Ruolo dei polimorfismi genetici nella definizione della sindrome Normal-weight obese

Come hanno rivelato numerosi studi, l’espressione, la produzione e il rilascio di un gran numero di citochine proinfiammatorie è aumentata nel tessuto adiposo dei soggetti obesi. Recentemente è stata identificata una nuova sindrome, denominata sindrome Normal Weight Obese (NWO) caratterizzata da peso ed indici antropometrici normali, ma da un’aumentata massa grassa >30%. I soggetti NWO pur non manifestando alterazioni metaboliche conclamate, rappresentano un sottogruppo dal profilo “vulnerabile”, che le rende suscettibili di sviluppare le complicanze tipiche dell’obesità. Gli obiettivi di questo studio sono stati sostanzialmente due: a) lo studio dell’associazione tra il fenotipo NWO e alcuni polimorfismi a carico di citochine proinfiammatorie; b) individuare eventuali markers genetici di rischio nei soggetti NWO. In una popolazione selezionata di soggetti caratterizzati da questa sindrome sono stati considerati i seguenti polimorfismi: il polimorfismo del gene del recettore per Interleuchina-1; il polimorfismo -174G/C a livello del promotore genico di Interleuchina-6; il polimorfismo del gene del recettore alpha di Interleuchina-15. I risultati ottenuti suggeriscono la natura multifattoriale della sindrome NWO e indicano che i soggetti affetti, presentano un profilo in termini di citochine infiammatorie che fa presupporre uno stato infiammatorio alterato. Inoltre sono stati individuati markers precoci di malattia utilizzabili al fine di evitare l’instaurarsi della sindrome o almeno di ritardarne la comparsa e progressione.In obese subjects, the adipose mass may represents an important source of proinflammatory cytokines. Recently it was identified a new syndrome - the normal-weight obese (NWO) syndrome – in subjects with normal weight and body mass index but whose fat mass is >30% of their total body weight and whose risk of developing obesity-related diseases is likely increased. Main objectives of the present study were: a) to tested the hypothesis that the polymorphism in a panel of three selected cytokines might be associated with NWO syndrome; b) to identified a risk genetic marker of the syndrome. The polymorphism of intron 2 in the interleukin-1 receptor antagonist gene, -174G/C IL-6 promoter gene polymorphism and polymorphisms of IL-15Rα receptor gene were evaluated in a selected population affected by NWO syndrome. As a whole our results indicated that the NWO syndrome is a multifactorial desease, and suggest that the study of proinflammatory cytokines could be regarded as significant indicators of the risk of obesity, CVD, and the metabolic syndrome in NWO subject. In particular the study of their polymorphism permitted to identified, time in advance, “vulnerable” individuals at risk of age and obesity related diseases

Ruolo dei polimorfismi genetici nella definizione della sindrome Normal-weight obese

Come hanno rivelato numerosi studi, l’espressione, la produzione e il rilascio di un gran numero di citochine proinfiammatorie è aumentata nel tessuto adiposo dei soggetti obesi. Recentemente è stata identificata una nuova sindrome, denominata sindrome Normal Weight Obese (NWO) caratterizzata da peso ed indici antropometrici normali, ma da un’aumentata massa grassa >30%. I soggetti NWO pur non manifestando alterazioni metaboliche conclamate, rappresentano un sottogruppo dal profilo “vulnerabile”, che le rende suscettibili di sviluppare le complicanze tipiche dell’obesità. Gli obiettivi di questo studio sono stati sostanzialmente due: a) lo studio dell’associazione tra il fenotipo NWO e alcuni polimorfismi a carico di citochine proinfiammatorie; b) individuare eventuali markers genetici di rischio nei soggetti NWO. In una popolazione selezionata di soggetti caratterizzati da questa sindrome sono stati considerati i seguenti polimorfismi: il polimorfismo del gene del recettore per Interleuchina-1; il polimorfismo -174G/C a livello del promotore genico di Interleuchina-6; il polimorfismo del gene del recettore alpha di Interleuchina-15. I risultati ottenuti suggeriscono la natura multifattoriale della sindrome NWO e indicano che i soggetti affetti, presentano un profilo in termini di citochine infiammatorie che fa presupporre uno stato infiammatorio alterato. Inoltre sono stati individuati markers precoci di malattia utilizzabili al fine di evitare l’instaurarsi della sindrome o almeno di ritardarne la comparsa e progressione.In obese subjects, the adipose mass may represents an important source of proinflammatory cytokines. Recently it was identified a new syndrome - the normal-weight obese (NWO) syndrome – in subjects with normal weight and body mass index but whose fat mass is >30% of their total body weight and whose risk of developing obesity-related diseases is likely increased. Main objectives of the present study were: a) to tested the hypothesis that the polymorphism in a panel of three selected cytokines might be associated with NWO syndrome; b) to identified a risk genetic marker of the syndrome. The polymorphism of intron 2 in the interleukin-1 receptor antagonist gene, -174G/C IL-6 promoter gene polymorphism and polymorphisms of IL-15Rα receptor gene were evaluated in a selected population affected by NWO syndrome. As a whole our results indicated that the NWO syndrome is a multifactorial desease, and suggest that the study of proinflammatory cytokines could be regarded as significant indicators of the risk of obesity, CVD, and the metabolic syndrome in NWO subject. In particular the study of their polymorphism permitted to identified, time in advance, “vulnerable” individuals at risk of age and obesity related diseases

Cyclooligomerization Reactions of Different Phosphaalkynes in the Presence of [W(CO)5thf] - A Route to Tungsten-Stabilised Phosphorus Heterocycles

The reactivity of various phosphaalkynes versus [W(CO)5thf] has been studied. The reaction with Mes*CP (Mes* = 2,4,6-tBu3C6H2) exclusively leads to the low yield formation of [W(CO)2{(2-PCMes*)W(CO)5}2] (1). The reaction of the less bulky tBuCP with [W(CO)5thf] results in high yields in [W(CO)2{4-(tBuC)2P2W(CO)5}{2-(tBuCP)W(CO)5}] (2) which possesses a 1,3-diphosphete ligand as well as a side-on coordinated tBuCP unit. Experiments employing MesCP (Mes = 2,4,6-Me3C6H2) give the complexes [W(CO)4{4-(MesC)2P2}] (3), [W(CO)2{4-(MesC)2P2}{2-(MesCP)W(CO)5}] (4) and [W(CO)2{4-(MesC)2P2W(CO)5}2-(MesCP)W(CO)5{µ-W(CO)4}] (5) which have a 1,3-diphosphete ligand in their coordination sphere and are partly substituted with an additional side-on coordinated MesCP unit. In 5, two P atoms of the 1,3-diphosphete and the side-on coordinated MesCP are further bridged by a W(CO)4 moiety. Additionally, the unusual product [{W(CO)3}6-1,2,4-(RC)3P3{RCPW(CO)5}2] (R = Mes) (6) resulting from a pentamerization of MesCP initiated by [W(CO)5thf], could be obtained in moderate yield. Comprehensive spectroscopical and structural investigations of all products are presented

Pheomelanin effect on UVB radiation-induced oxidation/nitration of L-tyrosine

Pheomelanin is a natural yellow-reddish sulfur-containing pigment derived from tyrosinase-catalyzed oxidation of tyrosine in presence of cysteine. Generally, the formation of melanin pigments is a protective response against the damaging effects of UV radiation in skin. However, pheomelanin, like other photosensitizing substances, can trigger, following exposure to UV radiation, photochemical reactions capable of modifying and damaging cellular components. The photoproperties of this natural pigment have been studied by analyzing pheomelanin effect on oxidation/nitration of tyrosine induced by UVB radiation at different pH values and in presence of iron ions. Photoproperties of pheomelanin can be modulated by various experimental conditions, ranging from the photoprotection to the triggering of potentially damaging photochemical reactions. The study of the photomodification of l-Tyrosine in the presence of the natural pigment pheomelanin has a special relevance, since this tyrosine oxidation/nitration pathway can potentially occur in vivo in tissues exposed to sunlight and play a role in the mechanisms of tissue damage induced by UV radiation

Topoisomerase poisoning activity of novel disaccharide anthracyclines.

International audienceDoxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases IIalpha and IIbeta. Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases IIalpha and IIbeta. The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I

MicroRNA-130b Promotes Tumor Development and Is Associated with Poor Prognosis in Colorectal Cancer

MicroRNA-130b (miR-130b) is involved in several biologic processes; its role in colorectal tumorigenesis has not been addressed so far. Herein, we demonstrate that miR-130b up-regulation exhibits clinical relevance as it is linked to advanced colorectal cancers (CRCs), poor patients' prognosis, and molecular features of enhanced epithelial-mesenchymal transition (EMT) and angiogenesis. miR-130b high-expressing cells develop large, dedifferentiated, and vascularized tumors in mouse xenografts, features that are reverted by intratumor injection of a specific antisense RNA. In contrast, injection of the corresponding mimic in mouse xenografts from miR-130b low-expressing cells increases tumor growth and angiogenic potential while reduces the epithelial hallmarks. These biologic effects are reproduced in human CRC cell lines. We identify peroxisome proliferator-activated receptor γ (PPARγ) as an miR-130b direct target in CRC in vitro and in vivo. Notably, the effects of PPARγ gain- and loss-of-function phenocopy those due to miR-130b down-regulation or up-regulation, respectively, underscoring their biologic relevance. Furthermore, we provide mechanistic evidences that most of the miR-130b-dependent effects are due to PPARγ suppression that in turn deregulates PTEN, E-cadherin, Snail, and vascular endothelial growth factor, key mediators of cell proliferation, EMT, and angiogenesis. Since higher levels of miR-130b are found in advanced tumor stages (III–IV), we propose a novel role of the miR-130b-PPARγ axis in fostering the progression toward more invasive CRCs. Detection of onco-miR-130b and its association with PPARγ may be useful as a prognostic biomarker. Its targeting in vivo should be evaluated as a novel effective therapeutic tool against CRC

Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer

Purpose Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors. Methods Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors. In vitro studies evaluated cell viability, PI3K signaling, and cell death upon treatment with MEN1611. In vivo efficacy of the compound was investigated in cell line- and patient-derived xenografts models. Results Consistent with its biochemical selectivity, MEN1611 demonstrated lower cytotoxic activity in a p110δ-driven cellular model when compared to taselisib, and higher cytotoxic activity in the p110β-driven cellular model when compared to alpelisib. Moreover, MEN1611 selectively decreased the p110α protein levels in PIK3CA mutated breast cancer cells in a concentration- and proteasome-dependent manner. In vivo, MEN1611 monotherapy showed significant and durable antitumor activity in several trastuzumab-resistant PIK3CA-mutant HER2 + PDX models. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment. Conclusions The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335)