Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.
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PMID:Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. 1532 87

Increased activity of proinflammatory/stress pathways has been implicated in the pathogenesis of insulin resistance in obesity. However, the effects of obesity on the activity of these pathways in skeletal muscle, the major insulin-sensitive tissue by mass, are poorly understood. Furthermore, the mechanisms that activate proinflammatory/stress pathways in obesity are unknown. The present study addressed the effects of diet-induced obesity (DIO; 6 wk of high-fat feeding) and acute (6-h) hyperlipidemia (HL) in rats on activity of IKK/IkappaB/NF-kappaB c-Jun NH(2)-terminal kinase, and p38 MAPK in three skeletal muscles differing in fiber type [superficial vastus (Vas; fast twitch-glycolytic), soleus (Sol; slow twitch-oxidative), and gastrocnemius (Gas; mixed)]. DIO decreased the levels of the IkappaBalpha in Vas (24 +/- 3%, P = 0.001, n = 8) but not in Sol or Gas compared with standard chow-fed controls. Similar to DIO, HL decreased IkappaBalpha levels in Vas (26 +/- 5%, P = 0.006, n = 6) and in Gas (15 +/- 4%, P = 0.01, n = 7) but not in Sol compared with saline-infused controls. Importantly, the fiber-type-dependent effects on IkappaBalpha levels could not be explained by differential accumulation of triglyceride in Sol and Vas. HL, but not DIO, decreased phospho-p38 MAPK levels in Vas (41 +/- 7% P = 0.004, n = 6) but not in Sol or Gas. Finally, skeletal muscle c-Jun NH(2)-terminal kinase activity was unchanged by DIO or HL. We conclude that diet-induced obesity and acute HL reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type-dependent manner.
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PMID:Diet-induced obesity and acute hyperlipidemia reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type dependent manner. 1608 81

Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast-like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)-1beta-induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL-1beta induced production of chemokines such as RANTES and ENA-78. In addition, Western blot analysis and gelatin zymography revealed that IL-1beta activated matrix metalloproteinase (MMP)-1 and -3 in FLS. However, pre-incubation with guggulsterone completely inhibited the ability of IL-1beta to induce the production of chemokines and to activate MMPs. Although the NF-kappaB binding activity and nuclear p50 and p65 subunit levels, as well as IkappaBalpha degradation in the cytoplasm was greater in cells stimulated with IL-1beta than in unstimulated cells, treatment with guggulsterone abolished all of these increases. Collectively, these results suggest that guggulsterone would be useful as an inhibitor of joint destruction in patients with rheumatoid arthritis.
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PMID:Guggulsterone blocks IL-1beta-mediated inflammatory responses by suppressing NF-kappaB activation in fibroblast-like synoviocytes. 1849 75

Agents that are safe, affordable, and efficacious are urgently needed for the prevention of chronic diseases such as cancer. Sesamin, a lipid-soluble lignan, is one such agent that belongs to a class of phytoestrogens, isolated from sesame (Sesamum indicum), and has been linked with prevention of hyperlipidemia, hypertension, and carcinogenesis through an unknown mechanism. Because the transcription factor NF-kappaB has been associated with inflammation, carcinogenesis, tumor cell survival, proliferation, invasion, and angiogenesis of cancer, we postulated that sesamin might mediate its effect through the modulation of the NF-kappaB pathway. We found that sesamin inhibited the proliferation of a wide variety of tumor cells including leukemia, multiple myeloma, and cancers of the colon, prostate, breast, pancreas, and lung. Sesamin also potentiated tumor necrosis factor-alpha-induced apoptosis and this correlated with the suppression of gene products linked to cell survival (e.g., Bcl-2 and survivin), proliferation (e.g., cyclin D1), inflammation (e.g., cyclooxygenase-2), invasion (e.g., matrix metalloproteinase-9, intercellular adhesion molecule 1), and angiogenesis (e.g., vascular endothelial growth factor). Sesamin downregulated constitutive and inducible NF-kappaB activation induced by various inflammatory stimuli and carcinogens, and inhibited the degradation of IkappaBalpha, the inhibitor of NF-kappaB, through the suppression of phosphorylation of IkappaBalpha and inhibition of activation of IkappaBalpha protein kinase, thus resulting in the suppression of p65 phosphorylation and nuclear translocation, and NF-kappaB-mediated reporter gene transcription. The inhibition of IkappaBalpha protein kinase activation was found to be mediated through the inhibition of TAK1 kinase. Overall, our results showed that sesamin may have potential against cancer and other chronic diseases through the suppression of a pathway linked to the NF-kappaB signaling.
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PMID:Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products. 2046 Apr 1