479 research outputs found
Molecular Targets of Curcumin
No full textCurcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/ oxidase, and inducible nitric oxide synthase ( iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and I kappa B kinase. Subsequently, curcumin inhibits the activation of NF -kappa B and the expressions of oncogenes including c-jun, c-fos c-myc, NIk, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC , mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c- fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway
The role of inflammation in lymphoma
No full textHuman lymphomas usually develop in specialized tissue microenvironments characterized by different populations of accessory stromal and lymphoid cells that interact with malignant cells. A clinical role of the tumor microenvironment has recently emerged, bringing new knowledge and suggesting new ideas and targets for treatment. This chapter analyzes the microenvironment in human lymphomas highlighting the role of inflammation in their pathogenesis. Microenvironmental specificity is detailed according to different models including classic Hodgkin lymphoma (HL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma, unspecified and angioimmunoblastic T-cell lymphoma (AITL)
Targeting Inflammation-Induced Obesity and Metabolic Diseases by Curcumin and Other Nutraceuticals
No full text Extensive research within the past two decades has revealed that obesity, a major risk factor for type 2 diabetes, atherosclerosis, cancer, and other chronic diseases, is a proinflammatory disease. Several spices have been shown to exhibit activity against obesity through antioxidant and anti-inflammatory mechanisms. Among them, curcumin, a yellow pigment derived from the spice turmeric (an essential component of curry powder), has been investigated most extensively as a treatment for obesity and obesity-related metabolic diseases. Curcumin directly interacts with adipocytes, pancreatic cells, hepatic stellate cells, macrophages, and muscle cells. There, it suppresses the proinflammatory transcription factors nuclear factor-kappa B, signal transducer and activators of transcription-3, and Wnt/β-catenin, and it activates peroxisome proliferator-activated receptor-γ and Nrf2 cell-signaling pathways, thus leading to the downregulation of adipokines, including tumor necrosis factor, interleukin-6, resistin, leptin, and monocyte chemotactic protein-1, and the upregulation of adiponectin and other gene products. These curcumin-induced alterations reverse insulin resistance, hyperglycemia, hyperlipidemia, and other symptoms linked to obesity. Other structurally homologous nutraceuticals, derived from red chili, cinnamon, cloves, black pepper, and ginger, also exhibit effects against obesity and insulin resistance. </jats:p
Suppression of antiproliferative effects of tumor necrosis factor by transfection of cells with human platelet-derived growth factor B/c-sis gene
No full textAbstractThe growth of cells is determined by the balance between growth-stimulatory and growth-inhibitory signals. In the present study, we demonstrate that the transfection of NIH 3T3 cells with a platelet-derived growth factor (PDGF-B/c-sis) gene induces resistance to the anticellular effects of tumor necrosis factor (TNF). Human tumor cell lines that express elevated levels of c-sis (e.g. epidermoid carcinoma, A-431) are also TNF resistant, whereas those that express no significant levels of this gene (e.g. breast adenocarcinoma, MCF-7) are TNF sensitive. Transfection of cells with the c-sis gene leads to down-modulation of TNF receptors and also a decrease in intracellular glutathione levels. Thus, our results demonstrate that over-expression of PDGF-B/c-sis by certain tumor cells can lead to their protection from the anticellular effects of TNF
Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey
No full textAbstractAlthough activity that induced tumor regression was observed and termed tumor necrosis factor (TNF) as early as the 1960s, the true identity of TNF was not clear until 1984, when Aggarwal and coworkers reported, for the first time, the isolation of 2 cytotoxic factors: one, derived from macrophages (molecular mass 17 kDa), was named TNF, and the second, derived from lymphocytes (20 kDa), was named lymphotoxin. Because the 2 cytotoxic factors exhibited 50% amino acid sequence homology and bound to the same receptor, they came to be called TNF-α and TNF-β. Identification of the protein sequences led to cloning of their cDNA. Based on sequence homology to TNF-α, now a total of 19 members of the TNF superfamily have been identified, along with 29 interacting receptors, and several molecules that interact with the cytoplasmic domain of these receptors. The roles of the TNF superfamily in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, and morphogenesis have been documented. Their roles in immunologic, cardiovascular, neurologic, pulmonary, and metabolic diseases are becoming apparent. TNF superfamily members are active targets for drug development, as indicated by the recent approval and expanding market of TNF blockers used to treat rheumatoid arthritis, psoriasis, Crohns disease, and osteoporosis, with a total market of more than US $20 billion. As we learn more about this family, more therapeutics will probably emerge. In this review, we summarize the initial discovery of TNF-α, and the insights gained regarding the roles of this molecule and its related family members in normal physiology and disease.</jats:p
Both type I and type II interferons down-regulate human tumor necrosis factor receptors in human hepatocellular carcinoma cell line Hep G2 Role of protein kinase C
No full textAbstractIt is well known that Interferon-γ (IFN-γ type II) potentiates various responses of human tumor necrosis factor (TNF) in a wide variety of cells and that this potentiation is accompanied by the up-regulation of TNF receptor synthesis. In the present studies we examined the regulation of TNF receptors by type I and type II IFNs in a hepatocellular carcinoma cell line, HEP G2. Exposure of these cells to IFN-γ led to a decrease in TNF receptor number (4029 vs. 2719 sites/cell) without any change in the receptor affinity (0.96 nM vs. 1.1 nM). The effect was time and dose-dependent. Like IFN-γ, IFN-α and IFN-β (type I) down-modulated the TNF receptors on these cells. The effect of IFNs on the TNF receptors was inhibited by staurosporin, a protein kinase C (PK-C) inhibitor. Furthermore, by the use of receptor-specific antibodies, we found that the IFN-dependent decrease was primarily due to the p60 form of the TNF receptor. Our results presented are the first to demonstrate that IFNs can also down-modulate TNF receptors in certain cells and that this effect is mediated through PK-C
P80 form of the human tumor necrosis factor receptor is involved in DNA fragmentation
No full textAbstractTwo different types of TNF receptors with molecular masses of 60 kDa (p60) and 80 kDa (p80) have been identified. TNF is known to cause DNA fragmentation in certain tumor cell lines but the role of p60 and p80 in this action is not understood. In the present study, we examined the role of these receptors in TNF-induced DNA fragmentation. Treatment of U-937 cells with phorbol ester caused downregulation of both types of TNF receptors and this was accompanied by disappearance of the TNF-induced DNA fragmentation. The removal of phorbol ester led to two time-dependent events: (1) the rapid regeneration of the p80 form but not the p60 form of the TNF receptor; and (2) the reappearance of TNF-induced DNA fragmentation. These results suggest that the p80 receptor could mediate the TNF-induced DNA fragmentation
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