Cladosporols A and B, two natural peroxisome proliferator-activated receptor gamma (PPARγ) agonists, inhibit adipogenesis in 3 T3-L1 preadipocytes and cause a conditioned-culture-medium-dependent arrest of HT-29 cell proliferation

Background: Obesity and type 2 diabetes mellitus, which are widespread throughout the world, require therapeutic interventions targeted to solve clinical problems (insulin resistance, hyperglycaemia, dyslipidaemia and steatosis). Several natural compounds are now part of the therapeutic repertoire developed to better manage these pathological conditions. Cladosporols, secondary metabolites from the fungus Cladosporium tenuissimum, have been characterised for their ability to control cell proliferation in human colon cancer cell lines through peroxisome proliferator-activated receptor gamma (PPAR\u3b3)-mediated modulation of gene expression. Here, we report data concerning the ability of cladosporols to regulate the differentiation of murine 3T3-L1 preadipocytes. Methods: Cell counting and MTT assay were used for analysing cell proliferation. RT-PCR and Western blotting assays were performed to evaluate differentiation marker expression. Cell migration was analysed by wound-healing assay. Results: We showed that cladosporol A and B inhibited the storage of lipids in 3T3-L1 mature adipocytes, while their administration did not affect the proliferative ability of preadipocytes. Moreover, both cladosporols downregulated mRNA and protein levels of early (C/EBP\u3b1 and PPAR\u3b3) and late (aP2, LPL, FASN, GLUT-4, adiponectin and leptin) differentiation markers of adipogenesis. Finally, we found that proliferation and migration of HT-29 colorectal cancer cells were inhibited by conditioned medium from cladosporol-treated 3T3-L1 cells compared with the preadipocyte conditioned medium. Conclusions: To our knowledge, this is the first report describing that cladosporols inhibit in vitro adipogenesis and through this inhibition may interfere with HT-29 cancer cell growth and migration. General significance: Cladosporols are promising tools to inhibit concomitantly adipogenesis and control colon cancer initiation and progression

Chiral phenoxyacetic acid analogues inhibit colon cancer cell proliferation acting as PPARγ partial agonists

Peroxisome Proliferator-Activated Receptor γ (PPARγ) is an important sensor at the crossroad of diabetes, obesity, immunity and cancer as it regulates adipogenesis, metabolism, inflammation and proliferation. PPARγ exerts its pleiotropic functions upon binding of natural or synthetic ligands. The molecular mechanisms through which PPARγ controls cancer initiation/progression depend on the different mode of binding of distinctive ligands. Here, we analyzed a series of chiral phenoxyacetic acid analogues for their ability to inhibit colorectal cancer (CRC) cells growth by binding PPARγ as partial agonists as assessed in transactivation assays of a PPARG-reporter gene. We further investigated compounds (R,S)-3, (S)-3 and (R,S)-7 because they combine the best antiproliferative activity and a limited transactivation potential and found that they induce cell cycle arrest mainly via upregulation of p21waf1/cip1. Interestingly, they also counteract the β-catenin/TCF pathway by repressing c-Myc and cyclin D1, supporting their antiproliferative effect. Docking experiments provided insight into the binding mode of the most active compound (S)-3, suggesting that its partial agonism could be related to a better stabilization of H3 rather than H11 and H12. In conclusion, we identified a series of PPARγ partial agonists affecting distinct pathways all leading to strong antiproliferative effects. These findings may pave the way for novel therapeutic strategies in CRC

Sequential spectral domain optical coherence tomography imaging of an eye after successful removal of subfoveal perfluorcarbon liquid collection

To evaluate retinal restoration after subfoveal perfluorcarbon liquid (PFCL) bubble removal by means of autofluorescence, infrared, and spectral domain optical coherence tomography over 2 years of follow-up

Synthesis and biological activity evaluation of novel diphenylmethane-based ligands for PPARα and PPARγ

Non previst

A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPARγ, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the β-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPARγ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPARγ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPARγ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPARγ ligands with reduced undesired harmful side effects

Temporal response properties of the macular cone system: effect of normal aging and age-related maculopathy.

PURPOSE: To evaluate the influence of aging and age-related maculopathy (ARM) on the temporal frequency response function (TFR) of macular focal electroretinography. METHODS: Macular (18 degrees ) focal electroretinograms (FERGs) in response to sinusoidal flicker, modulated at TFs between 3.7 and 52 Hz, were recorded from 13 young (age range, 14-29 years) and 9 old (age range, 55-80 years) healthy subjects and from 18 patients with ARM (stage 2 disease; age range, 55-80 years; visual acuity >/=0.4). Amplitude and phase of the Fourier-analyzed response fundamental (1F) and seconnd harmonic (2F) were measured. RESULTS: In young healthy subjects, mean 1F TFR showed a maximum amplitude at 41 Hz, a secondary peak at 3.7 Hz, a minimum at 8 Hz, and a high TF (32-52 Hz) roll-off. Mean 1F TFR of old, compared with young, healthy subjects showed amplitude enhancement at 10 to 14 Hz and a small loss at high TF. Mean 2F TFR of young and old healthy subjects had a maximum at 5.7 to 8 Hz and an attenuation beyond 10 Hz. Mean 1F and 2F TFRs of ARM patients were similar to those of old healthy subjects but were depressed in mean amplitude. FERG TFR changes of old healthy subjects and ARM patients were not mimicked by reducing stimulus retinal illuminance or modulation depth in young healthy subjects. CONCLUSIONS: FERG temporal properties are affected by normal aging and ARM. Because FERG TFR is shaped mainly by postreceptoral activity, the findings suggest that photoreceptor and postsynaptic dysfunction underlie aging- and ARM-related FERG changes

Early detection of central visual function decline in cone-rod dystrophy by the use of macular focal cone electroretinogram.

PURPOSE: To evaluate macular focal cone ERG (fERG) as a tool for reliable and early detection of central retinal function decay in cone-rod dystrophy (CRD). METHODS: A retrospective study of the time course of fERG amplitude and its relation to visual acuity alterations was performed in 47 CRD patients followed yearly for 6.0 \ub1 3.1 years. Macular focal cone ERG was evoked by a flickering uniform red field overlaying the central 18\ub0 of visual field. RESULTS: Macular focal cone ERG follow-up allowed a clear-cut identification of CRD patients as stationary or progressive, in agreement with visual acuity follow-up. In all progressive patients, fERG declined whenever visual acuity declined, and-in 50% of the cases-fERG loss anticipated acuity loss of several years. CONCLUSIONS: Macular focal cone ERG represents a sensitive assay to detect, categorize, and follow the progression of central retinal dysfunction in CRD. Its use as a diagnostic tool in CRD may help anticipate, for an individual patient, the likelihood and rate of further disease progression before visual acuity loss has occurred

New diphenylmethane derivatives as peroxisome proliferator-activated receptor alpha/gamma dual agonists endowed with anti-proliferative effects and mitochondrial activity

We screened a short series of new chiral diphenylmethane derivatives and identified potent dual PPARα/γ partial agonists. As both enantiomers of the most active compound 1 displayed an unexpected similar transactivation activity, we performed docking experiments to provide a molecular understanding of their similar partial agonism. We also evaluated the ability of both enantiomers of 1 and racemic 2 to inhibit colorectal cancer cells proliferation: (S)-1 displayed a more robust activity due, at least in part, to a partial inhibition of the Wnt/β-catenin signalling pathway that is upregulated in the majority of colorectal cancers. Finally, we investigated the effects of (R)-1, (S)-1 and (R,S)-2 on mitochondrial function and demonstrated that they activate the carnitine shuttle system through upregulation of carnitine/acylcarnitine carrier (CAC) and carnitine-palmitoyl-transferase 1 (CPT1) genes. Consistent with the notion that these are PPARα target genes, we tested and found that PPARα itself is regulated by a positive loop. Moreover, these compounds induced a significant mitochondrial biogenesis. In conclusion, we identified a new series of dual PPARα/γ agonists endowed with novel anti-proliferative properties associated with a strong activation of mitochondrial functions and biogenesis, a potential therapeutic target of the treatment of insulin resistance