Interference With Akt Signaling Protects Against Myocardial Infarction And Death By Limiting The Consequences Of Oxidative Stress
adhesion molecule-1 expression; Biochemistry & Molecular Biology; cardiac dysfunction; Cell Biology; density-lipoprotein; extends life-span; foam cell-formation; nf-kappa-b; nitric-oxide; oxidized phospholipids; scavenger receptor cd36; sr-bi
The intricacy of multiple feedback loops in the pathways downstream of Akt allows this kinase to control multiple cellular processes in the cardiovascular system and precludes inferring consequences of its activation in specific pathological conditions. Akt1, the major Akt isoform in the heart and vasculature, has a protective role in the endothelium during atherosclerosis. However, Akt1 activation may also have detrimental consequences in the cardiovascular system. Mice lacking both the high-density lipoprotein receptor SR-BI (scavenger receptor class B type I) and ApoE (apolipoprotein E), which promotes clearance of remnant lipoproteins, are a model of severe dyslipidemia and spontaneous myocardial infarction. We found that Akt1 was activated in these mice, and this activation correlated with cardiac dysfunction, hypertrophy, and fibrosis; increased infarct area; cholesterol accumulation in macrophages and atherosclerosis; and reduced life span. Akt1 activation was associated with inflammation, oxidative stress, accumulation of oxidized lipids, and increased abundance of CD36, a major sensor of oxidative stress, and these events created a positive feedback loop that exacerbated the consequences of oxidative stress. Genetic deletion of Akt1 in this mouse model resulted in decreased mortality, alleviation of multiple complications of heart disease, and reduced occurrence of spontaneous myocardial infarction. Thus, interference with Akt1 signaling in vivo could be protective and improve survival under dyslipidemic conditions by reducing oxidative stress and responses to oxidized lipids.
Kerr B A; Ma L N; West X Z; Ding L; Malinin N L; Weber M E; Tischenko M; Goc A; Somanath P R; Penn M S; Podrez E A; Byzova T V
Science Signaling
2013
2013-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1126/scisignal.2003948" target="_blank" rel="noreferrer noopener">10.1126/scisignal.2003948</a>
Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice
adiponectin receptors; adipose-tissue; CB1 receptors; disruption; endocannabinoid system; Endocrinology & Metabolism; fatty liver-disease; Inflammation; Insulin resistance; Kupffer cells; macrophage polarization; nf-kappa-b; nonalcoholic steatohepatitis; protein-2; reactive oxygen; siRNA; targeted; uncoupling
Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance. Methods: We used intravenously administered beta-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs. Results: We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation. Conclusion: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro inflammatory mechanism. Published by Elsevier GmbH.
Jourdan T; Nicoloro S M; Zhou Z; Shen Y F; Liu J; Coffey N J; Cinar R; Godlewski G; Gao B; Aouadi M; Czech M P; Kunos G
Molecular Metabolism
2017
2017-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.molmet.2017.08.011" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2017.08.011</a>
Delphinidin Inhibits Il-1 Beta-induced Activation Of Nf-kappa B By Modulating The Phosphorylation Of Irak-1(ser376) In Human Articular Chondrocytes
chondrocytes; COX-2; delphinidin; down-regulation; factor-alpha; gene-expression; human osteoarthritis chondrocytes; IL-1 beta; in-vitro; interleukin-1; kinase; nf-kappa-b; osteoarthritis; oxidative stress; PGE(2); rheumatoid-arthritis; Rheumatology; tumor-necrosis-factor
Objective. In OA, there is enhanced expression of pro-inflammatory cytokines such as IL-1 beta in the affected joint. Delphinidin, an anthocyanidin found in pigmented fruits and vegetables, has been shown to possess anti-inflammatory and antioxidant properties. In the present study we determined whether delphinidin would inhibit the IL-1 beta-induced activation of NF-kappa B in human chondrocytes and determined the mechanism of its action. Methods. PGE(2) levels and activation of NF-kappa B p65 in human OA chondrocytes were determined by ELISA-based assays. Protein expression of cyclo-oxygenase-2 (COX-2) and phosphorylation of kinases was determined by western immunoblotting. Expression level of mRNAs was determined by TaqMan assays. Results. Delphinidin inhibited IL-1 beta-induced expression of COX-2 and production of PGE(2) in human chondrocytes. Delphinidin also inhibited IL-1 beta-mediated phosphorylation of IL-1 receptor-associated kinase-1(Ser376), phosphorylation of IKK alpha/beta, expression of IKK beta, degradation of I kappa B alpha, and activation and nuclear translocation of NF-kappa B/p65. Phosphorylation of TGF-beta-activated kinase 1 was not observed but NF-kappa B-inducing kinase (NIK) was phosphorylated and phosphorylation of NIK was blocked by delphinidin in IL-1 beta-treated human chondrocytes. Conclusion. These data identify delphinidin as a novel inhibitor of IL-1 beta-induced production of cartilage-degrading molecule PGE(2) via inhibition of COX-2 expression and provide new insight into the mechanism of its action. Our results also identify inhibition of IRAK1(Ser376) phosphorylation by delphinidin in IL-1 beta-induced activation of NF-kappa B in human chondrocytes. Given the important role played by IL-1 beta-induced NF-kappa B activation, COX-2 expression and PGE(2) production in OA, our results may have important implications for the development of novel therapeutic strategies for the prevention/treatment of OA.
Haseeb A; Chen D X; Haqqi T M
Rheumatology
2013
2013-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1093/rheumatology/kes363" target="_blank" rel="noreferrer noopener">10.1093/rheumatology/kes363</a>
Black Currant Phytoconstituents Exert Chemoprevention Of Diethylnitrosamine-initiated Hepatocarcinogenesis By Suppression Of The Inflammatory Response
Biochemistry & Molecular Biology; cancer-cell proliferation; Chemoprevention; cyclooxygenase-2; cyclooxygenase-2 inhibitors; gamma-glutamyl-transferase; heat-shock proteins; heat-shock proteins; hepatocarcinogenesis; human hepatocellular-carcinoma; Inflammation; liver cancer; molecular chaperones; nf-kappa-b; nuclear factor-B; Oncology; ribes-nigrum; signaling; united-states
Black currant fruits containing high amounts of anthocyanins are known to possess potent antioxidant and anti-inflammatory properties. We have previously reported that anthocyanin-rich black currant skin extract (BCSE) inhibits diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats although the underlying mechanisms are not fully understood. Our present study investigates the anti-inflammatory mechanisms of BCSE during DENA rat liver carcinogenesis. Dietary BCSE (100 or 500mg/kg) treatment for 22wk afforded a striking inhibition of DENA-induced hepatic gamma-glutamyl transpeptidase-positive preneoplastic foci in a dose-responsive fashion. There was a significant increase in hepatic expression of heat shock proteins (HSP70 and HSP90), cyclooxygenase-2, and nuclear factor-B (NF-B) in DENA-exposed rat livers. Dietary BCSE dose-dependently abrogated all these elevated inflammatory markers. The possible cardiotoxicity of BCSE was assessed by monitoring cardiac functions using transthoracic echocardiography. BCSE-mediated anti-inflammatory effects during rat liver carcinogenesis have been achieved without any cardiotoxicity. Our results provide convincing evidence, for the very first time, that suppression of the inflammatory cascade through modulation of the NF-B signaling pathway could be implicated, at least in part, in the chemopreventive effects of black currant bioactive phytoconstituents against experimental hepatocarcinogenesis. These results coupled with an excellent safety profile of BCSE support the development of black currant phytochemicals for the chemoprevention of inflammation-driven hepatocellular cancer. (c) 2011 Wiley Periodicals, Inc.
Bishayee A; Thoppil R J; Mandal A; Darvesh A S; Ohanyan V; Meszaros J G; Haznagy-Radnai E; Hohmann J; Bhatia D
Molecular Carcinogenesis
2013
2013-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/mc.21860" target="_blank" rel="noreferrer noopener">10.1002/mc.21860</a>
Bcl-2 Regulates Chondrocyte Morphology And Aggrecan Gene Expression Independent Of Caspase Activation And Full Apoptosis
aging; apoptosis; Biochemistry & Molecular Biology; cartilage; Cell Biology; chondrocyte; differentiation; expression; gene regulation; growth-factor; hl-60 cells; hormone-related peptide; nerve; nf-kappa-b; programmed cell-death; protein; skeletal development; targeted disruption
Feng L X; Balakir R; Precht P; Horton W E
Journal of Cellular Biochemistry
1999
1999-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/(sici)1097-4644(19990915)74:4%3C576::aid-jcb7%3E3.3.co;2-e" target="_blank" rel="noreferrer noopener">10.1002/(sici)1097-4644(19990915)74:4%3C576::aid-jcb7%3E3.3.co;2-e</a>
Black Currant Phytoconstituents Exert Chemoprevention Of Diethylnitrosamine-initiated Hepatocarcinogenesis By Suppression Of The Inflammatory Response
Biochemistry & Molecular Biology; cancer-cell proliferation; chemoprevention; cyclooxygenase-2; cyclooxygenase-2 inhibitors; gamma-glutamyl-transferase; heat-shock proteins; heat-shock proteins; hepatocarcinogenesis; human hepatocellular-carcinoma; inflammation; liver cancer; molecular chaperones; nf-kappa-b; nuclear factor-B; Oncology; ribes-nigrum; signaling; united-states
Bishayee A; Thoppil R J; Mandal A; Darvesh A S; Ohanyan V; Meszaros J G; Haznagy-Radnai E; Hohmann J; Bhatia D
Molecular Carcinogenesis
2013
2013-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/mc.21860" target="_blank" rel="noreferrer noopener">10.1002/mc.21860</a>
Light-Activatable Gold Nanoshells for Drug Delivery Applications
cancer nanotheranostics; drug delivery; gold nanoshells; growth-factor receptor; in-vitro; nanocarrier; nanoparticles; nf-kappa-b; Pharmacology & Pharmacy; photothermal-chemotherapy; release; surface-plasmon resonance; targeted delivery; theranostics; thermal therapy; triggered; triggered release
Gold nanoshells (AuNSs) are currently being investigated as nanocarriers for drug delivery systems and have both diagnostic and therapeutic applications, including photothermal ablation, hyperthermia, drug delivery, and diagnostic imaging, particularly in oncology. AuNSs are valuable for their localized surface plasmon resonance, biocompatibility, low immunogenicity, and facile functionalization. AuNSs used for drug delivery can be spatially and temporally triggered to release controlled quantities of drugs inside the target cells when illuminated with a near-infrared (NIR) laser. Recently, many research groups have demonstrated that these AuNS complexes are able to deliver antitumor drugs (e.g., doxorubicin, paclitaxel, small interfering RNA, and single-stranded DNA) into cancer cells, which enhances the efficacy of treatment. AuNSs can also be functionalized with active targeting ligands such as antibodies, aptamers, and peptides to increase the particles' specific binding to the desired targets. This article reviews the current research on NIR light-activatable AuNSs used as nanocarriers for drug delivery systems and cancer theranostics.
Singhana B; Slattery P; Chen A; Wallace M; Melancon M P
Aaps Pharmscitech
2014
2014-06
Journal Article
<a href="http://doi.org/10.1208/s12249-014-0097-8" target="_blank" rel="noreferrer noopener">10.1208/s12249-014-0097-8</a>