Metabolic illnesses such as non-alcoholic fatty liver disease (NAFLD) are in constant increase worldwide. Highly consumed long chain fatty acids (LCFA) are among the most obesogenic and steatogenic ...nutrients. Hepatic steatosis is associated with several complications such as insulin resistance. Growing evidence points to medium chain fatty acids (MCFA), more efficiently oxidized than LCFA, as a promising dietary alternative against NAFLD. However, reports on the hepatic effects of MCFA are sometimes conflicting. In this study we exposed HepG2 cells, a human hepatocellular model, to 0.25 mM of hexanoic (C6), or octanoic (C8), and decanoic (C10) acids separately or in a C8 + C10 equimolar mix reflecting commercially available MCFA-rich oils. We found that C6, a poorly studied MCFA, as well as C8 and C10 did not provoke the deleterious lipid anabolism runaway typically induced by LCFA palmitate. MCFA tended, instead, to promote a balanced metabolic profile and were generally non-cytotoxic. Accordingly, mitochondrial integrity was mostly preserved following MCFA treatment. However, treatments with C8 induced a mitochondrial membrane potential decrease, suggesting prolonged exposure to this lipid could be problematic. Finally, MCFA treatments maintained optimal insulin sensitivity and even fostered basal and insulin-dependent phosphorylation of the Akt-mTOR pathway. Overall, MCFA could constitute an effective nutritional tool to manage liver steatosis and hepatic insulin resistance.
Catechol (cat) is a highly adhesive diphenol that can be chemically grafted to polymers such as chitosan (CH) to make them adhesive as well. However, catechol-containing materials experimentally show ...a large variability of toxicity, especially in vitro. While it is unclear how this toxicity emerges, most concerns are directed toward the oxidation of catechol into quinone that releases reactive oxygen species (ROS) which can, in turn, cause cell apoptosis through oxidative stress. To better understand the mechanisms at play, we examined the leaching profiles, hydrogen peroxide (H2O2) production, and in vitro cytotoxicity of several cat-chitosan (cat-CH) hydrogels that were prepared with different oxidation levels and cross-linking methods. To create cat-CH with different propensities toward oxidation, we grafted either hydrocaffeic acid (HCA, more prone to oxidation) or dihydrobenzoic acid (DHBA, less prone to oxidation) to the backbone of CH. Hydrogels were cross-linked either covalently, using sodium periodate (NaIO4) to trigger oxidative cross-linking, or physically, using sodium bicarbonate (SHC). While using NaIO4 as a cross-linker increased the oxidation levels of the hydrogels, it also significantly reduced in vitro cytotoxicity, H2O2 production, and catechol and quinone leaching in the media. For all gels tested, cytotoxicity could be directly related to the release of quinones rather than H2O2 production or catechol release, showing that oxidative stress may not be the main reason for catechol cytotoxicity, as other pathways of quinone toxicity come into play. Results also suggest that the indirect cytotoxicity of cat-CH hydrogels fabricated through carbodiimide chemistry can be reduced if (i) catechol groups are chemically bound to the polymer backbone to prevent leaching or (ii) the chosen cat-bearing molecule has a high resistance to oxidation. Coupled with the use of other cross-linking chemistries or more efficient purification methods, these strategies can be adopted to synthesize various types of cytocompatible cat-containing scaffolds.
Adoptive cell therapy (ACT) shows success against treatment-resistant cancers, but is limited by the large number of intravenously delivered T cells required and toxicity related to systemic ...administration. In this work, we hypothesized that localized T cell delivery in an
in situ
gelling chitosan hydrogel will allow similar treatment efficacy despite delivering fewer cells than systemic intravenous delivery. A rapidly gelling chitosan gel with good mechanical properties was used for this study. Gel biocompatibility and biodegradability were tested over 8 weeks in mice. No adverse effects were observed. The gel elicited a local granulomatous reaction (foreign body reaction), degrading by about 75% volume at 8 weeks. The survival, escape and bioactivity against the tumour cells of encapsulated murine lymphocytes (OT-I) and human Jurkat cells were confirmed
in vitro
by live/dead assay and flow cytometry. Efficacy was studied using a mouse tumour model where the injected OT-I can specifically recognize and attack ovalbumin (OVA) protein-expressing tumours. The OT-I cell delivery scaffold was compared to untreated controls, OT-I in saline and intravenous systemic treatment with 3-fold more OT-I, observing tumour growth and localization by intravital microscopy and histology. Gel-encapsulated OT-I limited tumour growth significantly up to 11 days after treatment compared to that of untreated mice and mice with longer PBS-suspended OT-I treatment (9 days), but slightly less than that of mice with IV-delivered OT-I treatment (14 days). No significant difference was observed when directly comparing the gel and IV treatments. Although further optimization of the treatment is required, this work shows the feasibility and potential of the chitosan gel for localised OT-I delivery in cancer immunotherapy.
T cells encapsulated in an
in situ
gelling biodegradable hydrogel reduce tumor growth in a mouse tumor model.
Context: Long chain fatty acids (LCFA) such as palmitate (C16) are potent contributors to obesity, fatty liver disease and insulin resistance (IR). Inversely, growing evidence suggests that medium ...chain fatty acids (MCFA), namely hexanoate (C6), octanoate (C8) and decanoate (C10), can improve metabolic health. Indeed, we recently reported (APNM, vol.42, 2017) that a high-fat diet loaded with medium chain triglyceride oil (MCT-oil) instead of lard (rich in LCFA) did not induce body-weight gain, liver steatosis, glucose intolerance, IR or global adiposity in mice. Objective: To elucidate the mechanisms by which MCFA avoid hepatic steatosis and IR. Methods: HepG2 cells were exposed 24h to increasing doses of C16, C6, C8 and/or C10 then submitted to an MTT viability test. HepG2 cells exposed 24h to 0.25mM of either C16 or MCFA were submitted to: a) BODIPY fluorophore staining; b) quantification of key anabolic (e.g. SREBP-1) and catabolic (e.g. CPT-1) gene expression, by Western blot and RT-qPCR; c) 3H-deoxyglucose uptake assay following a 1h exposure to 100nM insulin; d) evaluation of the phosphorylation levels of AKT1, mTOR and p70S6K kinases in response to insulin stimulation (100nM, 10min); e) and fatty acid betaoxidation assay based on the conversion rate of 14C-oleate into 14CO2. Results: While C16 significantly decreases HepG2 cell viability in a dose-response fashion, MCFA do not. At 0.25mM, the threshold of C16 toxicity, MCFA do not induce a rise in lipid droplet number and size, while C16 does so substantially. In the same time, MCFA maintain the basal beta-oxidation rate, while C16 inhibits it two-fold. Furthermore, anabolic and catabolic genes are respectively downregulated and upregulated by MCFA, at both mRNA and protein levels, and inversely regulated by C16. Finally, whereas C16 inhibits insulin-induced glucose uptake and the underlying phosphorylation of the AKT1-mTORp70S6K axis, MCFA treatment does not alter them. Conclusion: In hepatocytes, MCFA increase lipid oxidation and impede both lipogenesis and lipid esterification, thus do not cause steatosis or lipotoxicity. Then, insulin signalling pathway remains unaltered, preserving insulin sensitivity. These results demonstrate that MCFA are promising bioactive lipids in the management of metabolic diseases. (Support: NSERC and Aligo Innovation.)
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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