scholarly journals Anti-Atherosclerotic Effect of Hibiscus Leaf Polyphenols against Tumor Necrosis Factor-alpha-Induced Abnormal Vascular Smooth Muscle Cell Migration and Proliferation

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 620 ◽  
Author(s):  
Cheng-Chung Chou ◽  
Chi-Ping Wang ◽  
Jing-Hsien Chen ◽  
Hui-Hsuan Lin
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

The proliferation and migration of vascular smooth muscle cells (VSMCs) are major events in the development of atherosclerosis following stimulation with proinflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α). Plant-derived polyphenols have attracted considerable attention in the prevention of atherosclerosis. Hibiscus leaf has been showed to inhibit endothelial cell oxidative injury, low-density lipoprotein oxidation, and foam cell formation. In this study, we examined the anti-atherosclerotic effect of Hibiscus leaf polyphenols (HLPs) against abnormal VSMC migration and proliferation in vitro and in vivo. Firstly, VSMC A7r5 cells pretreated with TNF-α were demonstrated to trigger abnormal proliferation and affect matrix metalloproteinase (MMP) activities. Non-cytotoxic doses of HLPs abolished the TNF-α-induced MMP-9 expression and cell migration via inhibiting the protein kinase PKB (also known as Akt)/activator protein-1 (AP-1) pathway. On the other hand, HLP-mediated cell cycle G0/G1 arrest might be exerted by inducing the expressions of p53 and its downstream factors that, in turn, suppress cyclin E/cdk2 activity, preventing retinoblastoma (Rb) phosphorylation and the subsequent dissociation of Rb/E2F complex. HLPs also attenuated reactive oxygen species (ROS) production against TNF-α stimulation. In vivo, HLPs improved atherosclerotic lesions, and abnormal VSMC migration and proliferation. Our data present the first evidence of HLPs as an inhibitor of VSMC dysfunction, and provide a new mechanism for its anti-atherosclerotic activity.

scholarly journals TNF-α Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Pathology

2013 ◽  
Vol 33 (10) ◽  
pp. 1564-1573 ◽  
Author(s):  
Muhammad S Ali ◽  
Robert M Starke ◽  
Pascal M Jabbour ◽  
Stavropoula I Tjoumakaris ◽  
L Fernando Gonzalez ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Matrix Remodeling ◽  
Phenotypic Modulation ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF-α) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-α-actin, SM-22α, smooth muscle myosin heavy chain), while dominant-negative cells suppressed expression. Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased expression of KLF4, a known regulator of SMC differentiation. Kruppel-like transcription factor 4 (KLF4) small interfering RNA abrogated TNF-α activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF-α and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF-α inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays in vivo and in vitro demonstrated that TNF-α promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF-α induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF-α in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.

scholarly journals Inhibition of Tumor Necrosis Factor Alpha-Induced NF-κB Activation by the Adenovirus E3-10.4/14.5K Complex

2002 ◽  
Vol 76 (11) ◽  
pp. 5515-5521 ◽  
Author(s):  
Joshua M. Friedman ◽  
Marshall S. Horwitz
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
E3 Region ◽  
Necrosis Factor

ABSTRACT Recombinant adenoviruses (Ads) are useful tools in gene transfer because they are able to infect a wide variety of tissues and cell types and do not require a replicating target cell. However, transgene expression is only transient due to host innate and acquired immune responses to the virus. Most recombinant Ads have deletions of early region 3 (E3) genes, allowing more space for insertion of the transgene. Although the E3 region is not necessary for infection, it has been observed that these “nonessential” genes have immunomodulatory properties. We demonstrate here that the E3 region of Ad inhibits the activation of NF-κB induced by tumor necrosis factor alpha (TNF-α) and interleukin-1. Ad E3 is able to prevent NF-κB from entering the nucleus, where it is normally active. Ad E3 also appears to function by preventing the activation of the kinase complex, IKK, which is responsible for phosphorylation of IκB that retains NF-κB in the cytoplasm in an inactive state. The prevention of NF-κB activation has been mapped to a complex of two of the seven E3 products, E3-10.4K and E3-14.5K (RIDα/β). These and other studies indicate that, by using Ad vectors containing the E3 region, it may be possible to reduce the harmful proinflammatory effects of TNF-α and other cytokines that compromise the use of Ad gene therapy vectors in vivo.

scholarly journals Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

2002 ◽  
Vol 70 (12) ◽  
pp. 6628-6637 ◽  
Author(s):  
Christopher J. Papasian ◽  
Richard Silverstein ◽  
Jian Jun Gao ◽  
David M. Bamberger ◽  
David C. Morrison
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Potential Contribution ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The murine d-galactosamine (d-gal) model of tumor necrosis factor alpha (TNF-α) hypersensitization was used as an initial tool to investigate the potential contribution of TNF-α to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. d-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF-α antibody protected d-gal-treated, E. faecalis-infected mice, implicating TNF-α in the lethal response to E. faecalis infection in d-gal-treated mice. Circulating TNF-α was undetectable for at least 8 h following i.p. E. faecalis infection, although low peritoneal levels of TNF-α were detected within 3 h, suggesting that localized TNF-α production contributed to the lethal response to E. faecalis infection in d-gal-treated mice. Although i.p. E. faecalis infection failed to induce a detectable systemic TNF-α response, circulating Interleukin-6 (IL-6) was detected within 3 h of infection. IL-6 was also detected in the peritoneum within an hour of infection, prior to the appearance of peritoneal TNF-α. In striking contrast to in vivo results, E. faecalis induced a potent and rapid TNF-α response from both mouse peritoneal macrophages and the RAW 264.7 cell line in vitro. This led us to hypothesize that TNF-α production in response to E. faecalis infection is suppressed by IL-6 in vivo. In vitro experiments demonstrated a statistically significant, but modest, inhibitory effect of IL-6 on TNF-α production by RAW cells stimulated with E. faecalis. Collectively, these data indicate that acute, lethal E. faecalis infection appears to induce an unusual cytokine response that differs in character from that previously described for most other gram-positive and gram-negative bacteria.

scholarly journals FoxO4 Regulates Tumor Necrosis Factor Alpha-Directed Smooth Muscle Cell Migration by Activating Matrix Metalloproteinase 9 Gene Transcription

2007 ◽  
Vol 27 (7) ◽  
pp. 2676-2686 ◽  
Author(s):  
Hao Li ◽  
Jianping Liang ◽  
Diego H. Castrillon ◽  
Ronald A. DePinho ◽  
Eric N. Olson ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Tumor Necrosis Factor ◽  
Matrix Metalloproteinase ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Metalloproteinase 9 ◽  
Necrosis Factor

ABSTRACT Phenotypic modulation of vascular smooth muscle cells (SMCs) in the blood vessel wall from a differentiated to a proliferative state during vascular injury and inflammation plays an important role in restenosis and atherosclerosis. Matrix metalloproteinase 9 (MMP9) is a member of the MMP family of proteases, which participate in extracellular matrix degradation and turnover. MMP9 is upregulated and required for SMC migration during the development of restenotic and atherosclerotic lesions. In this study, we show that FoxO4 activates transcription of the MMP9 gene in response to tumor necrosis factor alpha (TNF-α) signaling. Inhibition of FoxO4 expression by small interfering RNA or gene knockout reduces the abilities of SMCs to migrate in vitro and inhibit neointimal formation and MMP9 expression in vivo. We further show that both the N-terminal, Sp1-interactive domain and the C-terminal transactivation domain of FoxO4 are required for FoxO4-activated MMP9 transcription. TNF-α signaling upregulates nuclear FoxO4. Our studies place FoxO4 in the center of a transcriptional regulatory network that links gene transcription required for SMC remodeling to upstream cytokine signals and implicate FoxO4 as a potential therapeutic target for combating proliferative arterial diseases.

scholarly journals Stimulus-Specific Assembly of Enhancer Complexes on the Tumor Necrosis Factor Alpha Gene Promoter

2000 ◽  
Vol 20 (6) ◽  
pp. 2239-2247 ◽  
Author(s):  
James V. Falvo ◽  
Adele M. Uglialoro ◽  
Brigitta M. N. Brinkman ◽  
Menie Merika ◽  
Bhavin S. Parekh ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Virus Infection ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Calcium Flux ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The human tumor necrosis factor alpha (TNF-α) gene is rapidly activated in response to multiple signals of stress and inflammation. We have identified transcription factors present in the TNF-α enhancer complex in vivo following ionophore stimulation (ATF-2/Jun and NFAT) and virus infection (ATF-2/Jun, NFAT, and Sp1), demonstrating a novel role for NFAT and Sp1 in virus induction of gene expression. We show that virus infection results in calcium flux and calcineurin-dependent NFAT dephosphorylation; however, relatively lower levels of NFAT are present in the nucleus following virus infection as compared to ionophore stimulation. Strikingly, Sp1 functionally synergizes with NFAT and ATF-2/c-jun in the activation of TNF-α gene transcription and selectively associates with the TNF-α promoter upon virus infection but not upon ionophore stimulation in vivo. We conclude that the specificity of TNF-α transcriptional activation is achieved through the assembly of stimulus-specific enhancer complexes and through synergistic interactions among the distinct activators within these enhancer complexes.

scholarly journals Mitochondrial Carrier Homolog 2 Is a Target of tBID in Cells Signaled To Die by Tumor Necrosis Factor Alpha

2005 ◽  
Vol 25 (11) ◽  
pp. 4579-4590 ◽  
Author(s):  
Michal Grinberg ◽  
Michal Schwarz ◽  
Yehudit Zaltsman ◽  
Tzipi Eini ◽  
Hagit Niv ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Biochemical Purification ◽  
Necrosis Factor Alpha ◽  
Mitochondrial Carrier ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT BID, a proapoptotic BCL-2 family member, plays an essential role in the tumor necrosis factor alpha (TNF-α)/Fas death receptor pathway in vivo. Activation of the TNF-R1 receptor results in the cleavage of BID into truncated BID (tBID), which translocates to the mitochondria and induces the activation of BAX or BAK. In TNF-α-activated FL5.12 cells, tBID becomes part of a 45-kDa cross-linkable mitochondrial complex. Here we describe the biochemical purification of this complex and the identification of mitochondrial carrier homolog 2 (Mtch2) as part of this complex. Mtch2 is a conserved protein that is similar to members of the mitochondrial carrier protein family. Our studies with mouse liver mitochondria indicate that Mtch2 is an integral membrane protein exposed on the surface of mitochondria. Using blue-native gel electrophoresis we revealed that in viable FL5.12 cells Mtch2 resides in a protein complex of ca. 185 kDa and that the addition of TNF-α to these cells leads to the recruitment of tBID and BAX to this complex. Importantly, this recruitment was partially inhibited in FL5.12 cells stably expressing BCL-XL. These results implicate Mtch2 as a mitochondrial target of tBID and raise the possibility that the Mtch2-resident complex participates in the mitochondrial apoptotic program.

scholarly journals Association of tumor necrosis factor-alpha -308 G/A and -238 G/A polymorphism with diabetic retinopathy: a systematic review and updated meta-analysis.

2020 ◽  
Author(s):  
Wenna Gao ◽  
Ruilin Zhu ◽  
liu yang
Keyword(s):  
Diabetic Retinopathy ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Meta Analysis ◽  
Entire Group ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

Background: Mounting evidence has suggested tumor necrosis factor-alpha (TNF-α) can promote the development of diabetic retinopathy (DR), and TNF-α gene variants may influence DR risk. However, the results are quite different. Objectives: To comprehensively address this issue, we performed the meta-analysis to evaluate the association of TNF-α-308 G/A and -238 G/A polymorphism with DR. Method: Data were retrieved in a systematic manner and analyzed using STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Allelic and genotypic comparisons between cases and controls were evaluated. Results: For the TNF-α-308 G/A polymorphism, overall analysis suggested a marginal association with DR [the OR(95%CI) of (GA versus GG), (GA + AA) versus GG, and (A versus G) are 1.21(1.04, 1.41), 1.20(1.03, 1.39), and 1.14(1.01, 1.30), respectively]. And the subgroup analysis indicated an enhanced association among the European population. For the TNF-α-238 G/A polymorphism, there was mild correlation in the entire group [the OR(95%CI) of (GA versus GG) is 1.55(1.14,2.11) ], which was strengthened among the Asian population. Conclusion: The meta-analysis suggested that -308 A and -238 A allele in TNF-α gene potentially increased DR risk and showed a discrepancy in different ethnicities.

scholarly journals Analysis of Subcellular RNA Fractions Revealed a Transcription-Independent Effect of Tumor Necrosis Factor Alpha on Splicing, Mediated by Spt5

2016 ◽  
Vol 36 (9) ◽  
pp. 1342-1353 ◽  
Author(s):  
Gil Diamant ◽  
Tal Eisenbaum ◽  
Dena Leshkowitz ◽  
Rivka Dikstein
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Independent Effect ◽  
Necrosis Factor Alpha ◽  
Pol Ii ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Genes ◽  
Necrosis Factor

The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) modulates the expression of many genes, primarily through activation of NF-κB. Here, we examined the global effects of the elongation factor Spt5 on nascent and mature mRNAs of TNF-α-induced cells using chromatin and cytosolic subcellular fractions. We identified several classes of TNF-α-induced genes controlled at the level of transcription, splicing, and chromatin retention. Spt5 was found to facilitate splicing and chromatin release in genes displaying high induction rates. Further analysis revealed striking effects of TNF-α on the splicing of 25% of expressed genes; the vast majority were not transcriptionally induced. Splicing enhancement of noninduced genes by TNF-α was transient and independent of NF-κB. Investigating the underlying basis, we found that Spt5 is required for the splicing facilitation of the noninduced genes. In line with this, Spt5 interacts with Sm core protein splicing factors. Furthermore, following TNF-α treatment, levels of RNA polymerase II (Pol II) but not Spt5 are reduced from the splicing-induced genes, suggesting that these genes become enriched with a Pol II-Spt5 form. Our findings revealed the Pol II-Spt5 complex as a highly competent coordinator of cotranscriptional splicing.

scholarly journals HSP70 Induction by ING Proteins Sensitizes Cells to Tumor Necrosis Factor Alpha Receptor-Mediated Apoptosis

2006 ◽  
Vol 26 (24) ◽  
pp. 9244-9255 ◽  
Author(s):  
Xiaolan Feng ◽  
Shirin Bonni ◽  
Karl Riabowol
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Kinase Inhibitor ◽  
Heat Shock Gene ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Primary Fibroblasts ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer of apoptosis, are regulated by ING proteins. To identify additional targets downstream of p33ING1 and p32ING2, cDNA microarrays were performed on phenotypically normal human primary fibroblasts. The 0.36% of genes affected by ING proteins in primary fibroblasts were distinct from targets seen in established cells and included the HSP70 heat shock gene, whose promoter was specifically induced >10-fold. ING1-induced expression of HSP70 shifted cells from survival to a death pathway in response to tumor necrosis factor alpha (TNF-α), and p33ING1b protein showed synergy with TNF-α in inducing apoptosis, which correlated with reduced NF-κB-dependent transcription. These findings are consistent with previous reports that HSP70 promotes TNF-α-mediated apoptosis by binding I-κΒ kinase gamma and impairing NF-κB survival signaling. Induction of HSP70 required the amino terminus of ING1b but not the plant homeodomain region that was recently identified as a histone binding domain. Regulation of HSP70 gene expression by the ING tumor suppressors provides a novel link between the INGs and the stress-regulated NF-κB survival pathway important in hypoxia and angiogenesis.

scholarly journals Comparative Analysis of Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Activity in Serum and Lethality in Mice and Rabbits Pretreated with the Staphylococcal Superantigen Toxic Shock Syndrome Toxin 1

2001 ◽  
Vol 69 (11) ◽  
pp. 7169-7172 ◽  
Author(s):  
Martin M. Dinges ◽  
Patrick M. Schlievert
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Host Susceptibility ◽  
Necrosis Factor Alpha ◽  
Lethal Effects ◽  
Tnf Α ◽  
Factor Alpha ◽  
Toxic Shock Syndrome Toxin ◽  
Necrosis Factor

ABSTRACT Host susceptibility to lipopolysaccharide (LPS) is correlated with the levels of circulating tumor necrosis factor alpha (TNF-α) that develop in response to circulating LPS. Mice are resistant, relative to rabbits, to the lethal effects of LPS. This study indicates that mice and rabbits are equally sensitive to the lethal effects of circulating TNF-α but that mice are more resistant than rabbits to the induction of circulating TNF-α by LPS.

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