Detection and Analysis of Florfenicol Residues and Metabolites in Nile Tilapia (Oreochromis niloticus) Tissues Post-Oral Administration in Tropical Waters.

Water temperature is a critical environmental parameter that significantly influences fish metabolism. This study assessed the metabolism of florfenicol (FF) in tilapia (Oreochromis niloticus) at water temperatures typical of tropical and subtropical regions. Fish were treated with FF by oral administration of a dose of 10 mg kg-1 bw for 10 consecutive days. Fish fillet, liver, and kidney were sampled during the treatment phase (1, 5, and 10 days) and posttreatment (1, 2, 3, and 5 days after the last FF administration). FF, florfenicol amine (FFA), monochloro florfenicol (FFCl), and florfenicol alcohol (FFOH) were determined in the sampled tissues using a validated LC-LC-MS/MS method. The highest FF, FFA, and FFOH concentrations were determined on day 5 during the treatment phase. For FF, the concentration order is kidney > liver > fillet, while for the metabolites FFOH and FFA, the order is liver > kidney > fillet. In fillet and liver, the concentrations of FFOH were higher than the FFA concentrations, indicating that FFOH was the primary metabolite in these tissues. FFCl was only quantified at concentrations lower than 90 µg kg-1 in all tissues. The results indicated that FF can be readily absorbed and rapidly eliminated in tilapia cultivated in warm water environments. This study revealed FFOH as the primary and most persistent metabolite in tilapia farmed in warm water, followed by FFA.

Catalytic redox-neutral C-H functionalisation with TEMPO in water to access aminomethyl-substituted pyrroles.

A redox-neutral C-H functionalisation in water employing catalytic TEMPO to synthesize aminomethyl-substituted pyrroles is reported. Starting from cheap and commercial chemical feedstocks (ketoesters and anilines), our approach delivered targeted products in good yields and represents an endeavour to address redox economy in radical transformations.

A base-promoted tandem approach to bicyclic 8-membered ring ketones.

A base-promoted tandem route toward unprecedented bicyclic 8-membered ring ketones is reported. Under our approach, the targeted products are delivered in high yields from phenylacetylenes and 1,3-diketones. The method has a good scope and gives access to a complex structure that offers a wealth of opportunities for further functionalization.

Visible-Light-Driven Epoxyacylation and Hydroacylation of Olefins Using Methylene Blue/Persulfate System in Water.

A visible-light-driven strategy for hydroacylation and epoxyacylation of olefins in water using methylene blue as photoredox catalyst and persulfate as oxidant is reported. In this unprecedented unified approach, two different transformations are accomplished using only one set of reagents. The method has a broad scope spanning a range of aromatic and aliphatic aldehydes as well as conjugated and nonconjugated olefins to deliver ketones and epoxyketones from abundant and inexpensive chemical feedstocks.

Defective regulation of POMC precedes hypothalamic inflammation in diet-induced obesity.

Obesity is the result of a long-term positive energy balance in which caloric intake overrides energy expenditure. This anabolic state results from the defective activity of hypothalamic neurons involved in the sensing and response to adiposity. However, it is currently unknown what the earliest obesity-linked hypothalamic defect is and how it orchestrates the energy imbalance present in obesity. Using an outbred model of diet-induced obesity we show that defective regulation of hypothalamic POMC is the earliest marker distinguishing obesity-prone from obesity-resistant mice. The early inhibition of hypothalamic POMC was sufficient to transform obesity-resistant in obesity-prone mice. In addition, the post-prandial change in the blood level of ß-endorphin, a POMC-derived peptide, correlates with body mass gain in rodents and humans. Taken together, these results suggest that defective regulation of POMC expression, which leads to a change of ß-endorphin levels, is the earliest hypothalamic defect leading to obesity.

n-3 Fatty Acids Induce Neurogenesis of Predominantly POMC-Expressing Cells in the Hypothalamus.

Apoptosis of hypothalamic neurons is believed to play an important role in the development and perpetuation of obesity. Similar to the hippocampus, the hypothalamus presents constitutive and stimulated neurogenesis, suggesting that obesity-associated hypothalamic dysfunction can be repaired. Here, we explored the hypothesis that n-3 polyunsaturated fatty acids (PUFAs) induce hypothalamic neurogenesis. Both in the diet and injected directly into the hypothalamus, PUFAs were capable of increasing hypothalamic neurogenesis to levels similar or superior to the effect of brain-derived neurotrophic factor (BDNF). Most of the neurogenic activity induced by PUFAs resulted in increased numbers of proopiomelanocortin but not NPY neurons and was accompanied by increased expression of BDNF and G-protein-coupled receptor 40 (GPR40). The inhibition of GPR40 was capable of reducing the neurogenic effect of a PUFA, while the inhibition of BDNF resulted in the reduction of global hypothalamic cell. Thus, PUFAs emerge as a potential dietary approach to correct obesity-associated hypothalamic neuronal loss.

Nitric oxide released from luminal s-nitroso-N-acetylcysteine increases gastric mucosal blood flow.

Nitric oxide (NO)-mediated vasodilation plays a key role in gastric mucosal defense, and NO-donor drugs may protect against diseases associated with gastric mucosal blood flow (GMBF) deficiencies. In this study, we used the ex vivo gastric chamber method and Laser Doppler Flowmetry to characterize the effects of luminal aqueous NO-donor drug S-nitroso-N-acetylcysteine (SNAC) solution administration compared to aqueous NaNO2 and NaNO3 solutions (pH 7.4) on GMBF in Sprague-Dawley rats. SNAC solutions (600 µM and 12 mM) led to a rapid threefold increase in GMBF, which was maintained during the incubation of the solutions with the gastric mucosa, while NaNO2 or NaNO3 solutions (12 mM) did not affect GMBF. SNAC solutions (600 µM and 12 mM) spontaneously released NO at 37 °C at a constant rate of 0.3 or 14 nmol·mL-1·min-1, respectively, while NaNO2 (12 mM) released NO at a rate of 0.06 nmol·mL-1·min-1 and NaNO3 (12 mM) did not release NO. These results suggest that the SNAC-induced GMBF increase is due to their higher rates of spontaneous NO release compared to equimolar NaNO2 solutions. Taken together, our data indicate that oral SNAC administration is a potential approach for gastric acid-peptic disorder prevention and treatment.

(-)-Tarchonanthuslactone exerts a blood glucose-increasing effect in experimental type 2 diabetes mellitus.

A number of studies have proposed an anti-diabetic effect for tarchonanthuslactone based on its structural similarity with caffeic acid, a compound known for its blood glucose-reducing properties. However, the actual effect of tarchonanthuslactone on blood glucose level has never been tested. Here, we report that, in opposition to the common sense, tarchonanthuslactone has a glucose-increasing effect in a mouse model of obesity and type 2 diabetes mellitus. The effect is acute and non-cumulative and is present only in diabetic mice. In lean, glucose-tolerant mice, despite a slight increase in blood glucose levels, the effect was not significant.

S-nitrosoglutathione inhibits inducible nitric oxide synthase upregulation by redox posttranslational modification in experimental diabetic retinopathy.

PURPOSE: Diabetic retinopathy (DR) is associated with nitrosative stress. The purpose of this study was to evaluate the beneficial effects of S-nitrosoglutathione (GSNO) eye drop treatment on an experimental model of DR. METHODS: Diabetes (DM) was induced in spontaneously hypertensive rats (SHR). Treated animals received GSNO eye drop (900 nM or 10 µM) twice daily in both eyes for 20 days. The mechanisms of GSNO effects were evaluated in human RPE cell line (ARPE-19). RESULTS: In animals with DM, GSNO decreased inducible nitric oxide synthase (iNOS) expression and prevented tyrosine nitration formation, ameliorating glial dysfunction measured with glial fibrillary acidic protein, resulting in improved retinal function. In contrast, in nondiabetic animals, GSNO induced oxidative/nitrosative stress in tissue resulting in impaired retinal function. Nitrosative stress was present markedly in the RPE layer accompanied by c-wave dysfunction. In vitro study showed that treatment with GSNO under high glucose condition counteracted nitrosative stress due to iNOS downregulation by S-glutathionylation, and not by prevention of decreased GSNO and reduced glutathione levels. This posttranslational modification probably was promoted by the release of oxidized glutathione through GSNO denitrosylation via GSNO-R. In contrast, in the normal glucose condition, GSNO treatment promoted nitrosative stress by NO formation. CONCLUSIONS: In this study, a new therapeutic modality (GSNO eye drop) targeting nitrosative stress by redox posttranslational modification of iNOS was efficient against early damage in the retina due to experimental DR. The present work showed the potential clinical implications of balancing the S-nitrosoglutathione/glutathione system in treating DR.

S-nitroso-N-acetylcysteine attenuates liver fibrosis in experimental nonalcoholic steatohepatitis.

S-Nitroso-N-acetylcysteine (SNAC) is a water soluble primary S-nitrosothiol capable of transferring and releasing nitric oxide and inducing several biochemical activities, including modulation of hepatic stellate cell activation. In this study, we evaluated the antifibrotic activity of SNAC in an animal model of nonalcoholic steatohepatitis (NASH) induced in Sprague-Dawley rats fed with a choline-deficient, high trans fat diet and exposed to diethylnitrosamine for 8 weeks. The rats were divided into three groups: SNAC, which received oral SNAC solution daily; NASH, which received the vehicle; and control, which received standard diet and vehicle. Genes related to fibrosis (matrix metalloproteinases [MMP]-13, -9, and -2), transforming growth factor ß-1 [TGFß-1], collagen-1α, and tissue inhibitors of metalloproteinase [TIMP-1 and -2] and oxidative stress (heat-shock proteins [HSP]-60 and -90) were evaluated. SNAC led to a 34.4% reduction in the collagen occupied area associated with upregulation of MMP-13 and -9 and downregulation of HSP-60, TIMP-2, TGFß-1, and collagen-1α. These results indicate that oral SNAC administration may represent a potential antifibrotic treatment for NASH.

S-nitroso-N-acetylcysteine attenuates liver fibrosis in cirrhotic rats.

This study was aimed to investigate the molecular mechanisms underlying prevention of hepatic fibrosis by S-nitroso-N-acetylcysteine (SNAC), a nitric oxide donor that inhibits lipid peroxidation. Secondary biliary cirrhosis was induced by 4 weeks of common bile duct ligation (CBDL). Both sham-operated and CBDL animals received SNAC (6.0 micromol/kg/day) starting 2 weeks after surgery. SNAC treatment reduced the increase in blood enzyme activities (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), induced by CBDL. Histological changes were attenuated and there was a significant decrease in the area of liver fibrosis and in the activation of stellate cells measured by alpha-smooth muscle actin (alpha-SMA) immunostaining. The increase in TBARS concentration and hydroperoxide-induced chemiluminescence were also reduced by SNAC treatment. SNAC down-regulated expression of collagen 1 alpha, alpha-SMA, tumor necrosis factor-alpha, tumor growth factor-beta, metalloproteinase-2, metalloproteinase inhibitor 1, platelet-derived growth factor (PDGF), and PDGF receptor in CBDL rats. These effects were accompanied by inhibited activation of extracellular signal-regulated kinases, Jun amino-terminal kinases, p38 and Akt. Antifibrotic effects were more efficient than those of the free thiol NAC administered at a dose of 60 mumol/kg. In conclusion, results obtained indicate that SNAC, beyond its antioxidant capacity, exerts antifibrotic effects in rats with secondary biliary cirrhosis by down-regulating increased expression of genes and modulating intracellular signaling pathways that contribute to the accumulation of matrix proteins. Thus, SNAC may be an interesting candidate for the treatment of human fibrosis and cirrhosis.

Antithrombogenic polynitrosated polyester/poly(methyl methacrylate) blend for the coating of blood-contacting surfaces.

A nitric oxide (NO) donor polyester containing multiple S-nitrosothiol (S-NO) groups covalently attached to the polymer backbone was synthesized through the esterification of poly(ethylene glycol) with mercaptosuccinic acid, followed by the nitrosation of the -SH moieties. The polynitrosated polyester (PNPE) obtained was blended with poly(methyl methacrylate) (PMMA), yielding solid films capable of releasing NO. Scanning electron microscopy analysis showed that acrylic plates and stainless steel intracoronary stents can be coated with continuous and adherent PNPE/PMMA films. After an initial NO burst, these films release NO spontaneously in dry condition or immersed in aqueous solution at constant rates of 1.8 and 180 nmol/g/h, respectively, for more than 24 h at physiological temperature. PNPE/PMMA coated surfaces were shown to inhibit platelet adhesion when in contact with whole blood. These results show that PNPE/PMMA blend can be used for the coating of blood-contacting surfaces, with potential to inhibit thrombosis and restenosis after stenting.