Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation ...that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
(1) Objective: Highlight the in vitro effects of 3T3-L1 cell exposure to polychlorinated biphenyls (PCB118 and 153) or benzo(a)pyrene (BaP) alone or as a cocktail on adipogenesis (ADG) by focusing on ...changes in lipid metabolism and inflammatory-related genes expression (INFG) and ADG-related genes expression (ADGG); (2) Results: Treatment from the early stage of cell differentiation by BaP alone or in combination with PCBs decreased the expression of some of the ADGG (
,
,
,
, and
). BaP enhanced the INFG, especially
and
. Co-exposure to BaP and PCB153 showed a synergistic effect on
and
expression. Treatment with BaP and PCBs during only the maturation period up-regulated the INFG (
,
,
). PCB118 alone also enhanced
,
, and
expression. The change in MCP-1 protein expression was in agreement with that of the gene. Finally, the BaP-induced up-regulation of the xenobiotic responsive element (XRE)-controlled luciferase activity was impaired by PCB153 but not by PCB118; (3) Conclusion: BaP and PCBs down-regulate a part of ADGG and enhance INFG. The direct regulatory effect of PCBs on both ADGG and INFG is usually rather lower than that of BaP and synergistic or antagonistic cocktail effects are clearly observed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Epidemiological studies have associated environmental exposure to polychlorinated biphenyls (PCBs) with an increased risk of type 2 diabetes; however, little is known about the underlying mechanisms ...involved in the metabolic side-effects of PCB. Our study evaluated the transcriptional effects of a subchronic exposure (gavage at Day 0 and Day 15 with 10 or 100 μmol/Kg bw) to PCB118 (dioxin-like PCB), PCB153 (non-dioxin-like PCB), or an equimolar mixture of PCB118 and PCB153 on various tissues (liver, visceral adipose tissue, muscle, and colon) in mice. Our results showed that a short-term exposure to PCB118 and/or PCB153 enhanced circulating triglyceride levels but did not affect glycemia. Among the studied tissues, we did not observe any modification of the expression of inflammation-related genes, such as cytokines or chemokines. The main transcriptional effects were observed in visceral adipose and liver tissues. We found a downregulation of lipin1 and glut4 expression in these two target organs. In adipose tissue, we also showed a downregulation of Agpat2, Slc25a1, and Fasn. All of these genes are involved in lipid metabolism and insulin resistance. In muscles, we observed an induction of CnR1 and Foxo3 expression, which may be partly involved in PCB metabolic effects. In summary, our results suggest that lipin1 and glut4, notably in adipose tissue, are the main targeted genes in PCB-induced metabolic disorders, however, further studies are required to fully elucidate the mechanisms involved.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We demonstrate that intestinal inflammation caused by high-fat diet is increased by the environmental contaminant benzo
apyrene. Our
in vivo results indicate that a high-fat diet (HFD) induces a ...pre-diabetic state in mice compared with animals fed normal chow. HFD increased IL-1βmRNA concentration in the jejunum, colon, and liver, and TNFα was increased in the colon and strongly increased in the liver. HFD also increased the expression of other genes related to type 2 diabetes, such as the uncoupling protein UCP2, throughout the bowel and liver, but not in the colon. The treatment of HFD with BaP enhanced the expression of IL-1β in the liver and TNFα throughout the bowel and in the liver. Adding BaP to the diet also caused a significant decrease in the expression of the incretin glucagon-like peptide 1, which plays an important role in insulin secretion. Our results suggest that intestinal inflammation may be involved in the onset of type 2 diabetes and that chronic exposure to environmental polycyclic aromatic hydrocarbons can increase the risk of type 2 diabetes by inducing pro-inflammatory cytokine production.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We revisited the action of a carotenoid, the lycopene, on the expression of proinflammatory genes, reactive oxygen species (ROS) production, and metalloprotease (MMP9) activity. THP1 and Caco2 cell ...lines were used as in vitro models for the two main cell types found in intestine tissue, that is, monocytes and epithelial cells. Proinflammatory condition was induced using either phorbol ester acetate (PMA), lipopolysaccharide (LPS) or tumor necrosis factor (TNF). In THP1 cells, short term pretreatment (2 h) with a low concentration (2 μM) of lycopene reinforce proinflammatory gene expression. The extent of the effect of lycopene is dependent on the proinflammtory stimulus (PMA, LPS or TNF) used. Lycopene enhanced MMP9 secretion via a c-AMP-dependent process, and reduced ROS production at higher concentrations than 2 μM. Cell culture media, conditioned by PMA-treated monocytes and then transferred on CaCo-2 epithelial cells, induced a proinflammatory state in these cells. The extent of this inflammatory effect was reduced when cells has been pretreated (12 h) with lycopene. At low concentration (2 μM or less), lycopene appeared to promote an inflammatory state not correlated with ROS modulation. At higher concentration (5 μM–20 μM), an anti-inflammatory effect takes place as a decrease of ROS production was detected. So, both concentration and time have to be considered in order to define the exact issue of the effect of carotenoids present in meals.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
We previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro.
Our purpose was (i) to identify the molecular mechanism involved and (ii) to characterize ...the inducer compound(s) in serum involved at least in part.
Serum was fractionated on hydrophobic columns. PPARα involvement was demonstrated by gene reporter assays, DNA mutagenesis and EMSA. Gene expression was evaluated by qRT-PCR. Serum samples were analyzed using HS-SPME-GC-MS.
The inductive effect of serum did not depend on the AhR pathway and was enhanced by cotransfection of PPARα cDNA. Mutations in the PPAR response elements of the CYP1A1 gene promoter suppressed this effect. One of the PPRE sites appeared highly specific for human PPARα, an unreported PPRE property. A link was found between CYP1A1 inducibility and serum hydrophobic compounds. Characterization of sera showed that hexanal, a metabolite produced by peroxidation of linoleic acid, was involved in CYP1A1 induction by serum, possibly along with other serum entities.
We demonstrate that serum induces CYP1A1 via the PPARα pathway and that hexanal is one of the serum inducers. The two PPRE sites within the CYP1A1 promoter are functional and one of them is specific for PPARα.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is an increasing prevalence of coincident cerebrovascular deficiency and cognitive dysfunction with aging. Increased oxidative stress as well as inflammation that occurs with aging are ...associated with the impairment of cerebral vascularization. Interestingly, Resveratrol (RSV), a natural phytoalexin, is known to be a strong antioxidant and possesses anti-inflammatory properties. Collectively, these observations strongly suggest that RSV could protect against cerebral vascularization defect and then improves the decline cognitive function associated with aging. In order to test this hypothesis, we investigated the effect of a long-term RSV treatment (1.25 mg/day for 5 months) on cognitive performances of animals that we have allowed to age normally. Then, we further analyzed the gene expression profile and the cerebral blood flow in the brain. By means of novel object recognition (NOR) test, we observed that RSV enhanced NOR performances of aged rats. In addition, RSV enhanced cerebral blood flow during NOR task in aged rats. Using microarrays experiments, we also showed that several pathways related to inflammation and oxidative stress (Eicosanoid signaling, MIF-mediated innate immunity, NF-kB signaling, TNFR2 signaling, IL6 signaling, Production of nitric oxide and ROS) were down-regulated in the brain of RSV treatments rats compared to control rats. In conclusion, these results support that a long-term treatment with RSV improves cognitive performance in the elderly male rat model. This effect is associated with an increase in cerebral blood flow and a decrease in the expression of several pro-inflammatory pathways in the brain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The polyphenols resveratrol (RSV) and curcumin (Cur) are phytoalexines and natural antibiotics with numerous pharmacological functions and metabolic impacts. Recent evidences show a broad control of ...gut microbiota by polyphenols which could influence glycemic regulation. The aim of this work is to estimate the respective effect of RSV and Cur alone or in association on the control of glycemia and on gut microbiota. A 5-week chronic treatment of hyperglycemic mice with RSV and/or Cur resulted in a differential effect on glucose tolerance test and modified gut microbiome. We precisely identified groups of bacteria representing a specific signature of the glycemic effect of RSV. Inferred metagenomic analysis and metabolic pathway prediction showed that the sulfur and branched-chain amino-acid (BCAA) metabolic activities are tightly correlated with the efficacy of RSV for the control of glycaemia. The impact on BCAA metabolism was further validated by serum metabolomics analysis. Altogether, we show that polyphenols specifically impact gut microbiota and corresponding metabolic functions which could be responsible for their therapeutic role.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Extra virgin olive oil has been associated with a reduced incidence of risk factors for coronary heart disease also owing to the presence of antioxidant biophenols. Reactive oxygen species (ROS) and ...matrix metalloproteinase-9 (MMP-9) have been implicated in numerous somatic illnesses, including cardiovascular disorders and cancer. The aim of this work was to study the capacity of virgin olive oil tyrosol (T) and hydroxytyrosol (HT) at impairing superoxide production and MMP-9 expressions in monocyte cells (THP-1) conveniently differentiated into adherent macrophages, taken as a model of human macrophages implicated in atheroma.
O
2
−
production was evaluated in THP-1 cells by using lucigenin as a specific chemiluminescent probe. Cells, after differentiation for 72
h, were preincubated in the presence of HT and T at increasing concentrations for 4, 15 and 24
h, and then, monocyte-like cells were stimulated by phorbol myristate acetate (PMA) and the O
2
−
-dependent luminescence was immediately recorded at 37
°C by means of a Luminometer. Enzymatic activity of MMP-9 derived from a medium of cells preincubated, or not, with T or HT was tested by zymography.
As compared to the cells without treatment, cells preincubated with HT, showed a decrease of O
2
−
production (50%) at 1
μM for 15
h of preincubation time. Tyrosol fully prevented ROS overproduction at 15
h and, like HT displayed a high degree of protection but at higher concentrations and later time points (24
h). Gelatin zymograms revealed a reduction of the expression of MMP-9 in conditioned medium derived from T and HT-treated cells. These findings give further evidence in favour of olive oil consumption to counteract cardiovascular diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background We previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro. Objective Our purpose was (i) to identify the molecular mechanism involved and ...(ii) to characterize the inducer compound(s) in serum involved at least in part. Methods Serum was fractionated on hydrophobic columns. PPARalpha involvement was demonstrated by gene reporter assays, DNA mutagenesis and EMSA. Gene expression was evaluated by qRT-PCR. Serum samples were analyzed using HS-SPME-GC-MS. Results The inductive effect of serum did not depend on the AhR pathway and was enhanced by cotransfection of PPARalpha cDNA. Mutations in the PPAR response elements of the CYP1A1 gene promoter suppressed this effect. One of the PPRE sites appeared highly specific for human PPARalpha, an unreported PPRE property. A link was found between CYP1A1 inducibility and serum hydrophobic compounds. Characterization of sera showed that hexanal, a metabolite produced by peroxidation of linoleic acid, was involved in CYP1A1 induction by serum, possibly along with other serum entities. Conclusion We demonstrate that serum induces CYP1A1 via the PPARalpha pathway and that hexanal is one of the serum inducers. The two PPRE sites within the CYP1A1 promoter are functional and one of them is specific for PPARalpha.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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