin peptides; antihypertensive agents; carboxypeptidase; Cardiovascular System & Cardiology; enzyme; inhibitors; kidney; MALDI-imaging; mass-spectrometry; Myocardial infarction; Physiology; renal damage; renin-angiotensin system; spontaneously hypertensive-rats; system
Aminopeptidase-A (APA) is a less well-studied enzyme of the renin-angiotensin system. We propose that it is involved in cardiac angiotensin (ANG) metabolism and its pathologies. ANG-(1-7) can ameliorate remodeling after myocardial injury. The aims of this study are to 1) develop mass spectrometric (MS) approaches for the assessment of ANG processing by APA within the myocardium; and 2) investigate the role of APA in cardiac ANG-(1-7) metabolism after myocardial infarction (MI) using sensitive MS techniques. MI was induced in C57Bl/6 male mice by ligating the left anterior descending (LAD) artery. Frozen mouse heart sections (in situ assay) or myocardial homogenates (in vitro assay) were incubated with the endogenous APA substrate, ANG II. Results showed concentration-and time-dependent cardiac formation of ANG III from ANG II, which was inhibited by the specific APA inhibitor, 4-amino-4-phosphonobutyric acid. Myocardial APA activity was significantly increased 24 h after LAD ligation (0.82 +/- 0.02 vs. 0.32 +/- 0.02 rho mol.min(-1).mu g(-1), MI vs. sham, P < 0.01). Both MS enzyme assays identified the presence of a new peptide, ANG-(2-7), m/z 784, which accumulated in the MI (146.45 +/- 6.4 vs. 72.96 +/- 7.0%, MI vs. sham, P < 0.05). Use of recombinant APA enzyme revealed that APA is responsible for ANG-(2-7) formation from ANG-(1-7). APA exhibited similar substrate affinity for ANG-(1-7) compared with ANG II {K-m (ANG II) = 14.67 +/- 1.6 vs. K-m [ANG-(1-7)] = 6.07 +/- 1.12 mu mol/l, P < 0.05}. Results demonstrate a novel role of APA in ANG-(1-7) metabolism and suggest that the upregulation of APA, which occurs after MI, may deprive the heart of cardioprotective ANG-(1-7). Thus APA may serve as a potentially novel therapeutic target for management of tissue remodeling after MI.
Alghamri M S; Morris M; Meszaros J G; Elased K M; Grobe N
American Journal of Physiology-Heart and Circulatory Physiology
2014
2014-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajpheart.00911.2013" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00911.2013</a>
Catalysis of the cysteine conjugation and protein binding of acetaminophen by microsomes from a human lymphoblast line transfected with the cDNAs of various forms of human cytochrome P450
activation; ethanol; hepatic microsomes; hepatocytes; inhibitors; monoclonal-antibodies; oxidation; para-benzoquinone imine; Pharmacology & Pharmacy; rat-liver; reactive metabolite formation
We have previously found that for acetaminophen kinetic differences exist between the hepatic microsomal catalyzed protein binding and cysteine conjugation. We have also observed that the protein binding of acetaminophen is only to intralumenal proteins. Together these data suggested that two pools of the reactive metabolite, N-acetyl-p-benzoquinone imine (NABQI), are formed during the oxidative metabolism of acetaminophen: one on the cytosolic surface and the other within the lumen of the microsomes. This would indicate that some of forms of cytochrome P450 (CYP) catalyzing NABQI formation have their active site on the cytosolic surface and others on the lumenal surface. We have examined this question by comparing the rates of cysteine conjugation and protein binding of acetaminophen by microsomes from lymphoblasts tranfected with the cDNAs for human CYPs. We found that CYP2D6 catalyzed only cysteine conjugation; CYP1A2 and 3A4 catalyzed only protein binding; CYP2E1 catalyzed both; and CYP1A1, CYP2A6 and CYP2B6 catalyzed neither. These data suggest that CYP2D6 has its active site only on the cytosolic surface; CYP1A2 and CYP3A4 only on the lumenal surface; and CYP2E1 has catalytic sites on both the lumenal and cytosolic surfaces of the membrane. In mouse studies we have found that ethanol administration increased acetaminophen protein binding by 265% but cysteine conjugation by only 61%. CYP2E1 and CYP2B increased, whereas CYP3A decreased and the others did not change. These data suggest that in control mice CYP2E1 catalyzes the bulk of protein binding, whereas CYP2D catalyzes slightly more cysteine conjugation than does CYP2E1.
Zhou L X; Erickson R R; Hardwick J P; Park S S; Wrighton S A; Holtzman J L
Journal of Pharmacology and Experimental Therapeutics
1997
1997-05
Journal Article
n/a