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.
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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

Despite the growing incidence of obesity, knowledge of how this condition, as well as associated steatosis, affects liver regeneration remains scarce. Many previous studies have used models of steatohepatitis or obesity induced by genetic alterations. In contrast, our studies on liver regeneration have focused on the effects of obesity resulting solely from high amounts of fat in the diet. This model more closely reflects the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in well-developed Western societies. Impairment of liver regeneration was observed after partial hepatectomy in mice fed a high-fat diet. Fatty livers were more susceptible to posthepatectomy damage and failure. The underlying molecular mechanism was associated with increased inhibitor of nuclear factor-kappa B alpha (IkappaBalpha) expression, which inhibited nuclear factor-kappa B (NF-kappaB) activation and induction of its target genes, cyclin D1 and Bcl-xL, increasing sensitivity to apoptosis initiated by elevated tumor necrosis factor-alpha. In addition, since mice fed with a high-fat diet have higher leptin levels caused by increased adiposity, our work supports the hypothesis that the impairment of regeneration previously seen in genetically obese mice indeed results from liver steatosis rather than the disruption of leptin signaling. In conclusion, high fat in the diet impairs liver regeneration and predisposes steatotic livers to increased injury through IkappaBalpha overexpression and subsequent NF-kappaB inhibition.
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PMID:A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaBalpha. 1625 44

Thyroid hormones regulate cell growth, cell differentiation, and metabolic functions via interaction with the thyroid hormone nuclear receptors (TRs). Recently, a small class of halogen-free high-affinity thyroid hormone agonists has been developed that are highly selective for the TRbeta subtype. Because of the selective hyperthyroidism generated by one of these agonists, GC-1, this compound has the potential to be developed as a new therapeutic agent for the treatment of a variety of metabolic disturbances, including lipid disorders and obesity; thus, it becomes important to determine whether GC-1 has other unknown effects on potential target organs. The purpose of this study was to investigate the effect of GC-1 on cell proliferation in rat liver and pancreas. Rats treated with GC-1 (50 or 100 mug/100 g body weight) were killed at different time points. Hepatic and pancreatic cell proliferation was monitored by immunohistochemical determination of bromodeoxyuridine incorporation. The expression of cell cycle-related genes was analyzed by Northern and Western analysis. The results show that GC-1 strongly stimulates rat hepatocyte proliferation in the absence of tissue injury. Although GC-1-induced hepatocyte proliferation was associated with a rapid increase in cyclin D1 mRNA levels, no change in the expression of c-jun and c-fos was observed. GC-1 also induced massive pancreatic cell proliferation. The results indicate that the TRbeta-selective agonist GC-1 is a strong mitogen for hepatocytes and pancreatic acinar cells. Furthermore, they suggest that the TRbeta receptor is the mediator for the mitogenic activity of thyroid hormone and other thyromimetics.
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PMID:The thyroid hormone receptor-beta agonist GC-1 induces cell proliferation in rat liver and pancreas. 1657 85

Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.
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PMID:Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. 1675 79

Obesity is considered a chronic low-grade inflammatory state. The white adipose tissue produces a variety of inflammation-related proteins whose expression is increased in obese subjects. The nonadipose cell fraction, which includes infiltrated macrophages, is a determinant source of inflammation-related molecules within the adipose tissue. Our working hypothesis is that macrophage infiltration affects fat expansion through a paracrine action on adipocyte differentiation. Human primary preadipocytes were then differentiated in the presence of conditioned media obtained from macrophages differentiated from blood monocytes. Preadipocytes treated by macrophage-conditioned medium displayed marked reduction of adipogenesis as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic and lipogenic markers. In addition to this effect, the activation of macrophages by lipopolysaccharides stimulated nuclear factor kappaB signaling, increased gene expression and release of proinflammatory cytokines and chemokines, and induced preadipocyte proliferation. This phenomenon was associated with increased cyclin D1 gene expression and maintenance of the fibronectin-rich matrix. Anti-TNFalpha neutralizing antibody inhibits the inflammatory state of preadipocytes positioning TNFalpha as an important mediator of inflammation in preadipocytes. Strikingly, conditioned media produced by macrophages isolated from human adipose tissue exerted comparable effects with activated macrophages, i.e. decreased adipogenesis and increased inflammatory state in the preadipocytes. These data show that macrophage-secreted factors inhibit the formation of mature adipocytes, suggesting possible role in limiting adipose tissue expansion in humans.
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PMID:Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes. 1708 59

Sex-determining region Y-box (SOX) 6 negatively regulates glucose-stimulated insulin secretion from beta-cells and is a down-regulated transcription factor in the pancreatic islet cells of hyperinsulinemic obese mice. To determine the contribution of SOX6 to insulin resistance, we analyzed the effects of SOX6 on cell proliferation. Small interfering RNA-mediated attenuation of SOX6 expression stimulated the proliferation of insulinoma INS-1E and NIH-3T3 cells, whereas retroviral overexpression resulted in inhibition of cell growth. Quantitative real time-PCR analysis revealed that the levels of cyclin D1 transcripts were markedly decreased by SOX6 overexpression. Luciferase-reporter assay with beta-catenin showed that SOX6 suppresses cyclin D1 promoter activities. In vitro binding experiments showed that the LZ/Q domain of SOX6 physically interacts with armadillo repeats 1-4 of beta-catenin. Furthermore, chromatin immunoprecipitation assay revealed that increased SOX6 expression significantly reduced the levels of acetylated histones H3 and H4 at the cyclin D1 promoter. By using a histone deacetylase (HDAC) inhibitor and co-immunoprecipitation analysis, we showed that SOX6 suppressed cyclin D1 activities by interacting withbeta-catenin and HDAC1. The data presented suggest that SOX6 may be an important factor in obesity-related insulin resistance.
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PMID:SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation. 1741 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.
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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

Obesity is a risk factor for postmenopausal breast cancer and is associated with poor prognosis. Leptin, a cytokine synthesized in adipose tissue, has been implicated as a link between obesity and breast cancer. In the present study, the effects of leptin on cell proliferation and proteins associated with leptin signaling and/or breast cell growth were investigated in ER-positive, MCF-7, T47-D and MDA-MB-361, and ER-negative, MDA-MB-231 and SK-BR-3, breast cancer cell lines. MDA-MB-361 and SK-BR-3 also overexpress HER2/neu. For proliferation assays, 96-well plates were used and for protein determinations cells were synchronized in 6-well plates for 18-24 h in serum-free medium. Leptin was added at 0, 5, 10, 25, 50 and 100 ng/ml for 24 and 48 h. For Western blot analyses, protein extracts were probed for Ob-Rb, Ob-R, leptin, Jak2, PI3K, Stat3, p-Stat3, PCNA, cyclin D1, Cox-2, VEGF, Bcl-2, Bcl-xL, Bax, insulin, IGF-I, IGFBP3, IGF-IRalpha, aromatase, CYP1A1 and CYP1B1. Overall, except for MCF-7 cells, leptin stimulated proliferation in all lines. MCF-7 cells expressed higher levels of Ob-Rb, Jak2, PI3K, Stat3 and p-Stat3 in a dose-dependent manner to 50 ng/ml at 24 h; and IGF-IRalpha increased at 24 h. Cyclin D1 and Cox-2 levels increased with leptin treatment. Higher CYP1B1 expression was observed at both 24 and 48 h. In MDA-MB-231 cells, p-Stat3 and Bcl-xL were increased at 48 h; whereas PCNA and cyclin D1 expression increased in leptin-treated cells at 24 and 48 h. In T47-D cells, Jak2 and Stat3 were elevated at higher leptin concentrations at 24 and 48 h. However, p-Stat3 and PCNA demonstrated an increase only in 48-h leptin-treated cells. Furthermore, cyclin D1 exhibited higher expression at both 24 and 48 h, while Bcl-xL expression was lower with increasing concentrations of leptin at 48 h. In MDA-MB-361 cells, Ob-Rb and VEGF increased at 24 and 48 h; whereas PI3K, Stat3, PCNA and insulin levels increased in leptin-treated MDA-MB-361 cells after 48 h. Bcl-2 and IGF-IRalpha were decreased at 24 h and a dose-dependent increase at 48 h was noted. Higher expression of CYP1B1 was observed with leptin for 24 h. In SK-BR-3 cells, Ob-R increased at both 24 and 48 h. A similar trend was found for IGF-I and IGFBP3 expression. Higher levels of Jak2 and PI3K were observed after 24 h. Interestingly, there was a gradual increase of leptin expression at 24 h, but a gradual decrease at 48 h in relation to the dose of leptin. In contrast, PCNA and IGF-IRalpha showed a decline at 24 h and an increase at 48 h. Elevated levels of cyclin D1, VEGF and Bax were detected at 48 h in cells and increased Cox-2 expression was observed at 24 h. These data indicate that leptin may influence breast cancer development in relation to ER status as well as to the presence or absence of HER2. Continued study on leptin may be helpful for a better understanding of breast cancer development in obese women.
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PMID:Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. 1748 72

Obesity serves as an important risk factor for incidences of both cirrhotic and non-cirrhotic hepatocellular carcinoma (HCC), which is the third leading cause of cancer death worldwide. Leptin, the obesity biomarker molecule secreted systemically by body fat mass and locally by activated hepatic stellate cells, is proposed to play a certain role in HCC growth. Here, we show both proliferative and anti-apoptotic effects of leptin in HCC cells. Leptin stimulated cyclin D1 promoter activity to increase cyclin D1 protein expression, which accelerated the cell cycle progression. The reduced ratio between anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) Bcl-2 family proteins by transforming growth factor (TGF)-beta 1 caused HCC cells degradation of poly(ADP-ribose) polymerase and consequential apoptosis; whereas, leptin protected cells from apoptosis by reversing TGF-beta 1-reduced Bcl-2/Bax ratio as a result of down-regulating Bax. Any inhibitor specific for Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase 1/2 (ERK1/2) blocked these leptin functions. When intrahepatocytic JAK2 was activated by leptin, the active JAK2 afterward triggered a signaling cascade involving activations of PI3K/Akt and MEK/ERK1/2 in order of occurrence. As yet, in most cases, the crosstalks among signaling pathways primarily studied in diverse cancer cell types for mediating somatotropic effect of leptin are not well clarified and seem to be cell-type dependent. For the first time, our results demonstrate the direct effects of leptin on HCC growth and define its signal pathway with a crosstalking JAK2-PI3K/Akt-MEK/ERK1/2 connection. The identified hierarchy of intrahepatocytic leptin signaling pathway provides a clear basis potentially beneficial to make accurate and effectual strategies for facing both cirrhotic and non-cirrhotic liver carcinogenesis.
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PMID:Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway. 1763 64

Although high-calcium diets have been reported to reduce the risk of colorectal cancer, our preliminary data with the adenomatous polyposis coli (Apc) Min mutation (Min/+;Apc(Min/+)) mouse shows a paradoxical increase in intestinal tumor loads (> 65%) with high calcium diets. Since we previously demonstrated that increasing dietary calcium reduces adiposity, and Apc(Min/+) mice on high calcium diets exhibited profound loss of adipose tissue, we hypothesized that loss of an adipose tissue-derived tumor suppressor factor(s) resulted in increased tumor susceptibility in animals on the high calcium diet. Accordingly, tumor prone Apc(Min/+) mice were crossed with obesity prone lethal yellow agouti (A(y)/a) mice to generate obese A(y)/Apc(Min/+) mice. Low (0.2%), normal (0.5%), and high (1.2%) calcium diets were fed to both A(y)/Apc(Min/+) mice and Apc(Min/+) mice from 35-40 days until 90 days of age (n=21/strain, n=7/diet group). The high calcium diet reduced weight gain in both strains (P < 0.01) and reduced fat pad mass by 46-57% in A(y)/Apc(Min/+)(P < 0.004) and by 65-82% in Apc(Min/+)(P < 0.03).Apc(Min/+) mice on the high calcium diet exhibited an increase in tumor number (76 vs. 29, P=0.009), but this effect was not seen in the A(y)/Apc(Min/+) mice. beta-Catenin and cyclin D1 gene expression were significantly induced with high calcium diet in intestinal tumor tissue of Apc(Min/+) mice but not in A(y)/Apc(Min/+) mice. We conclude that the differential effect of dietary calcium on intestinal tumorigenesis in lean vs. obese Apc(Min/+) may result from the loss of adipose-derived protective factor(s) due to the substantial loss of body fat in Apc(Min/+) mice fed a high calcium dairy diet, increasing beta-catenin and cyclin D1 in tumors.
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PMID:Adiposity-related protection of intestinal tumorigenesis: interaction with dietary calcium. 1764 Jan 61


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