Role Of Nuclear Factor Kappa Research Articles

Vascular inflammation, insulin resistance, and endothelial dysfunction in salt-sensitive hypertension: role of nuclear factor kappa B activation

Activation of the nuclear factor kappa B (NF kappaB) inflammatory pathway by angiotensin II and reactive oxygen species may play an important role in the development of insulin resistance and cardiovascular injury in hypertensive and metabolic diseases. We have shown that in hypertensive Dahl salt-sensitive rats, upregulation of angiotensin II and reactive oxygen species contributed to increased vascular inflammatory gene expression, endothelial dysfunction, and insulin resistance. Herein, we investigated whether activation of NF kappaB contributes to the development of endothelial dysfunction, vascular injury, and vascular and peripheral insulin resistance in salt-sensitive hypertension. Dahl salt-sensitive rats were fed a normal (0.5% NaCl) or high-salt diet (4% NaCl), or high-salt diet and pyrrolidine dithiocarbamat (150 mg/kg in drinking water), an inhibitor of NF kappaB activation, for 6 weeks. Hypertensive Dahl salt-sensitive rats manifested impaired endothelium-dependent relaxation to acetylcholine, aortic hypertrophy (35%), increased plasma C-reactive protein (25%), vascular superoxide (O2) production (148%), and expression of monocyte chemoattractant protein-1, tumor necrosis factor alpha, phospho-I kappaB alpha, and phospho-(Ser536)-p65NF kappaB. Pyrrolidine dithiocarbamat significantly improved endothelium-dependent relaxation, reduced vascular O2, and normalized aortic hypertrophy and systemic and local inflammation, despite only mildly reducing blood pressure. Hypertensive Dahl salt-sensitive rats also manifested impaired insulin-mediated vasorelaxation and Akt/endothelial nitric oxide synthase phosphorylation and decreased insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate, -32%). Pyrrolidine dithiocarbamat significantly improved insulin-mediated vascular relaxation and Akt/endothelial nitric oxide synthase phosphorylation as well as insulin sensitivity. The current findings strongly suggest that activation of the NF kappaB inflammatory pathway by angiotensin II-induced reactive oxygen species generation may importantly contribute to vascular injury, systemic inflammation, as well as vascular and peripheral insulin resistance in salt-sensitive hypertension.

NO Way to Relax

The roles of nitric oxide (NO) in the heart have been studied intensely ever since the first report nearly 2 decades ago showing that endogenous NO modulates cardiac myocyte function.1 All 3 NO synthase (NOS) isoforms have been found in mammalian heart tissues (see reviews in Massion et al2 and Belge et al3). A complex array of myocyte and nonmyocyte cells in the heart express NOS isoforms, and the local generation of NO2,3 and reactive oxygen species (ROS)4 may exert both autocrine and paracrine effects on cellular function. Not only is the endothelial isoform of NOS (eNOS, or NOS3) robustly expressed in the endothelial cells of the cardiac vasculature, but eNOS is also present within cardiac myocytes, where the enzyme associates with the scaffolding/regulatory protein caveolin-3 in T tubules in plasmalemmal caveolae.5 The neuronal NOS (nNOS, or NOS1) is also expressed in cardiac myocytes, where the enzyme appears to be localized in the sarcoplasmic reticulum and modulates phospholamban phosphorylation.6 Although both eNOS and nNOS appear to be physiologically expressed in cardiac tissues, the inflammation-related NOS isoform (iNOS, or NOS2) only appears in the heart after immunoactivation; iNOS may modulate the decline in myocardial function seen in sepsis.7 There have been innumerable studies of the cardiac effects of various NOS inhibitors, NO-donating drugs, and NO itself.2 The cardiac phenotypes of NOS “knockout” mouse models have been characterized extensively, and mice lacking 1, 2, or all 3 NOS isoforms have been generated and characterized.8 In addition, the roles of NOS substrates, cofactors, and allosteric modulators have been explored exhaustively in diverse cardiac model systems. Emerging from this broad range of experimental evidence is an increasingly clear view that NO and NOS are key determinants of cardiac function. Yet the molecular mechanisms and …

Recombinant murine cytomegalovirus vector activates human monocyte-derived dendritic cells in a NF- κB dependent pathway

To evaluate the potential use of recombinant murine cytomegalovirus (MCMV) as an antigen delivery vector, we examined the cytokine and CD80 and CD86 expression profiles of MCMV encoding either enhanced green fluorescent protein gene (MCMV-EGFP) or human immunodeficiency virus-1 glycoprotein gp120 gene (MCMV-gp120) infected monocyte-derived dendritic cells (Mo-DC) and investigated the role of nuclear factor kappa B (NF-κB) in Mo-DC activation. Results showed that MCMV triggered the induction of inflammatory cytokines and/or CD80 and CD86 up-regulation in Mo-DC. UV-inactivated MCMV exhibited a reduced production of inflammatory cytokines and a lowered expression of CD80 and CD86 compared with live MCMV infection. Treatment of cells with a NF-κB peptide inhibitor prior to MCMV infection reduced the induction of cytokines and CD80 and CD86 up-regulation. Overall, the results suggest that recombinant MCMV vectors activate human Mo-DC in a NF-κB dependent pathway. The abortive infection or de novo gene expression greatly enhances the activation of Mo-DC by MCMV vectors.

42. The mood stabilizer valproic acid down regulates neuronal cyclooxygenase-2 expression: Central role of nuclear factor-kappa B after long-term, but not short-term treatment

42. The mood stabilizer valproic acid down regulates neuronal cyclooxygenase-2 expression: Central role of nuclear factor-kappa B after long-term, but not short-term treatment

Activated Nuclear Factor Kappa B and Airway Inflammation After Smoke Inhalation and Burn Injury in Sheep

In a recent study, we have shown a rapid inflammatory cell influx across the glandular epithelium and strong proinflammatory cytokine expression at 4 hours after inhalation injury. Studies have demonstrated a significant role of nuclear factor kappa B in proinflammatory cytokine gene transcription. This study examines the acute airway inflammatory response and immunohistochemical detection of p65, a marker of nuclear factor kappa B activation, in sheep after smoke inhalation and burn injury. Pulmonary tissue from uninjured sheep and sheep at 4, 8, 12, 24, and 48 hours after inhalation and burn injury was included in the study. Following immunostaining for p65 and myeloperoxidase, the cell types and the percentage of bronchial submucosal gland cells staining for p65 and the extent of myeloperoxidase stained neutrophils in the bronchial submucosa were determined. Results indicate absence of detection of P65 before 12 hours after injury. At 12 hours after injury, strong perinuclear staining for p65 was evident in bronchial gland epithelial cells, macrophages, and endothelial cells. Bronchial submucosal gland cells showed a significant increase in the percentage of cells stained for p65 compared with uninjured animals and earlier times after injury, P < .05. At 24 and 48 hours after injury, p65 expression was evident in the bronchiolar epithelium, Type II pneumocytes, macrophages, and endothelial cells. Quantitation of the neutrophil influx into the bronchial submucosa showed a significant increase compared with uninjured tissue at 24 and 48 hours after injury, P < .05. In conclusion, immunohistochemical detection of activated p65 preceded the overall inflammatory response measured in the lamina propria. However, detection of p65 did not correlate with a recent study showing rapid emigration of neutrophils at 4 hours postinjury. Together, these results suggest that p65 immunostaining may identify cells that are activated to produce proinflammatory cytokines after injury; however, the immunoexpression may not adequately reflect the temporal activation of gene transcription that may occur with proinflammatory cytokine production with inhalation injury.

Lésion pigmentée épigastrique

We have explored the role of nuclear factor kappa B(NF-κB) in the pathogenesis of chronic glomerulonephritis, and investigated the effect of rhododendron root on the activation of NF-κB .Thirty-six Wistar rats were randomly divided into three groups: a control group, a glomerulonephritis model group and a therapy group(glomerulonephritis animals treated with the root of rhododendron). Bovine serum albumin(BSA) nephritis was induced by subcutaneous immunization and daily intraperitoneal administration of BSA. Twenty-four-hour urinary protein and serum creatinine values were measured, and renal pathology was assessed histologically by optical microscopy and electron microscopy. NF-κB activity was determined by an electrophoretic mobility shift assay(EMSA).Compared with the control rats, glomerulonephritis model rats exhibited a significant increase in both 24 h urinary protein and serum creatinine, and had abnormal renal histology. The administration of the root of rhododendron ameliorated these changes. NF-κB activity in glomerulonephritis model group was greater than that in rhododendron-treated group, and NF-κB activity was greater in both glomerulonephritis groups than in the control group(P < 0.01).These observations suggest that NF-κB plays a role in the pathogenesis of chronic glomerulonephritis, and rhododendron root may attenuate renal damages by downregulating the activation of NF-κ B in this model.

Suppression of nuclear factor kappa B ameliorates astrogliosis but not amyloid burden in APPswe/PS1dE9 mice

Neuroinflammation has been linked to the pathologies of Alzheimer's disease (AD), however, its effects on beta-amyloid (Aβ) burden are unclear. This study investigated the role of nuclear factor kappa B (NF-κB) in regulating neuroinflammation and Aβ deposition in a transgenic mouse model of AD. The APPswe/PS1dE9 mice and their wild-type controls received either the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC, i.p. 50 mg/kg daily) or saline starting at 7 months of age for 5 months. Expression of cyclooxygenase-2 (COX-2), tissue necrosis factor alpha (TNFα) precursor protein and microtubule-associated protein 2 was determined, and astrogliosis was assessed. Hippocampal and cortical levels of Aβ 1-40 and Aβ 1-42 were measured using ELISA. PDTC treatment effectively suppressed NF-κB signaling in APPswe/PS1dE9 mice as evidenced by the abolishment of COX-2 and TNFα induction. Inhibition of NF-κB further attenuated astrogliosis in the transgenic AD mice, yet markedly increased cerebral Aβ 1-42 burden. Our findings suggest that NF-κB can mediate induction of COX-2, TNFα and astrogliosis in APPswe/PS1dE9 mice. Additionally, these results support the idea that neuroinflammation contributes to the clearance of Aβ.

The effect of root of rhododendron on the activation of NF-κ B in a chronic glomerulonephritis rat model

Objective We have explored the role of nuclear factor kappa B(NF-κB) in the pathogenesis of chronic glomerulonephritis, and investigated the effect of rhododendron root on the activation of NF-κB . Methods Thirty-six Wistar rats were randomly divided into three groups: a control group, a glomerulonephritis model group and a therapy group(glomerulonephritis animals treated with the root of rhododendron). Bovine serum albumin(BSA) nephritis was induced by subcutaneous immunization and daily intraperitoneal administration of BSA. Twenty-four-hour urinary protein and serum creatinine values were measured, and renal pathology was assessed histologically by optical microscopy and electron microscopy. NF-κB activity was determined by an electrophoretic mobility shift assay(EMSA). Results Compared with the control rats, glomerulonephritis model rats exhibited a significant increase in both 24 h urinary protein and serum creatinine, and had abnormal renal histology. The administration of the root of rhododendron ameliorated these changes. NF-κB activity in glomerulonephritis model group was greater than that in rhododendron-treated group, and NF-κB activity was greater in both glomerulonephritis groups than in the control group( P < 0.01). Conclusion These observations suggest that NF-κB plays a role in the pathogenesis of chronic glomerulonephritis, and rhododendron root may attenuate renal damages by downregulating the activation of NF-κ B in this model.

Diethyl dithiocarbamic acid, a possible nuclear factor kappa B inhibitor, attenuates ischemic postconditioning-induced attenuation of cerebral ischemia–reperfusion injury in mice

The present study was designed to pharmacologically investigate the possible role of nuclear factor kappa B (NF-kappaB) in the reversal of global cerebral injury induced by ischemia and reperfusion after ischemic postconditioning. Bilateral carotid artery occlusion for 17 min followed by reperfusion for 24 h was employed to produce ischemia- and reperfusion-induced cerebral injury in mice. Cerebral infarct size was measured by using triphenyltetrazolium chloride staining. Memory was evaluated using the Morris water maze test. The rotarod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced a marked increase in cerebral infarct size, impairment of memory, and motor coordination. A set of 5 episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia-reperfusion-induced cerebral infarct size and behavioral deficits measured in terms of loss of memory and motor coordination. Diethyl dithiocarbamic acid sodium salt trihydrate (DDA) (100 mg/kg, i.p.), an inhibitor of NF-kappaB, given 30 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that the beneficial effects of ischemic postconditioning on global cerebral ischemia- and reperfusion-induced cerebral injury and behavioral deficits may involve activation of the NF-kappaB-linked pathway.

Występowanie oraz patogeneza zespołu jadłowstrętu i wyniszczenia nowotworowego w raku płuca

The cachexia-anorexia syndrome (CACS) is common and important implication of cancer. It occurs in 30% to 80% cancer patients. At the time of diagnosis of lung cancer CACS is not yet very important problem, but the weight loss increases with progression of the cancer. CACS is characterized by anorexia, weight loss, weakness, impaired immune system and metabolic dysfunction. Weight loss is a potent stimulus to food intake in normal humans. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response. The weight loss in patients with CACS differs from that in simple starvation or anorexia nervosa. Most research effort has focused on the role of cytokines as mediators of CACS. The role of TNF-alpha, IL-1 and IL-6 in CACS development has been evaluated and confirmed in many research, but some investigators suggest that the changes in cytokines' levels could be the result rather than the cause of CACS. A few of the latest studies concentrate on the role of nuclear factor kappa B and prevention of CACS by its inhibitors. CACS is an independent predictor of shorter survival and increases the risk of treatment failure and toxicity.

Proteomic analysis of brain protein expression levels in NF-κβ p50 −/− homozygous knockout mice

Abstract The role of nuclear factor kappa B (NF-κB) in oxidative stress, and most recently in pro- and anti-apoptotic-related mechanistic pathways, has well been established. Because of the dual nature of NF-κB, the wide range of genes it regulates and the plethora of stimuli that activate it, various studies addressing the functional role of NF-κB proteins have resulted in a number of differing findings. The present study examined the effect of a stimulus-free environment on the frontal cortex of mice brain with the p50 subunit of NF-κB knocked out p50 (−/−). Homozygous p50 mice knockout (KO) and wild type (WT) were used, and at 7–9 weeks they were sacrificed and various brain regions dissected. We analyzed the levels of oxidation in the frontal cortex of both the p50 (−/−) and WT mice. There was a significant reduction in the levels of protein-bound 4-hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3NT), and protein carbonyls in the p50 (−/−) mice when compared to the WT. A proteomic profile analysis identified ATP synthase gamma chain, ubiquinol-cyt-C reductase, heat shock protein 10 (Hsp10), fructose bisphosphate aldolase C, and NADH–ubiquinone oxidoreductase as proteins whose expressions were significantly increased in the p50 (−/−) mice compared to the WT. With the reduction in the levels of oxidative stress and the increase in expression of key proteins in the p50 (−/−) brain, this study suggests that the p50 subunit can potentially be targeted for the development of therapeutic interventions in disorders in which oxidative stress plays a key role.

The profile of gene expression and role of nuclear factor kappa B on glomerular injury in rats with Thy-1 nephritis.

Mesangioproliferative glomerulonephritis (MsPGN) is a disease of high incidence in humans. Rats with Thy-1 nephritis (Thy-1 N) are used as an animal model for studying MsPGN. Although several studies have demonstrated that many pathological factors could cause the injury of glomerular mesangial cells (GMCs) in Thy-1 N, changes of profile and the molecular mechanism of the disease (i.e. the role of transcription factors) at intervals remain unclear. The purpose of this study was to identify the changes in gene expression profile and to observe the role of nuclear factor kappa B (NF-kappaB) on the pathological change of renal tissue in Thy-1 N rats. Our results showed that the pathological changes of GMCs in Thy-1 N included three phases: apoptosis (40 min), necrosis (24 h) and proliferation (7 days). Concomitantly, at 40 min and on day 7, the up-regulation of 341 genes and 250 genes were observed, while 392 genes and 119 genes were down-regulated in Thy-1 N. Expression of interleukin (IL)-1beta, IL-6, proliferating cell nuclear antigen, alpha-smooth muscle actin, collagen type IV and excretion of urinary protein was increased in rats with Thy-1 N and decreased in pyrrolidine dithiocarbamate-treated rats with Thy-1 N. These data indicated that the significant changes in the gene profile were coupled with the pathological changes of Thy-1 N, and activation of NF-kappaB may contribute to the pathogenesis of GMCs apoptosis, proliferation, extracelluar matrix accumulation and proteinuria in Thy-1 N.

Roles of nuclear factor-kappa B, tumor necrosis factor-α and Bcl-2 in acute hepatic injury and their mechanisms

Roles of nuclear factor-kappa B, tumor necrosis factor-α and Bcl-2 in acute hepatic injury and their mechanisms

Protective effects of N-acetylcysteine against liver injury in rats with severe acute pancreatitis

AIM:To investigate the role of nuclear factor-kappa B(NF-κB)activation in liver injury in rats with severe acute pancreatitis(SAP),and to explore the protective effect of N-acetylcysteine(NAC)against SAP-associated liver injury in rats.METHODS:Forty-two Wistar male rats were divided into sham operation group(SO,n = 6),SAP group(n = 18),and SAP + NAC group(NAC,300 mg/kg body wt,n = 18).SO group underwent laparotomy only.SAP model was established by retrograde injection of 50 g/L so-dium taurocholate into the bili-pancreatic duct in Wistar rats.SAP + NAC group were given NAC 300 mg/kg body weight intaperitoneally 2 h before SAP model was established.Rats were sacrificed at 3,6 and 12 h after operation.The liver and pancreas tissues were obtained to observe their pathological changes with light microscopy.The levels of serum ALT and AST were determined at three time points(8 rats for each time point).The expression of TNF-α mRNA was detected by reverse transcription polymerase chain reaction(RT-PCR).The activ-ity of NF-κB in liver was examined by immuno-histochemical methods.RESULTS:The levels of serum ALT and AST increased significantly in SAP group as com-pared with those in SO group at 3,6 and 12 h(ALT:186.67 ± 27.28,321.17 ± 56.14,492.50 ± 69.77 vs 36.83 ± 7.02;AST:255.50 ± 44.15,343.17 ± 43.70,425.33 ± 58.37 vs 41.67 ± 5.35;P 0.05 or 0.01).The level of TNF-α mRNA in SAP group was significantly higher than that in SO group at 3,6 and 12 h(0.37 ± 0.03,0.77 ± 0.04,0.54 ± 0.04 vs 0.24 ± 0.03;P 0.05 or 0.01).The activity of NF-κB was also higher in SAP group than that in SO group at 3 or 6 h(51.95 ± 4.76,24.67 ± 4.93 vs 9.33 ± 2.05;P 0.01 or 0.05).Liver and pan-creas pathological damages were more severe in SAP group than those in SO group under light microscope.In SAP + NAC group,the levels of serum ALT and AST(143.67 ± 16.62,203.33 ± 25.41,301.17 ± 26.82;136.33 ± 26.27,221.50 ± 38.31,310.50 ± 38.17)decreased significantly in comparison with those in SAP group(P 0.05 or 0.01),and the expression of TNF-α mRNA was significantly lower than that in SAP group at the three time points(0.25 ± 0.03,0.50 ± 0.05,0.43 ± 0.03,P 0.05 or 0.01).The activity of NF-κB in SAP + NAC group was lower than that in SAP group at 3 or 6 h(37.60 ± 6.37,12.88 ± 2.66,P 0.05).CONCLUSION:NF-κB activation and TNF-α mRNA up-regulation involve in the pathogen-esis of liver injury in SAP rats.NAC at a dose of 300 mg/kg can alleviate the pathological dam-age to liver,and its mechanism might relate to inhibition of NF-κB activation and reduction of cytokines such as TNF-α.

F.62. Essential Role of Nuclear Factor-kappa B for NADPH Oxidase Activity, CYBB and NCF-1 Gene Expression in Normal and Anhidrotic Ectodermal Dysplasia Leukocytes

F.62. Essential Role of Nuclear Factor-kappa B for NADPH Oxidase Activity, CYBB and NCF-1 Gene Expression in Normal and Anhidrotic Ectodermal Dysplasia Leukocytes

Regulation of adhesion molecule expression in human endothelial and smooth muscle cells by omega-3 fatty acids and conjugated linoleic acids: Involvement of the transcription factor NF- κB?

We previously showed conjugated linoleic acids (CLA) inhibited TNF- α-induced monocyte (THP-1) adhesion to human umbilical vein endothelial cells (HUVEC) in vitro which involved an increase in platelet activating factor (PAF). Here we show adhesion molecule (ADM) regulation by fatty acids and the differing role of nuclear factor kappa B (NF- κB) activation in HUVEC and vascular smooth muscle cells (vSMC). CLA and omega-3 long-chain polyunsaturated fatty acids (PUFA) (FA) reduced TNF-ά-induced expression of ADMs (intercellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule-1 (VCAM-1) but not E-selectin) on HUVEC and vSMC to different extents depending on FA type and concentration, cell type and method of analysis. I κBά phosphorylation in HUVEC and vSMC and transient transfection with NF- κB-luciferase reporter plasmid (HUVEC only) indicated differential NF- κB involvement during FA modulation ( cis-9, trans-11; trans-10, cis-12 and a 50:50 mix of both CLA isomers; eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA)). TNF- α-induced ADM expression in both cell types by 2–10-fold. In HUVEC, CLA t10, c12 and CLA mix (50:50 mixture of CLA c9, t11 and t10, c12) and EPA and DHA reduced ICAM-1 expression (15–35%) at 12.5, 25 and/or 50 μM. VCAM-1 expression was reduced by 25 μM t10, c12 isomer and mix; omega-3 PUFA and other concentrations of CLA and TNF- α-induced E-selectin expression were unaffected. TNF α-induced inhibitor kappa B (I κB) phosphorylation was biphasic peaking at 5 min in both cell types and 60 and 120 min in HUVEC and SMC, respectively. I κB α phosphorylation and NF- κB activity was reduced (29% and 30%, respectively) by 25 μM CLA mix. n-3 PUFA did not reduce I κB α phosphorylation or NF- κB activity but reduced ADM expression. We show that n-3 PUFA and CLA reduce expression of ADM on HUVEC and vSMC. This reflected reduced adherence of monocytes to HUVEC previously reported by our group. Reduction of ICAM-1 and VCAM-1 protein expression by n-3 PUFA was less dependent on the NF- κB pathway than reduction by CLA which reflected the parallel attenuation of NF- κB activity. This indicated involvement of other transcription factors (i.e. AP-1) in the FA regulation of ADM expression and has, to our knowledge, not been previously reported.

Role of NF-κB and MAPKs in Light-Induced Photoreceptor Apoptosis

To elucidate the role of nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) in light-induced apoptosis of photoreceptors in culture and to explore the potential inhibitory effect of minocycline and sulforaphane on apoptosis. Apoptosis of 661W cells was induced by exposure to light and was detected by terminal dUTP transferase nick end labeling (TUNEL). The mRNA expression and protein production of 10 chemokines and noxious factors were examined by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The protein expression of the p65 subunit of NF-kappaB, and the MAPKs p-p38, p-p44/42, and p-JNK were examined by Western blot and immunofluorescence analyses. After exposure to light for 4 hours, 60% to 70% of the 661W cells underwent apoptosis. The expression of five selected chemokines and noxious factors was upregulated. The protein expression of the p65 subunit of NF-kappaB was downregulated, and the expression of the MAPKs p-p38, p-p44/42, and p-JNK was upregulated. Pretreatment with SB203580 for 1 hour inhibited light-induced upregulation of p-p38 and inhibited photoreceptor apoptosis. Pretreatment with minocycline or sulforaphane for 1 hour inhibited light-induced downregulation of the NF-kappaB p65 subunit and inhibited photoreceptor apoptosis. Apoptotic photoreceptors secrete chemokines and noxious factors to induce an immunologic response. The NF-kappaB and MAPK pathways both are involved in light-induced 661W photoreceptor apoptosis. Minocycline and sulforaphane inhibit light-induced photoreceptor apoptosis, partly through an NF-kappaB-dependent mechanism, but not through the MAPK pathway.

New-Onset Diabetes, Antihypertensive Treatment, and Outcome

New-onset diabetes (NOD) confers increased risk for cardiovascular disease and all-cause mortality in different clinical settings.1,2 In the specific context of hypertensive subjects exposed to the long-term effects of antihypertensive drugs, a study from our group3 and a recent 28-year follow-up study from Sweden4 showed a greater risk of major cardiovascular disease in hypertensive subjects who developed NOD than in those who did not. Notably, the yearly incidence of NOD ranged from 1.0% in the Swedish study4 to 1.9% in our study.3 This issue of Hypertension hosts a posthoc analysis of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) database, which tested the hypothesis that NOD is a predictor of cardiac morbidity and cardiac and all-cause mortality.5 The hypertensive subjects who developed NOD showed a 43% higher risk of cardiac morbidity (ie, a composite of sudden death, myocardial infarction, death associated with revascularization, and congestive heart failure requiring hospitalization) when compared with those who did not develop diabetes. When the determinants of the composite pool of cardiovascular events were examined separately, NOD was associated with a marginally higher risk of myocardial infarction (hazard ratio [HR]: 1.30; 95% CI: 0.99 to 1.70; P =0.057) and a significantly higher risk of congestive heart failure (HR: 1.41; 95% CI: 1.06 to 1.87; P =0.017). These findings are in full agreement with a recent report from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), in which NOD was associated with a 74% excess risk …

Role of nuclear factor kappa B and reactive oxygen species in the tumor necrosis factor-a-induced epithelial-mesenchymal transition of MCF-7 cells

The microenvironment of the tumor plays an important role in facilitating cancer progression and activating dormant cancer cells. Most tumors are infiltrated with inflammatory cells which secrete cytokines such as tumor necrosis factor-alpha (TNF-alpha). To evaluate the role of TNF-alpha in the development of cancer we studied its effects on cell migration with a migration assay. The migrating cell number in TNF-alpha-treated group is about 2-fold of that of the control group. Accordingly, the expression of E-cadherin was decreased and the expression of vimentin was increased upon TNF-alpha treatment. These results showed that TNF-alpha can promote epithelial-mesenchymal transition (EMT) of MCF-7 cells. Further, we found that the expression of Snail, an important transcription factor in EMT, was increased in this process, which is inhibited by the nuclear factor kappa B (NFkappaB) inhibitor aspirin while not affected by the reactive oxygen species (ROS) scavenger N-acetyl cysteine. Consistently, specific inhibition of NFkappaB by the mutant IkappaBalpha also blocked the TNF-alpha-induced upregulation of Snail promoter activity. Thus, the activation of NFkappaB, which causes an increase in the expression of the transcription factor Snail is essential in the TNF-alpha-induced EMT. ROS caused by TNF-alpha seemed to play a minor role in the TNF-alpha-induced EMT of MCF-7 cells, though ROS per se can promote EMT. These findings suggest that different mechanisms might be responsible for TNF-alpha- and ROS-induced EMT, indicating the need for different strategies for the prevention of tumor metastasis induced by different stimuli.

Ultraviolet B Regulation of Transcription Factor Families: Roles of Nuclear Factor-kappa B (NF-&amp;#954;B) and Activator Protein-1 (AP-1) in UVB-Induced Skin Carcinogenesis

Prolonged and repeated exposure of the skin to ultraviolet light (UV) leads not only to aging of the skin but also increases the incidence of non-melanoma skin cancer (NMSC). Damage of cells induced by ultraviolet B (UVB) light both at the DNA level and molecular level initiates the activation of transcription factor pathways, which in turn regulate the expression of a number of genes termed the "UV response genes". Two such transcription factor families that are activated in this way are those of the nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) families. These two transcription factor families have been identified to be involved in the processes of cell proliferation, cell differentiation and cell survival and therefore play important roles in tumorigenesis. The study of these two transcription factor pathways and the cross-talk between them in response to UVB exposure may help with the development of new chemopreventive strategies for the prevention of UVB-induced skin carcinogenesis.