Enhanced tolerance of Cupriavidus necator NCIMB 11599 to lignocellulosic derived inhibitors by inserting NAD salvage pathway genes.

Polyhydroxybutyrate (PHB) is a bio-based, biodegradable and biocompatible plastic that has the potential to replace petroleum-based plastics. Lignocellulosic biomass is a promising feedstock for industrial fermentation to produce bioproducts such as polyhydroxybutyrate (PHB). However, the pretreatment processes of lignocellulosic biomass lead to the generation of toxic byproducts, such as furfural, 5-HMF, vanillin, and acetate, which affect microbial growth and productivity. In this study, to reduce furfural toxicity during PHB production from lignocellulosic hydrolysates, we genetically engineered Cupriavidus necator NCIMB 11599, by inserting the nicotine amide salvage pathway genes pncB and nadE to increase the NAD(P)H pool. We found that the expression of pncB was the most effective in improving tolerance to inhibitors, cell growth, PHB production and sugar consumption rate. In addition, the engineered strain harboring pncB showed higher PHB production using lignocellulosic hydrolysates than the wild-type strain. Therefore, the application of NAD salvage pathway genes improves the tolerance of Cupriavidus necator to lignocellulosic-derived inhibitors and should be used to optimize PHB production.

An in-situ bio-remediation of nitrobenzene in stimulated aquifer using emulsified vegetable oil.

Widespread nitrobenzene (NB) contamination in groundwater requires an economical and effective remediation technology. In situ microbial reactive zone enhanced by injecting emulsified vegetable oil (EVO) is an effective method for remediating NB-contaminated groundwater, which can be reduced to aniline (AN) effectively in the reactive zone. However, the bio-mechanism of NB remediation in a real contaminated site is still unclear. Thus, a 3-D tank was established to conduct a pilot-scale experiment and the bacterial communities in the tank were analyzed by 16S rDNA high-throughput sequencing. The results suggested that the injection of EVO can stimulate some certain microorganisms to grow, and reduce NB though biological and biochemical processes. There were three degradation pathways of NB: (1) direct oxidation by Pseudomonas; (2) direct mineralization by Clostridium sensu stricto; and (3) coupled reduction of NB through microbial dissimilatory iron reduction by Geobacter and Arthrobacter. Among these pathways, the coupled reduction process is the main degradation pathway.

PEG-PEI-modified gated N-doped mesoporous carbon nanospheres for pH/NIR light-triggered drug release and cancer phototherapy.

A novel hybrid drug carrier has been designed, taking N-doped mesoporous carbon (NMCS) as the core and PEG-PEI as the outer shell. NMCS was functionalized with a photocleavable nitrobenzyl-based linker following a click reaction. Gemcitabine was loaded into NMCS prior to the functionalization via π-π stacking interactions. NIR and the pH-responsive behavior of NMCS-linker-PEG-PEI bestow the multifunctional drug carrier with the controlled release of gemcitabine triggered by dual stimuli. The NMCS core upconverts NIR light to UV, which is absorbed by a photosensitive molecular gate and results in its cleavage and drug release. Further, NMCS converts NIR to heat, which deforms the outside polymer shell, thus triggering the drug release process. The release can be promptly arrested if the NIR source is switched off. A promising gemcitabine release of 75% has been achieved within 24 h under the dual stimuli of pH and temperature. NMCS-linker-PEG-PEI produced reactive oxygen species (ROS), which were verified in FaDu cells using flow cytometry. In vitro experiments showed that the NMCS-linker-PEG-PEI-GEM hybrid particle can induce synergistic therapeutic effects in FADU cells when exposed to the NIR light.

Naoxintong restores ischemia injury and inhibits thrombosis via COX2-VEGF/ NFκB signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Naoxintong (NXT) is a traditional Chinese medicine preparation that is often used in combination with aspirin in the treatment of cardiovascular diseases (CVD). One of the main symptoms of CVD is hypoxic-ischemia (HI). The purpose of this study is to find out the molecular nodes targeted by NXT and its related molecular pathways in vascular repair. MATERIALS AND METHODS: First, human vein umbilical endothelial cells (EA.hy926) were utilized to set up the Oxygen-Glucose Deprivation-Reoxygenation (OGD/R) model and treated with NXT. Cell proliferation, damage and apoptosis were detected by MTT, LDH, and flow cytometry assays. Second, transcriptional responses of OGD/R cells to NXT treatment were investigated. qRT-PCR, western blotting and inhibitor assays were performed. Third, the anti-thrombotic effect of NXT was evaluated by the zebrafish thrombosis model. Morphological observation, histological staining and qRT-PCR assays were implemented on zebrafish model to further observe in vivo the therapeutic effects of NXT on ischemia and thrombosis. RESULTS: In OGD/R EA.hy926 cells, NXT treatment could reduce ischemic vascular injury, increase cell viability and decrease the proportion of apoptosis. Through RNA-seq analysis, 183 differentially expressed genes (DEGs) were screened with 110 up-regulated genes and 73 down-regulated genes between OGD/R and OGD/R + NXT treated EA.hy926 cells. VEGF and NFκB pathways were enriched. Among these genes, COX2 was identified as one of important targets via which NXT could restore vascular injury. COX2 inhibitor (NS-398), and aspirin, a drug that prevents the development of CVD by targeting COX2, exhibited similar effects to NXT in the treatment of OGD/R EA.hy926 cells. In zebrafish thrombosis model, NXT could attenuate tail venous thrombus and recover the quantity of heart red blood cells. Furthermore, NXT could prevent the formulation of thrombosis and eliminate inflammation in zebrafish by COX2-VEGF/NFκB signaling. CONCLUSION: Our studies implicated that NXT could restore HI injury and inhibit thrombosis through COX2-VEGF/NFκB signaling, which is consistent with the molecular target of aspirin. This finding might explain the principle of NXT combined with aspirin in the treatment of cardiovascular diseases.

Doxorubicin Intracellular Release Via External UV Irradiation of Dextran-g-poly(o-nitrobenzyl acrylate) Photosensitive Nanoparticles.

In the present study, innovative doxorubicin-loaded nanoparticles (NPs) made of a photosensitive poly(o-nitrobenzyl acrylate) (PNBA) hydrophobic matrix and an hydrophilic dextran (Dex) shell were first formulated by the emulsion-solvent evaporation process. Doxorubicin (DOX), a very well-known anticancer drug, was herein chosen as the model. DOX-loaded NPs were successfully produced by covering the hydrophobic PNBA core with Dex chains either physically adsorbed or covalently linked by changing process parameters as the presence of a catalyst (CuBr or CuSO4/ascorbic acid). It was then proved that the neutralization of DOX optimized drug loading. DOX loading and release were independent of the coverage mechanism if the catalyst used to covalently link the shell to the core was correctly chosen. Second, the kinetics of DOX release were investigated by simple diffusion or light irradiation of the NPs. Experiments showed that less than 20% of DOX was released by simple diffusion after 48 h in PBS or DMEM media when 45% of DOX released after only 30 s of light irradiation of the NPs. Finally, the impact of the phototriggered DOX release on cell viability was investigated on various cell lines [Caco-2, HepG2, HCT-116, and HT-29 cells as well as murine macrophages (RAW 264.7)]. Cellular mortality was evaluated to be dependent on the cell lines tested. Our approach provided an improved DOX release toward the human liver cancer cell line, and a high internalization of the PNBA-based NPs into HepG2 cells was observed using fluorescence microscopy.

Bioenergetics impairment of Trypanosoma cruzi by the antihypertensive manidipine: A drug repurposing strategy.

Considering the lack of effective and safe therapy for the treatment of Chagas disease, the antihypertensive drug manidipine (MDP) was in vitro evaluated against Trypanosoma cruzi. The bioenergetics of trypomastigotes was studied in the presence of the drug using fluorimetric and luminescent assays. Manidipine showed a potent antiparasitic activity, with IC50 values of 0.1 µM (intracellular amastigotes) and 3 µM (trypomastigotes), resulting in a promising selectivity index against the amastigotes (>1459). Using fluorimetric analysis, the drug showed depolarisation of the electric potential of the plasma membrane with no alteration of the permeability. A decrease in ATP levels suggested a bioenergetic alteration of the mitochondria, which was confirmed by the depolarisation of the mitochondrial membrane potential and a slight increase of the ROS levels. This is the first study to show the promising in vitro effectiveness of the antihypertensive MDP against T. cruzi, which may represent a candidate for future investigations in animal models.

Structural features and antioxidant behavior of lignins successively extracted from ginkgo shells (Ginkgo biloba L).

Ginkgo shells as by-products from Ginkgo biloba L. industries with a remarkable annual output up to now are not fully analyzed and exploited. For the application of ginkgo shells beyond their current roles, structure and antioxidant activity of milled wood lignins successively extracted from two ginkgo shell species were investigated. Results showed lignin in ginkgo shells is abundant in guaiacyl units with the presence of ferulates and p-coumarates and demonstrates a high yield of vanillin (1.47-1.65 mmol/g-lignin) by nitrobenzene oxidation, much higher than general softwoods and hardwoods (0.6-0.9 mmol/g-lignin), which makes ginkgo shells good feedstocks for the production of food and beverage flavoring agent. By increasing the extent of ball-milling (4-8 h), the polydispersity of lignin molecular weight exhibits negligible change, but condensation and aldol interconversion occur to its Cß/C5 structure and end-groups, respectively. Lignin in ginkgo shells also features outstanding antioxidant activity with the optimal radical scavenging index of 6.9, much higher than commercial butyl hydroxyanisole (3.85) and butylated hydroxytoluene (0.29), and the phenolic hydroxyl is demonstrated to dominate this contribution by the analysis of statistical product and service solutions. These results reveal lignin in ginkgo shells shows many unique structural and biological properties for materials.

Biogenesis of Prism-Like Silver Oxide Nanoparticles Using Nappa Cabbage Extract and Their p-Nitrophenol Sensing Activity.

The present study aimed to explore the eco-friendly synthesis of prism-like silver oxide nanoparticles (Ag2ONPs) from nappa cabbage extract and its p-nitrophenol sensing activity. The prepared Ag2ONPs were characterized by X-ray diffraction (XRD), field-emission scanning spectroscopy (FESEM), energy-dispersive spectroscopy (EDS), transmission electron microscopy (TEM), and ultraviolet (UV)-visible light spectral analysis (UV-Vis). p-Nitrophenol sensing properties of the prepared nanoparticles were also determined using a simple I-V method. The results showed that the as-prepared Ag2ONPs have a face-centered cubic (fcc) crystalline nature and a prism-like morphology with particle size in the range 21.61-92.26 nm. The result also showed a high intensity of the (111) facet, making the Ag2ONP-carbon black/nickel foam electrode (Ag2ONP-C/NFE) exhibit a high-performance response to p-nitrophenol spanning a wide range of concentrations from 1.0 mM to 0.1 pM and a response time of around 5 s, indicating a high potential for water treatment applications.

Photoelectrochemical determination of the activity of histone acetyltransferase and inhibitor screening by using MoS2 nanosheets.

The enzyme histone acetyltransferase (HAT) catalyzes the acetylation of a substrate peptide, and acetyl coenzyme A is converted to coenzyme A (CoA). A photoelectrochemical method is described for the determination of the HAT activity by using exfoliated MoS2 nanosheets, phos-tag-biotin, and ß-galactosidase (ß-Gal) based signal amplification. The MoS2 nanosheets are employed as the photoactive material, graphene nanosheets as electron transfer promoter, gold nanoparticles as recognition and capture reagent for CoA, and phos-tag-biotin as the reagent to link CoA and ß-Gal. The enzyme ß-Gal catalyzes the hydrolysis of substrate O-galactosyl-4-aminophenol to generate free 4-aminophenol which is a photoelectrochemical electron donor. The photocurrent increases with the activity of HAT. Under optimal conditions, the response is linear in the 0.3 to 100 nM activity range, and the detection limit is 0.14 nM (at S/N = 3). The assay was applied to HAT inhibitor screening, specifically for the inhibitors C646 and anacardic acid. The IC50 values are 0.28 and 39 µM, respectively. The method is deemed to be a promising tool for epigenetic research and HAT-targeted cancer drug discovery. Graphical abstract Histone acetyltransferase was detected using a sensitive photoelectrochemical method using MoS2 nanosheets as photoactive material.

An Application of Photoactivatable Substrate for the Evaluation of Epithelial-mesenchymal Transition Inhibitors.

Epithelial-mesenchymal transition (EMT), phenotypic changes in cell adhesion and migration, is involved in cancer invasion and metastasis, hence becoming a target for anti-cancer drugs. In this study, we report a method for the evaluation of EMT inhibitors by using a photoactivatable gold substrate, which changes from non-cell-adhesive to cell-adhesive in response to light. The method is based on the geometrical confinement of cell clusters and the subsequent migration induction by controlled photoirradiation of the substrate. As a proof-of-concept experiment, a known EMT inhibitor was successfully evaluated in terms of the changes in cluster area or leader cell appearance, in response to biochemically and mechanically induced EMT. Furthermore, an application of the present method for microbial secondary metabolites identified nanaomycin H as an EMT inhibitor, potentially killing EMTed cells in disseminated conditions. These results demonstrate the potential of the present method for screening new EMT inhibitors.

Assessment of heavy metals, fungicide quintozene and its hazardous impurity residues in medical Panax notoginseng (Burk) F.H.Chen root.

A quick, easy, cheap, effective, rugged, and safe extraction approach and gas chromatography/tandem mass spectrometry with programmed temperature vaporization sampling technology were used to determine fungicide quintozene and its hazardous impurity hexachlorobenzene (HCB) in Panax notoginseng root, which is commonly used as a rare traditional Chinese medicine worldwide. The mean recoveries were in the ranges of 94-125 and 84-119% for quintozene and HCB with relative standard deviations of 6.2-16.1% at three concentrations: 0.01, 0.1 and 1 mg kg-1 . Heavy metals arsenic, cadmium, copper and lead were simultaneously detected by an inductively coupled plasma-mass spectrometry approach after digestion with nitric acid. The above methods were used to analyze 50 samples of P. notoginseng roots collected at markets and planting bases from the special local producing areas, namely, Honghe, Kunming and Wenshan in Yunnan province, China. Quintozene and HCB in root samples were determined at <0.0015-1.50 and <0.0015-0.125 mg kg-1 . In the 50 samples, 60, 16, 56, 2 and 6% exceeded the maximum permissible levels in medicinal plants (WM/T2-2004) for quintozene, arsenic, cadmium, lead and copper. The results showed that the method is robust and suitable for measuring quintozene, its hazardous impurity and heavy metals in P. notoginseng roots.

The epithelial zinc transporter ZIP10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity.

BACKGROUND: The skin is the first organ that manifests changes in response to zinc deficiency. However, the molecular mechanism underlying how zinc is involved in skin homeostasis, especially its epigenetic regulation, is largely unknown. OBJECTIVES: In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP10 in the epigenetic maintenance of human epidermal homeostasis. METHODS: Adult human skin, including skin appendages, were stained with anti-ZIP10 antibody. Histone acetyltransferase (HAT) activity was assessed after treating human keratinocytes with ZIP10 small interfering (si)RNAs or the zinc chelator TPEN. ZIP10- or HAT-regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP10 siRNAs or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP10 in epidermal differentiation and the functional association between ZIP10 and HAT. RESULTS: ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the activity of the epigenetic enzyme HAT. This decreased HAT activity, resulting from either ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC39A10 (encoding ZIP10) and HAT inhibition, we demonstrated that ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. CONCLUSIONS: Our study suggests that ZIP10-mediated zinc distribution is crucial for epidermal homeostasis via HATs. Therefore, zinc-dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects.

Efficacy of spent black tea for the removal of nitrobenzene from aqueous media.

Nitrobenzene (NB) is a kind of persistent organic pollutant. A ubiquitous and cost-effective substance spent black tea (SBT) was investigated for the removal of nitrobenzene from aqueous media. The maximum uptake potential of dried biomass (SBT) for NB was found to be 14.86 mg per gram (qmax) in a batch experimental set-up. Equilibration time for NB sorption was about 50 min, and optimal removal efficiency was achieved at a dosage of 2 g/L with an initial concentration of 100 mg/L of NB. Findings revealed that NB uptake increased with an increase in the temperature from 273 K to 353 K. Sorption was also found to be pH sensitive, sorption improved as the pH value changes from alkaline to acidic (from 10 to 2). Different isotherm (Langmuir, Freundlich, Temkin and Dubinin Radushkevich) and kinetic models (pseudo-1st order, pseudo-2nd order and Elovich models) were applied to experimental results; the sorption mechanism was well described by the Freundlich and pseudo-2nd order models. Moreover, Scanning electron micrographs, ATR-FTIR spectra and the results of elemental analysis also supported the efficacy of SBT as an efficient bio-sorbent for the elimination of NB from water.

Mechanism on emulsified vegetable oil stimulating nitrobenzene degradation coupled with dissimilatory iron reduction in aquifer media.

Microbial dissimilatory iron reduction could remediate reducible pollutants in groundwater, such as nitrobenzene (NB). But the natural attenuation rate in aquifer is limited. To stimulate this process, emulsified vegetable oil (EVO) was injected as a remediation agent. The mechanism of this process was studied. Results showed that the addition of EVO made iron easier used by microorganisms and thus promoted dissimilatory iron reduction. The readily used Fe(III) served as electron acceptor and was reduced to Fe(II). Fe(II) supplied electrons to NB, with NB reduced to aniline. Sulphide in the aquifer media also donated electrons and oxidized to polysulfide, then forming precipitates with Fe(II) to the surface of aquifer media, and thus slowing down the electron supplying of EVO and forming permanent efficiency for NB remediation. The work helps to complete a systematic understanding of NB remediation process under stimulation of EVO.

Improving biocathode community multifunctionality by polarity inversion for simultaneous bioelectroreduction processes in domestic wastewater.

Bioelectrochemical systems (BESs) have been tentatively applied for wastewater treatment processes, but the complex composition of wastewater could lead to difficulties in establishing functional biofilm or result in performance instability. Few studies have investigated the enrichment of biocathode with domestic wastewater (DW) and the function. A biocathode with multi-pollutant removal capabilities was enriched based on polarity inverted bioanode, which was established with DW. The biocathode function was examined using model pollutants (nitrate, nitrobenzene and Acid Orange 7) supplemented as sole or mixed electron acceptors. When compared to the anaerobic control treatment, the biofilm demonstrated significantly enhanced reduction abilities in the open circuit. For the closed circuit, their removal efficiencies were further enhanced for both the sole and mixed substrates conditions. The bioanodes community structure and diversity markedly changed after operating for 50 d as biocathodes. The biocathode multifunctionality and stability could be related to the maintenance of organic matters fermentative bacteria (mainly belonging to Bacteroidetes, Firmicutes and Synergistetes) and the enrichment of versatile pollutant-reducing bacteria (e.g. Pseudomonas, Thauera and Comamonas from Proteobacteria). Other pollutants, such as perchlorate, sulfate, heavy metals, and halogenated organics, may also work as potential electron acceptors. This study provides a new strategy to improve the biocathode community multifunctionality for simultaneous bioelectroreduction, which can be combined with other wastewater treatment processes in actual application.

Accelerated removal of high concentration p-chloronitrobenzene using bioelectrocatalysis process and its microbial communities analysis.

p-Chloronitrobenzene (p-CNB) is a persistent refractory and toxic pollutant with a concentration up to 200 mg/L in industrial wastewater. Here, a super-fast removal rate was found at 0.2-0.8 V of external voltage over a p-CNB concentration of 40-120 mg/L when a bioelectrochemical technology is used comparing to the natural biodegradation and electrochemical methods. The reduction kinetics (k) was fitted well according to pseudo-first order model with respect to the different initial concentration, indicating a 1.12-fold decrease from 1.80 to 0.85 h-1 within the experimental range. Meanwhile, the highest k was provided at 0.5 V with the characteristic of energy saving. It was revealed that the functional bacterial (Propionimicrobium, Desulfovibrio, Halanaerobium, Desulfobacterales) was selectively enriched under electro-stimulation, which possibly processed Cl-substituted nitro-aromatics reduction. The possible degradation pathway was also proposed. This work provides the beneficial choice on the rapid treatment of high-concentration p-CNB wastewater.

Kinetics of nitrobenzene degradation coupled to indigenous microorganism dissimilatory iron reduction stimulated by emulsified vegetable oil.

Widespread contamination by nitrobenzene (NB) in sediments and groundwater requires better understanding of the biogeochemical removal process of the pollutant. NB degradation, coupled with dissimilatory iron reduction, is one of the most efficient pollutant removal methods. However, research on NB degradation coupled to indigenous microorganism dissimilatory iron reduction stimulated by electron donors is still experimental. A model for remediation in an actual polluted site does not currently exist. Therefore, in this study, the dynamics was derived from the Michaelis-Menten model (when the mass ratio of emulsified vegetable oil and NB reached the critical value 91:1). The effect of SO42-, NO3-, Ca2+/Mg2+, and the grain size of aquifer media on the dynamics were studied, and the NB degradation dynamic model was then modified based on the most significant factors. Utilizing the model, the remediation time could be calculated in a contaminated site.

Biosynthesis of silver nanoparticles by using Camellia japonica leaf extract for the electrocatalytic reduction of nitrobenzene and photocatalytic degradation of Eosin-Y.

In the present study, sphere-like silver nanoparticles (Ag-NPs) were synthesized by using Camellia japonica leaf extract and its remediation industrial pollutants such as nitrobenzene and Eosin-Y (EY). As-prepared sphere-like Ag-NPs were characterized by various analytical and spectroscopic methods such as UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), High-resolution transmission electron microscopy (HR-TEM), Energy dispersive X-ray spectra (EDX), and the chemical constituents of the leaf extract were also analyzed by using Gas chromatography and Mass Spectroscopy (GC-MS). Fascinatingly, the as-prepared sphere-like Ag-NPs exhibits excellent electrocatalytic and photocatalytic activity for the reduction of nitrobenzene and photo-degradation of EY dye respectively. The Cyclic voltammetry (CV) and amperometric (i-t) studies realized that the electrochemical behavior of sphere-like Ag-NPs modified electrode on nitrobenzene reduction. The proposed nitrobenzene sensor exhibited appreciable wide linear response range and low detection limit of 0.05-21µM, 23-2593µM and 12nM, respectively. The Ag-NPs modified electrode showed excellent selectivity towards the nitrobenzene detection even in the presence of common metal ions and nitroaromatic containing substances. On the other hand, Ag-NPs have excellent photocatalytic activity with >97% degradation of EY dye after irradiated 60min. These results indicated that the growth of sphere-like Ag-NPs should be a proficient.

A synthetic Nitraria alkaloid, isonitramine protects pancreatic ß-cell and attenuates postprandial hyperglycemia.

OBJECTIVE: The extracts of Nitraria genus are composed of Nitraria alkaloids and have been used traditionally as a hypoglycemic medicine. However, the efficacy and precise mechanism of Nitraria alkaloids remain largely unknown. METHODS: Previously, we reported the total synthesis of (+)-isonitramine, one of Nitraria alkaloids. In this study, we investigated the anti-diabetic potential of isonitramine in diabetes mellitus and its underlying molecular mechanism in carbohydrate catabolism in vitro and in vivo. RESULTS: Isonitramine exerted significant inhibitory effect on α-glucosidases but not α-amylase in vitro. In zebrafish, isonitramine alleviated the streptozotocin (STZ)-induced postprandial hyperglycemia and protected the pancreatic damages against alloxan-induced oxidative stress in vivo. Also, isonitramine induced insulin without any toxicities and downregulated phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the first committed step in gluconeogenesis. CONCLUSION: Taken together, isonitramine inhibited α-glucosidase activity and PEPCK expression, while increased insulin expression, resulting in attenuating the postprandial hyperglycemia. Also, isonitramine protected the pancreas from ROS-mediated toxicities. Therefore, isonitramine may be a new drug candidate for the treatment of diabetes mellitus.

Treatment with high dose of atorvastatin reduces vascular injury in diabetic rats.

BACKGROUND: Previous reports showed conflicting results regarding the treatment effects of statin on Diabetes mellitus (DM). We investigated how treatment with high dose of atorvastatin affects the impaired vascular function in diabetic rats. METHODS: Atorvastatin (80mg/kg/day, oral gavage, 4 weeks) or its vehicle was administered to male control or streptozotocin (STZ)-induced diabetic rats. Aortic segments were used to investigate the vascular reactivity, protein expression of cyclooxygenase-2 (COX-2) and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) 1 (NOX1) and superoxide anions levels. RESULTS: Atorvastatin treatment did not affect glycemia levels. In diabetic rats, the vascular reactivity to phenylephrine increased compared with controls and the atorvastatin treatment reduced this response. Removal of the endothelium increased the response to phenylephrine in control rats, but not in the diabetic group. Atorvastatin increased the endothelial modulation in diabetic rats. L-NAME (100µM) increased the reactivity in all groups, but this effect was greater in atorvastatin-treated diabetic rats. Indomethacin (10µM) and NS398 (1µM) decreased the contractile response in diabetic rats and atorvastatin reversed these effects, without changing COX-2 expression. Apocynin (30µM) decreased the phenylephrine response in diabetic rats, which also showed increased NOX1 and superoxide anions; these effects were prevented by atorvastatin treatment. CONCLUSIONS: The results suggest that treatment with high dose of atorvastatin, independent of glycemia, improves endothelial function in aortas from diabetic rats by reducing the constrictor prostanoids derived from COX-2 and by reducing the oxidative stress by NADPH oxidase, as well as a possible increasing of nitric oxide participation.