共查询到20条相似文献,搜索用时 15 毫秒
1.
Mauro Gaya Victoria Repetto Judith Toneatto Claudia Anesini Graciela Piwien-Pilipuk Silvia Moreno 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Obesity is a serious health problem all over the world, and inhibition of adipogenesis constitutes one of the therapeutic strategies for its treatment. Carnosic acid (CA), the main bioactive compound of Rosmarinus officinalis extract, inhibits 3T3-L1 preadipocytes differentiation. However, very little is known about the molecular mechanism responsible for its antiadipogenic effect.Methods
We evaluated the effect of CA on the differentiation of 3T3-L1 preadipocytes analyzing the process of mitotic clonal expansion, the level of adipogenic markers, and the subcellular distribution of C/EBPβ.Results
CA treatment only during the first day of 3T3-L1 differentiation process was enough to inhibit adipogenesis. This inhibition was accompanied by a blockade of mitotic clonal expansion. CA did not interfere with C/EBPβ and C/EBPδ mRNA levels but blocked PPARγ, and FABP4 expression. C/EBPβ has different forms known as LIP and LAP. CA induced an increase in the level of LIP within 24 h of differentiation, leading to an increment in LIP/LAP ratio. Importantly, overexpression of LAP restored the capacity of 3T3-L1 preadipocytes to differentiate in the presence of CA. Finally, CA promoted subnuclear de-localization of C/EBPβ.Conclusions
CA exerts its anti-adipogenic effect in a multifactorial manner by interfering mitotic clonal expansion, altering the ratio of the different C/EBPβ forms, inducing the loss of C/EBPβ proper subnuclear distribution, and blocking the expression of C/EBPα and PPARγ.General significance
Understanding the molecular mechanism by which CA blocks adipogenesis is relevant because CA could be new a food additive beneficial for the prevention and/or treatment of obesity. 相似文献2.
Xinni Xie Xinbo Zhou Wei Chen Long Long Wei Li Xiuyan Yang Song Li Lili Wang 《Biochimica et Biophysica Acta (BBA)/General Subjects》2015
Background
Selective PPARγ modulators (sPPARγM) retains insulin sensitizing activity but with minimal side effects compared to traditional TZDs agents, is thought as a promising strategy for development of safer insulin sensitizer.Methods
We used a combination of virtual docking, SPR-based binding, luciferase reporter and adipogenesis assays to analyze the interaction mode, affinity and agonistic activity of L312 to PPARγ in vitro, respectively. And the anti-diabetic effects and underlying molecular mechanisms of L312 was studied in db/db mice.Results
L312 interacted with PPARγ-LBD in a manner similar to known sPPARγM. L312 showed similar PPARγ binding affinity, but displayed partial PPARγ agonistic activity compared to PPARγ full agonist pioglitazone. In addition, L312 displayed partial recruitment of coactivator CBP yet equal disassociation of corepressor NCoR1 compared to pioglitazone. In db/db mice, L312 (30 mg/kg·day) treatment considerably improved insulin resistance with the regard to OGTT, ITT, fasted blood glucose, HOMA-IR and serum lipids, but elicited less weight gain, adipogenesis and hemodilution compared with pioglitazone. Further studies demonstrated that L312 is a potent inhibitor of CDK5-mediated PPARγ phosphorylation and displayed a selective gene expression profile in epididymal WAT.Conclusions
L312 is a novel sPPARγM.General significance
L312 may represent a novel lead for designing ideal sPPARγM for T2DM treatment with advantages over current TZDs. 相似文献3.
Atanas G. Atanasov Jian N. Wang Shi P. Gu Jing Bu Matthias P. Kramer Lisa Baumgartner Nanang Fakhrudin Angela Ladurner Clemens Malainer Anna Vuorinen Stefan M. Noha Stefan Schwaiger Judith M. Rollinger Daniela Schuster Hermann Stuppner Verena M. Dirsch Elke H. Heiss 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.Methods
We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.Results
The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.Conclusion
We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.General significance
This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. 相似文献4.
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Fernanda Aparecida Domenici Maria José Franco Brochado Ana de Lourdes Candolo MartinelliSergio Zucoloto Selma Freire de Carvalho da CunhaHelio Vannucchi 《Gene》2013
Background
Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD.Methods
One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).Results
NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP.Conclusions
We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the progression of NAFLD. 相似文献8.
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Surya Prakash Bhatt Priyanka Nigam Anoop Misra Randeep Guleria Kalpana Luthra Ravindra Mohan Pandey M.A. Qadar Pasha 《Gene》2013
Background
Genetics of non-alcoholic fatty liver (NAFLD) in Asian Indians has been inadequately studied. We investigated the association of polymorphisms C161T and Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARγ) with clinical and biochemical parameters in Asian Indians with NAFLD.Methods
In this case–control study, 162 NAFLD cases and 173 controls were recruited. Abdominal ultrasound, clinical and biochemical profiles, fasting insulin levels and value of homeostasis model assessment of insulin resistance were determined. Polymerase chain reaction–restriction fragment length polymorphisms of two polymorphisms were performed. The association of these polymorphisms with clinical and biochemical parameters was analysed.Results
Higher frequency of Ala and T alleles of PPARγ was obtained in cases. Ala/Ala genotype of PPARγ (Pro12Ala) was associated with significantly higher serum triglycerides (TG), alkaline phosphatase (ALK) and waist–hip ratio in cases as compared to controls. In C161T polymorphism, TT genotype was significantly increased TG (p = 0.04), total cholesterol (p = 0.01), ALK (p = 0.04) and gamma-glutamyl transpeptidase (p = 0.007) in cases. The linkage disequilibrium for these two single-nucleotide polymorphisms of PPARγ was differed in cases (D1 = 0.1; p = 0.006) and controls (D1 = 0.07; p = 0.1). Using a multivariate analysis after adjusting for age, sex and body mass index, the presence of NAFLD was linked to these two polymorphisms (odds ratio 1.64 (95% CI: 1.09–2.45, p = 0.05)].Conclusion
Asian Indians in north India carrying the alleles Ala and T of PPARγ (Pro12Ala and C161T) polymorphisms are predisposed to develop NAFLD. 相似文献11.
Gopalsamy Rajiv Gandhi Antony Stalin Kedike Balakrishna Savarimuthu Ignacimuthu Michael Gabriel Paulraj Rajagopal Vishal 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The present study was aimed at isolating an antidiabetic molecule from a herbal source and assessing its mechanism of action.Methods
Embelin, isolated from Embelia ribes Burm. (Myrsinaceae) fruit, was evaluated for its potential to regulate insulin resistance, alter β-cell dysfunction and modulate key markers involved in insulin sensitivity and glucose transport using high-fat diet (HFD) fed-streptozotocin (STZ) (40 mg/kg)-induced type 2 diabetic rats. Molecular-dockings were performed to investigate the binding modes of embelin into PPARγ, PI3K, p-Akt and GLUT4 active sites.Results
Embelin (50 mg/kg b wt.) reduced body weight gain, blood glucose and plasma insulin in treated diabetic rats. It further modulated the altered lipid profiles and antioxidant enzymes with cytoprotective action on β-cell. Embelin significantly increased the PPARγ expression in epididymal adipose tissue compared to diabetic control group; it also inhibited adipogenic activity; it mildly activated PPARγ levels in the liver and skeletal muscle. It also regulated insulin mediated glucose uptake in epididymal adipose tissue through translocation and activation of GLUT4 in PI3K/p-Akt signaling cascade. Embelin bound to PPARγ; it disclosed stable binding affinities to the active sites of PI3K, p-Akt and GLUT4.Conclusions
These findings show that embelin could improve adipose tissue insulin sensitivity without increasing weight gain, enhance glycemic control, protect β-cell from damage and maintain glucose homeostasis in adipose tissue.General significance
Embelin can be used in the prevention and treatment of type 2 diabetes mellitus caused due to obesity. 相似文献12.
Fouad Brahimi Jing Liu Andrey Malakhov Shafinaz Chowdhury Enrico O. Purisima Ljubica Ivanisevic Antoine Caron Kevin Burgess H. Uri Saragovi 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Background
Receptor tyrosine kinases (RTK) act through dimerization. Previously it was thought that only bivalent ligands could be agonistic, whereas monovalent ligands should be antagonistic. This notion changed after the demonstration that monovalent ligands can be agonistic, including our report of a small molecule monovalent ligand “D3” that is a partial agonist of the NGF receptor TrkA. A bivalent “D3-linker-D3” was expected to increase agonism.Methods
Dimeric analogs were synthesized and tested in binding, biochemical, and biological assays.Results
One analog, 1-ss, binds TrkA with higher affinity than D3 and induces or stabilizes receptor dimers. However, 1-ss exhibited antagonistic activity, through two mechanisms. One mechanism is that 1-ss blocks NGF binding, unlike D3 which is non-competitive. Inhibition of NGF binding may be due to the linker of 1-ss filling the inter-receptor space that NGF traverses before docking. In a second mechanism, 1-ss acts as a pure antagonist, inhibiting NGF-independent TrkA activity in cells over-expressing receptors. Inhibition is likely due to 1-ss “freezing” the TrkA dimer in the inactive state.Conclusions
Dimerization of an RTK can result in antagonism, through two independent mechanisms.General significance
we report a small molecule monovalent agonist being converted to a bivalent antagonist. 相似文献13.
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Nibedita Mahata Debasis PoreAmit Pal Manoj K. Chakrabarti 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Background
IP3-mediated calcium mobilization from intracellular stores activates and translocates PKC-α from cytosol to membrane fraction in response to STa in COLO-205 cell line. The present study was undertaken to determine the involvement of cytoskeleton proteins in translocation of PKC-α to membrane from cytosol in the Escherichiacoli STa-mediated signaling cascade in a human colonic carcinoma cell line COLO-205.Methods
Western blots and consequent densitometric analysis were used to assess time-dependent redistribution of cytoskeletal proteins. This redistribution was further confirmed by using confocal microscopy. Pharmacological reagents were applied to colonic carcinoma cells to disrupt the microfilaments (cytochalasin D) and microtubules (nocodazole).Results
STa treatment in COLO-205 cells showed dynamic redistribution and an increase in actin content in the Triton-insoluble fraction, which corresponds to an increase in polymerization within 1 min. Moreover, pharmacological disruption of actin-based cytoskeleton greatly disturbed PKC-α translocation to the membrane.Conclusions
These results suggested that the organization of actin cytoskeleton is rapidly rearranged following E. coli STa treatment and the integrity of the actin cytoskeleton played a crucial role in PKC-α movement in colonic cells. Depolymerization of tubulin had no effect on the ability of the kinase to be translocated to the membrane.General significance
In the present study, we have shown for the first time that in colonic carcinoma cells, STa-mediated rapid changes of actin cytoskeleton arrangement might be involved in the translocation of PKC-α to membrane. 相似文献16.
Kamaldeep Gill Abhay K. Singh Vaishali Kapoor Lokesh Nigam Rahul Kumar Prasida Holla Satya N. Das Savita Yadav Naidu Subbarao Bidhu K. Mohanti Sharmistha Dey 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The p38α MAP kinase pathway is involved in inflammation, cell differentiation, growth, apoptosis and production of pro-inflammatory cytokines TNF-α and IL-1β. The overproduction of these cytokines plays an important role in cancer. The aim of this work was to design a peptide inhibitor on the basis of structural information of the active site of p38α.Methods
A tetrapeptide, VWCS as p38α inhibitor was designed on the basis of structural information of the ATP binding site by molecular modeling. The inhibition study of peptide with p38α was performed by ELISA, binding study by Surface Plasmon Resonance and anti-proliferative assays by MTT and flow cytometry.Results
The percentage inhibition of designed VWCS against pure p38α protein and serum of HNSCC patients was 70.30 and 71.5%, respectively. The biochemical assay demonstrated the KD and IC50 of the selective peptide as 7.22 × 10− 9 M and 20.08 nM, respectively. The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC50 value of 10 μM and induced apoptosis by activating Caspase 3 and 7.Conclusions
VWCS efficiently interacted at the ATP binding pocket of p38α with high potency and can be used as a potent inhibitor in case of HNSCC.General significance
VWCS can act as an anticancer agent as it potentially inhibits the cell growth and induces apoptosis in oral cancer cell-line in a dose as well as time dependent manner. Hence, p38α MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer. 相似文献17.
Hirofumi Yoshida Yohei Kanamori Hiroki Asano Osamu Hashimoto Masaru Murakami Teruo Kawada Tohru Matsui Masayuki Funaba 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Brown adipocytes generate heat through the expression of mitochondrial Ucp1. Compared with the information on the regulatory differentiation of white preadipocytes, the factors affecting brown adipogenesis are not as well understood. The present study examined the roles of the Tgf-β family members Bmp, Tgf-β and Activin during differentiation of HB2 brown preadipocytes.Methods
Endogenous Bmp activity and effects of exogenous Tgf-β family members were examined. Role of Srebp1c in brown adipogenesis was further explored.Results
Although Bmp7 has been suggested to be a potent stimulator of brown adipogenesis, it affected neither the expression of brown adipocyte-selective genes nor Ucp1 induction in response to a β adrenergic receptor agonist. Unlike in 3T3-L1 white preadipocytes, endogenous Bmp activity was not required for brown adipogenesis; treatment with inhibitors of the Bmp pathway did not affect differentiation of preadipocytes. Administration of Tgf-β1 or Activin A efficiently decreased the insulin-induced expression of brown adipocyte-selective genes. Tgf-β1 and Activin A decreased the expression of Pparγ2 and C/ebpα, suggesting the inhibition of adipogenesis. The Tgf-β- and Activin-induced inhibition of brown adipogenesis was mediated by the repression of Srebp1c expression; Tgf-β1 and Activin A blocked Srebp1c gene induction in response to the differentiation induction, and knock-down of Srebp1 expression inhibited brown adipogenesis.Conclusion
Endogenous Bmp is dispensable for brown adipogenesis, and Srebp1c is indispensable, which is negatively regulated by Tgf-β and Activin.General significance
Control of activity of the Tgf-β family is potentially useful for maintenance of energy homeostasis through manipulation of brown adipogenesis. 相似文献18.
K. Sri Manjari A. Jyothy P. Shravan Kumar B. Prabhakar M. Uma Devi M. Ramanna Pratibha Nallari A. Venkateshwari 《Gene》2014
Objective
Chronic pancreatitis is a gradual, long-term inflammation of the pancreas that results in alteration of its normal structure and function. The study aims to investigate the role of − 308 (G/A) polymorphism of TNF-α gene in chronic pancreatitis.Material and methods
A total of 200 subjects were included in this case–control study. A total of 100 in patients admitted in the Gastroenterology Unit of Gandhi Hospital and Osmania General Hospital, Hyderabad were included in the present study. An equal number of healthy control subjects were randomly selected for the study. The genotyping of TNF-α gene was carried out by tetra-primer ARMS PCR followed by gel electrophoresis. The TNF-α levels were assayed by enzyme-linked immunosorbent assay.Results
A significant variation with respect to the genotypic and allelic distribution in the disease group when compared to control subjects [OR = 2.001 (1.33–3.005), p < 0.0001**] was observed. Subjects homozygous for the A allele had higher TNF-α levels compared to G allele.Conclusion
The present study revealed a significant association of the TNF-α gene promoter polymorphism with chronic pancreatitis. Thus, TNF-α genotype can be considered as one of the biological markers in the etiology of chronic pancreatitis. 相似文献19.
Background
Inhibition of angiogenesis may impair adipose tissue development.Methods
The effect of fumagillin (a methionine aminopeptidase-2 inhibitor) on adipocyte differentiation and de novo adipogenesis was investigated in murine model systems.Results
During in vitro differentiation of murine 3T3-F442A preadipocytes, administration of fumagillin (≥ 1 μM) resulted in reduced expression of methionine aminopeptidase-2, and in enhanced differentiation rate. In vivo, de novo development of adipose tissue following injection of preadipocytes in nude mice kept on high fat diet was somewhat, but not significantly (p = 0.06), reduced by administration of fumagillin (1 mg/kg/day during 4 weeks by oral gavage). This was not associated with effects on blood vessel size or density, whereas blood vessel density normalized to adipocyte density was enhanced upon fumagillin treatment. In vivo BrdU incorporation experiments did not reveal effects of fumagillin on cell proliferation in adipose tissues, and cellular apoptosis was also not affected.Treatment with fumagillin enhances in vitro differentiation of preadipocytes, but has only a minor effect on in vivo adipogenesis.General Significance
These studies on in vitro and in vivo preadipcoyte differentiation thus do not support an anti-obesity effect of fumagillin as a result of effects on adipocyte differentiation. 相似文献20.
Chai Siah Ku Tho X. Pham Youngki Park Bohkyung Kim Min Sun Shin Insoo Kang Jiyoung Lee 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013