Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 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.
 ...
PMID:Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. 1532 87

Guggulsterone (GS) is the active substance in guggulipid, an extract of the guggul tree, Commiphora mukul, used to treat a variety of disorders in humans, including dyslipidemia, obesity, and inflammation. The activity of GS has been suggested to be mediated by antagonism of the receptor for bile acids, the farnesoid X receptor (FXR). Here, we demonstrate that both stereoisomers of the plant sterol, (E)- and (Z)-GS, bind to the steroid receptors at a much higher affinity than to FXR. Both stereoisomers bind to the mineralocorticoid receptor (MR) with a Ki value of approximately 35 nM, which is greater than 100 times more potent than their affinity for FXR. Both (E)- and (Z)-GS also displayed high affinity for other steroid receptors, including the androgen (AR), glucocorticoid (GR), and progesterone receptors (PR) with Ki values ranging from 224 to 315 nM. In cell-based functional cotransfection assays, GSs behaved as antagonists of AR, GR, and MR, but as agonists of PR. Agonist activity was also demonstrated with estrogen receptor (ER) alpha; however, the potency was very low (EC50 > 5000 nM). In addition, GS displayed activity in functional assays in cell lines expressing endogenous AR, GR, ER, and PR. These data suggest that the variety of pharmacological effects exhibited by GS may be mediated by targeting several steroid receptors.
 ...
PMID:The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand. 1560 4

Guggulsterone is the active ingredient in gugulipid, an organic extract of the Commiphora mukul plant. Gugulipid has been used for nearly 3000 years in Ayurvedic medicine, mainly as a treatment for arthritis. Herbal practitioners currently use gugulipid therapy in conditions as diverse as rheumatism, coronary artery disease, arthritis, hyperlipidemia, acne, and obesity. The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand. We show herein that guggulsterone treatment represses the expression of cytochrome P450 2b10 (Cyp2b10) gene expression by inhibiting constitutive androstane receptor (CAR; NR1I3) activity in hepatocytes lacking functional PXR (PXR-knockout). We also show that PXR-CAR cross-talk determines the net activity of guggulsterone treatment toward Cyp2b10 gene expression. Using mammalian two-hybrid assays, we show that treatment with guggulsterone differentially affects protein cofactor recruitment to these two nuclear receptors. These data identify guggulsterone as an inverse agonist of the nuclear receptor CAR. When viewed together with the data showing that PXR and CAR expression is highly variable in different ethnic populations and that CAR expression is under the control of a circadian rhythm, our data provide important insight into the molecular mechanism of interindividual variability of drug metabolism. These data, together with the recent resolution of the crystal structures of PXR and CAR, will likely aid in the rational design of more specific CAR inverse agonists that are currently viewed as potential antiobesity drugs.
 ...
PMID:The ratio of constitutive androstane receptor to pregnane X receptor determines the activity of guggulsterone against the Cyp2b10 promoter. 1583 98

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
 ...
PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

Oleogum resin (known as guggul) from the guggul tree, Commiphora mukul, found in India, Bangladesh, and Pakistan, has been used to treat various diseases including hyper-cholesterolemia, atherosclerosis, rheumatism, and obesity over several thousands of years. Guggulsterone isolated from guggul has been identified as the bioactive constituent responsible for guggul's therapeutic effects. Since the first study demonstrating the therapeutic effects of guggul in an animal model in 1966, numerous preclinical and clinical trails have been carried out. Although differences in study design, methodological quality, statistical analysis, sample size, and subject population result in certain inconsistencies in the response to therapy, the cumulative data from in vitro, preclinical, and clinical studies largely support the therapeutic claims for guggul described in the ancient Ayurvedic text. However, future clinical studies with much larger size and longer term are required to confirm these claims. The cardiovascular benefits of the therapy are derived from the multiple pharmacological activities associated with guggul or guggulsterone, notably its hypolipidemic, antioxidant, and antiinflammatory activities. It has been established that guggulsterone is an antagonist at farnesoid x receptor (FXR), a key transcriptional regulator for the maintenance of cholesterol and bile acid homeostasis. The FXR antagonism by guggulsterone has been proposed as a mechanism for its hypolipidemic effect. A recent study demonstrates that guggulsterone upregulates the bile salt export pump (BSEP), an efflux transporter responsible for removal of cholesterol metabolites, bile acids from the liver. Such upregulation of BSEP expression by guggulsterone favors cholesterol metabolism into bile acids, and thus represents another possible mechanism for its hypolipidemic activity. Guggulsterone has been found to potently inhibit the activation of nuclear factor-kappaB (NF-kappaB), a critical regulator of inflammatory responses. Such repression of NF-kappaB activation by guggulsterone has been proposed as a mechanism of the antiinflammatory effect of guggulsterone.
 ...
PMID:Therapeutic effects of guggul and its constituent guggulsterone: cardiovascular benefits. 1807 36

Guggulsterone has been used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on pancreatic beta cells is unknown. Therefore, in this study, the effect of guggulsterone on IL-1beta- and IFN-gamma-induced beta-cell damage was investigated. Treatment of RINm5F (RIN) rat insulinoma cells with IL-1beta and IFN-gamma induced cell damage, and this damage was well correlated with nitric oxide (NO) and prostaglandin E2 (PGE2) production. However, guggulsterone completely prevented cytokines-mediated cytotoxicity, as well as NO and PGE2 production, and these effects were correlated with reduced levels of the inducible form of NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein expressions. The molecular mechanism by which guggulsterone inhibits iNOS and COX-2 gene expressions appeared to involve the inhibition of NF-kappaB activation. The cytoprotective effects of guggulsterone were also mediated through the suppression of the JAK/STAT pathway. Cells treated with the cytokines downregulated the protein level of SOCS-3, however pretreatment with guggulsterone attenuated this decrease. Additionally, in a second set of experiments in which rat islets were used, the findings regarding the beta-cell protective effects of guggulsterone were essentially the same as those observed when RIN cells were used; guggulsterone prevented cytokines-induced NO and PGE2 production, iNOS and COX-2 expressions, JAK/STAT activation, NF-kappaB activation, downregulation of SOCS-3, and impairment of glucose-stimulated insulin secretion. Collectively, these results suggest that guggulsterone may be used to preserve functional beta-cell mass.
 ...
PMID:Guggulsterone, a plant sterol, inhibits NF-kappaB activation and protects pancreatic beta cells from cytokine toxicity. 1834 24

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.
 ...
PMID:Guggulsterone blocks IL-1beta-mediated inflammatory responses by suppressing NF-kappaB activation in fibroblast-like synoviocytes. 1849 75

Identification of active principles and their molecular targets from traditional medicine is an enormous opportunity for modern drug development. Gum resin from Commiphora wightii (syn C. mukul) has been used for centuries in Ayurveda to treat internal tumors, obesity, liver disorders, malignant sores and ulcers, urinary complaints, intestinal worms, leucoderma (vitiligo), sinuses, edema and sudden paralytic seizures. Guggulsterone has been identified as one of the major active components of this gum resin. This steroid has been shown to bind to the farnesoid X receptor and modulate expression of proteins with antiapoptotic (IAP1, XIAP, Bfl-1/A1, Bcl-2, cFLIP, survivin), cell survival, cell proliferation (cyclin D1, c-Myc), angiogenic, and metastatic (MMP-9, COX-2, VEGF) activities in tumor cells. Guggulsterone mediates gene expression through regulation of various transcription factors, including NF-kappaB, STAT-3 and C/EBPalpha, and various steroid receptors such as androgen receptor and glucocorticoid receptors. Modulation of gene expression by guggulsterone leads to inhibition of cell proliferation, induction of apoptosis, suppression of invasion and abrogation of angiogenesis. Evidence has been presented to suggest that guggulsterone can suppress tumor initiation, promotion and metastasis. This review describes the identification of molecular targets of guggulsterone, cellular responses to guggulsterone, and animal studies and clinical trials of guggulsterone in cancer and other diseases.
 ...
PMID:The guggul for chronic diseases: ancient medicine, modern targets. 1918 46

Sedentary lifestyle, consumption of energy-rich diet, obesity and longer lifespan are some of the major reasons for the rise of metabolic disorders like type II diabetes, obesity, hypertension and dyslipidemia among people of various age groups. High fat diet induced diabetic rodent models resembling type II diabetic condition in human population were used to assess the anti-diabetic and hypolipidemic activity of guggulsterone (isolated from Commiphora mukul resin). Four groups of rats were fed high fat diet, for 16 weeks. On feeding the normal rats with fat rich diet they showed increased serum glucose, cholesterol and triglyceride levels along with increase in insulin resistance significantly (p<0.05) in comparison to control animals. Different biochemical parameters like GTT, glycogen content, glucose homeostatic enzymes (like glucose-6-phosphatase, hexokinase), insulin release in vivo and expression profiles of various genes involved in carbohydrate and lipid metabolism clearly demonstrated the hypoglycemic effect of this extract. Guggulsterone demonstrated a differential effect with a significantly improved PPARgamma expression and activity in in vivo and in vitro conditions, respectively. However, it inhibited 3T3-L1 preadipocytes differentiation in vitro. The results presented here suggest that the guggulsterone has both hypoglycemic and hypolipidemic effect which can help to cure type II diabetes.
 ...
PMID:Effects of guggulsterone isolated from Commiphora mukul in high fat diet induced diabetic rats. 1963 21

Guggulsterone or guggulipid is a steroidal constituent present in the neutral fraction of gum resin of Commiphora mukul, commonly known as guggul. The traditional uses of guggul-resin extract are well documented in the Ayurveda-where it is prescribed to treat a variety of ailments including lipid-related disorders such as obesity and arteriosclerosis. The hypolipidemic activity of the extracts known since ancient times can be traced to the two closely related steroidal ketones, E-guggulsterone and Z-guggulsterone. In this study, we have investigated the dose dependent (100, 200, 400 mg/kg body weight) effect of guggulsterones on appetite regulating hormones [ghrelin, leptin, cholecystokinin (CCK)] and neurotransmitters (serotonin and dopamine), which play a major role in the energy homeostasis and thus influence obesity related factors. We have also studied its effect on food intake, body weight and plasma triglycerides and glucose in rats. Guggulsterones at the dose of 400 mg/kg body weight was able to significantly reduce food intake and limit body weight gain over a period of 15 days. It also significantly decreased the plasma ghrelin, glucose, triglyceride levels and increased plasma leptin, serotonin, dopamine levels, but did not show much effect on CCK levels.
 ...
PMID:The appetite regulatory effect of guggulsterones in rats: a repertoire of plasma hormones and neurotransmitters. 2502 86


1 2 Next >>