Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a ...selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes.
Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation.
Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota.
We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions during obesity and diabetes.
Green tea (
Camellia sinensis) is rich in catechins, of which (−)-epigallocatechin-3-gallate (EGCG) is the most abundant. Studies in animal models of carcinogenesis have shown that green tea and EGCG ...can inhibit tumorigenesis during the initiation, promotion and progression stages. Many potential mechanisms have been proposed including both antioxidant and pro-oxidant effects, but questions remain regarding the relevance of these mechanisms to cancer prevention. In the present review, we will discuss the redox chemistry of the tea catechins and the current literature on the antioxidant and pro-oxidative effects of the green tea polyphenols as they relate to cancer prevention. We report that although the catechins are chemical antioxidants which can quench free radical species and chelate transition metals, there is evidence that some of the effects of these compounds may be related to induction of oxidative stress. Such pro-oxidant effects appear to be responsible for the induction of apoptosis in tumor cells. These pro-oxidant effects may also induce endogenous antioxidant systems in normal tissues that offer protection against carcinogenic insult. This review is meant point out understudied areas and stimulate research on the topic with the hope that insights into the mechanisms of cancer preventive activity of tea polyphenols will result.
Obtaining a tar-free biosyngas from biomass gasification processes has been the subject of many studies in the past 2 decades, and it still remains the major technologic and economic challenge. ...Unfortunately, the countless publications about gasification technologies and different techniques permitting reduction of the tar present at the outlet of gasifier reactors usually confuse inexperienced persons who attempt to further research this subject. More than presenting the basis of biomass gasification technologies and positioning them among other bioenergies, this work mainly aims at reviewing and comparing the different methods developed in order to produce a tar-free biosyngas. In this way, biosyngas quality improvement can be obtained through different operating processes such as reactor designs, gasifying ratios, feedstock, temperature, and space ratio. Since catalytic destruction has proved to be one of the most convenient and efficient ways to eliminate undesirable tars, an important part of this work also highlights the catalytic and deactivating phenomena involved. Furthermore, this work takes inventory of numerous studies conducted to understand the influence of different properties, especially supports and active site compositions, on the tar reforming activities and lifetime of catalyst materials. Thus, this review aims at summarizing basic and more recent improvements applied to biomass gasification processes and catalytic syngas purification.
Opioids targeting mu;μ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and ...addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ35S binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ35S and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands.
Opioid addicts are more likely to present with infections suggesting opioids are immune modulators. The potential sites/mechanism(s) for this modulation are controversial and on close inspection not ...well supported by the current literature. It has long been assumed that opioid-induced immune modulation occurs via a combination of direct actions on the immune cell itself, via the hypothalamic-pituitary-adrenal (HPA) axis, or both. Opioid receptors are classified as MOP (μ, mu), DOP (δ, delta), and KOP (κ, kappa)'classical naloxone sensitive receptors'or NOP (the receptor for nociceptin/orphanin FQ), which is naloxone insensitive. Opioids currently used in clinical practice predominantly target the MOP receptor. There do not appear to be classical opioid receptors present on immune cells. The evidence for HPA activation is also poor and shows some species dependence. Most opioids used clinically or as drugs of abuse do not target the NOP receptor. Other possible target sites for immune modulation include the sympathetic nervous system and central sites. We are currently unable to accurately define the cellular target for immune modulation and suggest further investigation is required. Based on the differences observed when comparing studies in laboratory animals and those performed in humans we suggest that further studies in the clinical setting are needed.
There is a vast amount of pharmacological evidence favouring the existence of multiple subtypes of opioid receptors. In addition to the primary classification of µ (mu: MOP), δ (delta: DOP), κ ...(kappa: KOP) receptors, and the nociceptin/orphanin FQ peptide receptor (NOP), various groups have further classified the pharmacological µ into µ1–3, the δ into δ1–2/δcomplexed/non-complexed, and the κ into κ1–3. From an anaesthetic perspective, the suggestions that µ1 produced analgesia and µ2 produced respiratory depression are particularly important. However, subsequent to the formal identification of the primary opioid receptors (MOP/DOP/KOP/NOP) by cloning and the use of this information to produce knockout animals, evidence for these additional subtypes is lacking. Indeed, knockout of a single gene (and hence receptor) results in a loss of all function associated with that receptor. In the case of MOP knockout, analgesia and respiratory depression is lost. This suggests that further sub-classification of the primary types is unwise. So how can the wealth of pharmacological data be reconciled with new molecular information? In addition to some simple misclassification (κ3 is probably NOP), there are several possibilities which include: (i) alternate splicing of a common gene product, (ii) receptor dimerization, (iii) interaction of a common gene product with other receptors/signalling molecules, or (iv) a combination of (i)–(iii). Assigning variations in ligand activity (pharmacological subtypes) to one or more of these molecular suggestions represents an interesting challenge for future opioid research.
Opioids are characterised as classical (mu, delta, and kappa) along with the non-classical nociceptin/orphanin FQ (N/OFQ) receptor or NOP. Targeting NOP has therapeutic indications in control of the ...cardiovascular and respiratory systems and micturition, and a profile as an antidepressant. For all of these indications, there are translational human data. Opioids such as morphine and fentanyl (activating the mu receptor) are the mainstay of pain treatment in the perioperative period, despite a challenging side-effect profile. Opioids in general have poor efficacy in neuropathic pain. Moreover, longer term use is associated with tolerance. There is good evidence interactions between opioid receptors, and receptor co-activation can reduce side-effects without compromising analgesia; this is particularly true for mu and NOP co-activation. Recent pharmaceutical development has produced a mixed opioid/NOP agonist, cebranopadol. This new chemical entity is effective in animal models of nociceptive and neuropathic pain with greater efficacy in the latter. In animal models, there is little evidence for respiratory depression, and tolerance (compared with morphine) only develops after long treatment periods. There is now early phase clinical development in diabetic neuropathy, cancer pain, and low back pain where cebranopadol displays significant efficacy. In 1996, N/OFQ was formally identified with an innovative analgesic profile. Approximately 20 yr later, cebranopadol as a clinical ligand is advancing through the human trials process.
Atmospheric parameters and oxygen abundances of 825 nearby FGK stars are derived using high-quality spectra and a non-local thermodynamic equilibrium analysis of the 777 nm OI triplet lines. We ...assign a kinematic probability for the stars to be thin-disk (P sub(1)), thick-disk (P sub(2)), and halo (P sub(3)) members. We confirm previous findings of enhanced O/Fe in thick-disk (P sub(2) > 0.5) relative to thin-disk (P sub(1) > 0.5) stars with Fe/H lap -0.2, as well as a "knee" that connects the mean O/Fe-Fe/H trend of thick-disk stars with that of thin-disk members at Fe/H gap -0.2. Nevertheless, we find that the kinematic membership criterion fails at separating perfectly the stars in the O/Fe-Fe/H plane, even when a very restrictive kinematic separation is employed. Stars with "intermediate" kinematics (P sub(1) < 0.7, P sub(2) < 0.7) do not all populate the region of the O/Fe-Fe/H plane intermediate between the mean thin-disk and thick-disk trends, but their distribution is not necessarily bimodal. Halo stars (P sub(3) > 0.5) show a large star-to-star scatter in O/Fe-Fe/H, but most of it is due to stars with Galactocentric rotational velocity V < -200 km s super(-1); halo stars with V > -200 km s super(-1) follow an O/Fe-Fe/H relation with almost no star-to-star scatter. Early mergers with satellite galaxies explain most of our observations, but the significant fraction of disk stars with "ambiguous" kinematics and abundances suggests that scattering by molecular clouds and radial migration have both played an important role in determining the kinematic and chemical properties of solar neighborhood stars.
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