Increased Tissue Concentrations Research Articles

Sport technology in combination with neural guidance channels loaded with Inula helenium extract for peripheral nervous system repair

The peripheral nervous system (PNS) consists of nerves that extend beyond the brain and spinal cord, connecting the body to the central nervous system (CNS). Peripheral nerve injuries, caused by trauma, compression, or disease, often result in sensory and motor deficits. In the current study, a nanofibrous neural conduit was developed by loading Inula helenium extract into electrospun PCL/gelatin scaffolds. Then, the scaffolds were characterized in vitro using different analysis methods. Then, the electrospun sheets were rolled up to produce neural conduits. Finally, the healing efficacy of the developed system was investigated in a rat model of sciatic nerve injury. Results showed that the animals that were treated with both treadmill exercise and the Inula helenium extract-loaded conduits had significantly better functional recovery and histopathological recovery. ELISA assay showed that the hybrid treatment method increased tissue concentrations of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) and decreased tumor necrosis factor- α (TNF- α) tissue levels.

Infliximab Tissue Concentrations in Patients With Stable Ulcerative Colitis Are Correlated With More Durable Infliximab-associated Disease Remission.

We aimed to determine the correlation between tissue and plasma infliximab concentrations in an outpatient ulcerative colitis (UC) cohort based on histologic disease activity in addition to their relationship with long-term clinical outcomes. We assessed intraparticipant variability in infliximab concentrations between adjacent intestinal samples and the correlation between disease activity and tumor necrosis factor-α (TNF-α). A prospective cohort study was conducted in participants with UC receiving infliximab. Blood and 2 sigmoid colon biopsies were obtained at the index colonoscopy for infliximab and TNF-α quantification. Histological disease activity was assessed. Participants were followed for 2 years for the occurrence of hospitalization, surgery, disease relapse, and infliximab discontinuation. A positive correlation was observed between mean plasma and uninflamed tissue infliximab concentrations only (Rs = 0.75, P = .0071). Lower mean tissue infliximab concentrations correlated with a shorter time to disease relapse vs those with higher mean tissue concentrations (Rs = 0.77, P = .032). This was not seen when using plasma infliximab concentrations. Additionally, no significant intraparticipant variability of infliximab concentrations was observed for all participants independent of disease activity. Neither plasma nor tissue TNF-α correlated with disease activity. These findings support data generated in patients with Crohn's disease: plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab. Neither plasma nor tissue TNF-α appear to correlate with UC disease activity. Larger follow-up studies would be of benefit.

Neopolyploidy causes increased nutrient requirements and a shift in plant growth strategy in Heuchera cylindrica.

Functional traits fall along a continuum from resource-conservative to acquisitive and are powerful predictors of the ecological settings necessary for a species to persist and establish. As a consequence, a major problem that functional trait analysis could address is understanding the ecological contexts necessary for the persistence of polyploid plants, because early generation polyploids, or "neopolyploids", are at a high extinction risk. Since neopolyploidy could increase nutrient limitation, growth strategies should shift to accommodate the increased need for resources, but this prediction is untested. To address this gap, we compared the functional trait responses of diploids, synthetic neotetraploids, and naturally occurring tetraploids of Heuchera cylindrica, an herbaceous perennial plant, to nutrient manipulations in a greenhouse experiment. We found strong support for the hypothesis that neotetraploidy increases nutrient requirements, as evidenced by reduced productivity and increased tissue concentrations of nitrogen and phosphorus in neotetraploids. We also found that repeated formation of independent origins of neotetraploidy led to differing responses to nutrient supply, but neotetraploidy generally shifted functional traits to be more resource-acquisitive and inefficient. Taken together, our results suggest that shifts in functional trait responses may constrain the ability of neopolyploids to establish in nutrient-poor habitats. This article is protected by copyright. All rights reserved.

Uptake of Per- and Polyfluoroalkyl Substances by Fish, Mussel, and Passive Samplers in Mobile-Laboratory Exposures Using Groundwater from a Contamination Plume at a Historical Fire Training Area, Cape Cod, Massachusetts.

Aqueous film-forming foams historically were used during fire training activities on Joint Base Cape Cod, Massachusetts, and created an extensive per- and polyfluoroalkyl substances (PFAS) groundwater contamination plume. The potential for PFAS bioconcentration from exposure to the contaminated groundwater, which discharges to surface water bodies, was assessed with mobile-laboratory experiments using groundwater from the contamination plume and a nearby reference location. The on-site continuous-flow 21-day exposures used male and female fathead minnows, freshwater mussels, polar organic chemical integrative samplers (POCIS), and polyethylene tube samplers (PETS) to evaluate biotic and abiotic uptake. The composition of the PFAS-contaminated groundwater was complex and 9 PFAS were detected in the reference groundwater and 17 PFAS were detected in the contaminated groundwater. The summed PFAS concentrations ranged from 120 to 140 ng L-1 in reference groundwater and 6100 to 15,000 ng L-1 in contaminated groundwater. Biotic concentration factors (CFb) for individual PFAS were species, sex, source, and compound-specific and ranged from 2.9 to 1000 L kg-1 in whole-body male fish exposed to contaminated groundwater for 21 days. The fish and mussel CFb generally increased with increasing fluorocarbon chain length and were greater for sulfonates than for carboxylates. The exception was perfluorohexane sulfonate, which deviated from the linear trend and had a 10-fold difference in CFb between sites, possibly because of biotransformation of precursors such as perfluorohexane sulfonamide. Uptake for most PFAS in male fish was linear over time, whereas female fish had bilinear uptake indicated by an initial increase in tissue concentrations followed by a decrease. Uptake of PFAS was less for mussels (maximum CFb = 200) than for fish, and mussel uptake of most PFAS also was bilinear. Although abiotic concentration factors were greater than CFb, and values for POCIS were greater than for PETS, passive samplers were useful for assessing PFAS that potentially bioconcentrate in fish but are present at concentrations below method quantitation limits in water. Passive samplers also accumulate short-chain PFAS that are not bioconcentrated.

Elevated Maternal Testosterone Levels Alter PFOA Elimination and Tissue Distribution in Pregnant Rats.

Perfluorooctanoic acid (PFOA) is an enduring synthetic chemical that harms human health. Recent studies indicate heightened bioaccumulation of PFOA, particularly in pregnant women experiencing preeclampsia. Since plasma testosterone levels are elevated in pregnant women with preeclampsia, we hypothesized that hyperandrogenic conditions during pregnancy may hinder PFOA elimination and contribute to their higher body burden. Pregnant Sprague-Dawley rats were s/c injected with vehicle or testosterone propionate from gestational day (GD) 15 to 20 to increase plasma testosterone levels by 2-fold, similar to levels in preeclampsia. On GD 16, [14C]-PFOA (9.4 pmol/kg) was given intravenously, and subsequently, 14C radioactivity was measured in maternal blood, urine, feces, and tissues. PFOA was primarily eliminated through urine; however, less PFOA was excreted in urine of pregnant rats with elevated testosterone levels than controls. Fecal excretion of PFOA was minimal and did not significantly differ between groups. The total elimination of PFOA (urine plus feces) was significantly reduced by 12% in pregnant rats with elevated testosterone levels. In controls, PFOA distribution was highest in placenta, followed by the kidneys, liver, brain, heart, lungs, and spleen. Pregnant rats with elevated testosterone levels displayed 12% higher concentrations of PFOA in these tissues than controls. Furthermore, the renal expression of Oat2 and Oat3 was significantly decreased, while Oatp1 and Oat-k expression was significantly increased in pregnant rats with elevated testosterone levels than controls. In conclusion, elevated maternal testosterone levels decrease urinary elimination of PFOA, possibly through altered expression of renal transporters leading to increased tissue concentrations of PFOA in pregnant rats.

Effect of the human endotoxin challenge on tedizolid tissue penetration.

The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75-1.15] vs. 1.14 [1.11-1.43] mg × h/L, P = .0078) and muscle tissue fCmax (0.15 [0.14-0.19] vs. 0.19 [0.18-0.24] mg/L, P = .0078) were significantly increased by 38% and 24%, respectively. The human endotoxin challenge was associated with increased tissue concentrations of tedizolid, without affecting its plasma concentration-time profile. The human endotoxin challenge combined with microdialysis may be used to investigate the influence of systemic inflammation on tissue pharmacokinetics.

Dependence on Nitrogen Availability and Rhizobial Symbiosis of Different Accessions of Trifolium fragiferum, a Crop Wild Relative Legume Species, as Related to Physiological Traits.

Biological nitrogen fixation by legume-rhizobacterial symbiosis in temperate grasslands is an important source of soil nitrogen. The aim of the present study was to characterize the dependence of different accessions of T. fragiferum, a rare crop wild relative legume species, from their native rhizobia as well as additional nitrogen fertilization in controlled conditions. Asymbiotically cultivated, mineral-fertilized T. fragiferum plants gradually showed signs of nitrogen deficiency, appearing as a decrease in leaf chlorophyll concentration, leaf senescence, and a decrease in growth rate. The addition of nitrogen, and the inoculation with native rhizobia, or both treatments significantly prevented the onset of these symptoms, leading to both increase in plant shoot biomass as well as an increase in tissue concentration of N. The actual degree of each type of response was genotype-specific. Accessions showed a relatively similar degree of dependence on nitrogen (70–95% increase in shoot dry mass) but the increase in shoot dry mass by inoculation with native rhizobia ranged from 27 to 85%. In general, there was no correlation between growth stimulation and an increase in tissue N concentration by the treatments. The addition of N or rhizobial inoculant affected mineral nutrition at the level of both macronutrient and micronutrient concentration in different plant parts. In conclusion, native rhizobial strains associated with geographically isolated accessions of T. fragiferum at the northern range of distribution of the species represent a valuable resource for further studies aimed at the identification of salinity-tolerant N2-fixing bacteria for the needs of sustainable agriculture, as well as in a view of understanding ecosystem functioning at the level of plant-microorganism interactions.

Phenotypic convergence in a natural Daphnia population acclimated to low temperature.

Fluidity of a given membrane decreases at lower ambient temperatures, whereas it rises at increasing temperatures, which is achieved through changes in membrane lipid composition. In consistence with homeoviscous adaptation theory, lower temperatures result in increased tissue concentrations of polyunsaturated fatty acids (PUFAs) in Daphnia magna, suggesting a higher PUFA requirement at lower temperatures. However, so far homeoviscous adaptation has been suggested for single or geographically separated Daphnia genotypes only. Here, we investigated changes in relative fatty acid (FA) tissue concentrations in response to a lower temperature (15°C) within a D. magna population. We determined juvenile growth rates (JGR) and FA patterns of 14 genotypes that were grown on Chlamydomonas klinobasis at 15°C and 20°C. We report significant differences of JGR and the relative body content of various FAs between genotypes at either temperature and between temperatures. Based on slopes of reaction norms, we found genotype‐specific changes in FA profiles between temperatures suggesting that genotypes have different strategies to cope with changing temperatures. In a hierarchical clustering analysis, we grouped genotypes according to differences in direction and magnitude of changes in relative FA content, which resulted in three clusters of genotypes following different patterns of changes in FA composition. These patterns suggest a lower importance of the PUFA eicosapentaenoic acid (EPA, C20:5ω3) than previously assumed. We calculated an unsaturation index (UI) as a proxy for membrane fluidity at 15°C, and we neither found significant differences for this UI nor for fitness, measured as JGR, between the three genotype clusters. We conclude that these three genotype clusters represent different physiological solutions to temperature changes by altering the relative share of different FAs, but that their phenotypes converge with respect to membrane fluidity and JGR. These clusters will be subjected to different degrees of PUFA limitation when sharing the same diet.

510 Late-Breaking: Dietary Glycine Supplementation During Growing and Finishing Phases Increases Tissue Concentrations of Total Creatine and Gene Expression of Creatine-synthetic Enzymes in Low-birthweight Pigs

Abstract Dietary glycine is required for maximum growth and development in animals by stimulating muscle protein synthesis and as a component of creatine. Creatine is synthesized from glycine, arginine, and S-adenosylmethionine by arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). Sufficient creatine synthesis for growth requires adequate substrate supply. However, swine diets are deficient in glycine. Additionally, intrauterine growth restricted (IUGR) pigs have reduced glycine synthesis. This results in decreased creatine synthesis and lower total creatine content in tissues, leading to reduced cellular energy metabolism and diminished muscle protein accretion. This study was designed to test the hypothesis that dietary glycine supplementation in corn-and-soybean-meal-based diets would improve overall growth and skeletal muscle accretion in post-weaning IUGR pigs by increasing the expression of creatine-synthetic enzymes and tissue concentrations of total creatine. Fourteen IUGR pigs (birthweight = 0.98±0.03 kg, mean±SEM) and 20 normal birthweight pigs (birthweight = 1.44±0.02 kg, mean±SEM) were obtained at weaning for this study. Pigs from each birthweight group were randomly assigned to 1% glycine + 0.19% corn starch treatment group or 1.19% alanine group (isonitrogenous control) for the study (21 d to 188 d of age); tissues were collected at d 188. Data were analyzed by using 2-way ANOVA and the Duncan multiple comparison test. Glycine-supplemented IUGR pigs had greater tissue concentrations of creatine, creatinine, and creatine phosphate than control IUGR in all tissues measured (P< 0.05). Control IUGR pigs showed diminished activity and mRNA expression of creatine-synthetic enzymes (P < 0.05); this was mitigated by glycine supplementation as glycine supplemented IUGR pigs showed normal levels of enzyme activity and mRNA expression. Overall, results of this study indicate dietary glycine supplementation to IUGR pigs between weaning and market weight effectively restores creatine-synthetic enzyme activities and increase tissue concentrations of total creatine, leading to increased lean tissue growth. (Supported by USDA-NIFA)

Ameilorative effect of lycopine against cisplatin toxicity in rats

The following study aimed to investigate the hepato and neuro protective efficacy of Lycopine against Cisplatin which induced hepatotoxicity and neurotoxicity. Twenty Five male Wister rats were used for this experiment they were equally divided into 5 groups (5 rats per group): group (1) served as control group they were injected 1ml saline orally once daily for 20 day, group (2) served as Corn Oil group and they were administrated 1 mL Corn Oil orally once daily for 20 days, group (3) served as Lycopine group and they were administrated (10 mg/kg b.wt) Lycopine orally once daily for 20 days. , group (4) served as Cisplatin treated group and they were injected (6 mg/kg b.wt.) intrapertonialy once at day 10 of experiment and group (5) Lycopine+Cisplatin group and were administrated 10 mg/kg b.wt Lycopine orally once daily for 20 days and injected 6 mg/kg b.wt.) intraperitonialy once at day 10 . Result revealed that Cisplatin induced liver damage indicated by significant increase in liver biomarkers ALP, AlT, AST along with significant decrease in albumin, Moreover marked increase increase in tissue concentrations of malondialdehyde(MDA) and Total antioxidant(TAC) and reduce tissue Glutathione reductase(GSH),that indicated oxidative stress Also results revealed up regulation IL-6 and down regulation IL-10 in liver and brain tissue in compared to control group . However, interestingly concurrent adminsteration of the Lycopine orally at dose level of 10mg/kg b.wt for 20 days with Cisplatin can mitigate these toxic effects caused by Cisplatin.So it is concluded that the antioxidant and the anti-inflammatory effects of Lycopine moderate the Cisplatin-induced hepato and neurotoxicity.

Antioxidant tempol modulates the increases in tissue nitric oxide metabolites concentrations after oral nitrite administration

Nitric oxide (NO) metabolites have physiological and pharmacological importance and increasing their tissue concentrations may result in beneficial effects. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) has antioxidant properties that may improve NO bioavailability. Moreover, tempol increases oral nitrite-derived gastric formation of S-nitrosothiols (RSNO). We hypothesized that pretreatment with tempol may further increase tissue concentrations of NO-related species after oral nitrite administration and therefore we carried out a time-dependent analysis of how tempol affects the concentrations of NO metabolites in different tissues after oral nitrite administration to rats. NO metabolites (nitrate, nitrite and RSNO) were assessed by ozone-based reductive chemiluminescence assays in plasma, stomach, aorta, heart and liver samples obtained from anesthetized rats at baseline conditions and 15 min, 30 min, 2 h or 24 h after oral nitrite (15 mg/kg) was administered to rats pretreated with tempol (18 mg/kg) or vehicle 15 min prior to nitrite administration. Aortic protein nitrosation was assessed by resin-assited capture (SNO-RAC) method. We found that pretreatment with tempol transiently enhanced nitrite-induced increases in nitrite, RSNO and nitrate concentrations in the stomach and in the plasma (all P < 0.05), particularly for 15–30 min, without affecting aortic protein nitrosation. Pretreatment with tempol enhanced nitrite-induced increases in nitrite (but not RSNO or nitrate) concentrations in the heart (P < 0.05). In contrast, tempol attenuated nitrite-induced increases in nitrite, RSNO or nitrate concentrations in the liver. These findings show that pretreatment with tempol affects oral nitrite-induced changes in tissue concentrations of NO metabolites depending on tissue type and does not increase nitrite-induced vascular nitrosation. These results may indicate that oral nitrite therapy aiming at achieving increased nitrosation of cardiovascular targets requires appropriate doses of nitrite and is not optimized by tempol.

Ginsenoside Rh2 reduces depression in offspring of mice with maternal toxoplasma infection during pregnancy by inhibiting microglial activation via the HMGB1/TLR4/NF-κB signaling pathway

BackgroundMaternal Toxoplasma gondii (T. gondii) infection during pregnancy has been associated with various mental illnesses in the offspring. Ginsenoside Rh2 (GRh2) is a major bioactive compound obtained from ginseng that has an anti-T. gondii effect and attenuates microglial activation through toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. GRh2 also alleviated tumor-associated or lipopolysaccharide-induced depression. However, the effects and potential mechanisms of GRh2 on depression-like behavior in mouse offspring caused by maternal T. gondii infection during pregnancy have not been investigated. MethodsWe examined GRh2 effects on the depression-like behavior in mouse offspring, caused by maternal T. gondii infection during pregnancy, by measuring depression-like behaviors and assaying parameters at the neuronal and molecular level. ResultsWe showed that GRh2 significantly improved behavioral measures: sucrose consumption, forced swim time and tail suspended immobility time of their offspring. These corresponded with increased tissue concentrations of 5-hydroxytryptamine and dopamine, and attenuated indoleamine 2,3-dioxygenase or enhanced tyrosine hydroxylase expression in the prefrontal cortex. GRh2 ameliorated neuronal damage in the prefrontal cortex. Molecular docking results revealed that GRh2 binds strongly to both TLR4 and high mobility group box 1 (HMGB1). ConclusionThis study demonstrated that GRh2 ameliorated the depression-like behavior in mouse offspring of maternal T. gondii infection during pregnancy by attenuating the excessive activation of microglia and neuroinflammation through the HMGB1/TLR4/NF-κB signaling pathway. It suggests that GRh2 could be considered a potential therapy in preventing and treating psychiatric disorders in the offspring mice of mothers with prenatal exposure to T. gondii infection.

The Effect of Aerobic Training and Tribulus terrestris Extract on Some Oxidative Stress Indices in the Heart Tissue of Male Wistar Rats Poisoned with Hydrogen Peroxide

Background: Oxidative stress plays a key role in cardiovascular diseases. Hydrogen peroxide poisoning also increases oxidative stress. In contrast, aerobic exercise and the use of Tribulus terrestris (Tt) extract can individually play an antioxidant defense balance. Objectives: The aim of this study was to investigate the simultaneous effect of aerobic training (AT), and alcoholic extract of Tt on some oxidative stress indices in the heart tissue of hydrogen peroxide poisoned male Wistar rats. Methods: Forty-two male Wistar rats were randomly divided into seven groups, including (1) healthy-control, (2) H2O2, (3) H2O2 + AT, (4) H2O2 + Tt 1 (5 mg/kg), (5) H2O2 + Tt 2 (10 mg/kg), (6) H2O2 + AT + Tt 1, and (7) H2O2 + AT + Tt 2. The AT protocol consisted of eight weeks (5 sessions per week) of treadmill running at 20 m/min for 60 minutes per session. Tissue samples were collected to measure oxidative stress indices. Two-way analysis of variance was used for statistical analysis. Results: A significant decrease in tissue concentration of cytochrome C (ng/mL), MDA (Pmol/mL), PAB index (HK), while an increase in tissue concentration of ATP (µM) was observed in the H2O2 + AT + Tt 2 group compared to other groups (P ≤ 0.05). Conclusions: Combining AT and Tt can be a good strategy to reduce the complications of hydrogen peroxide poisoning. Because the observed changes were far from complete improvement compared to the healthy control group, it is likely that longer treatment periods and higher drug doses should be used. Future studies should use Tribulus terrestris (Tt) supplementation in addition to Tribulus terrestris (Tt) intake prior to training sessions.

Effects of Linoleic Acid-Rich Diet on Plasma Profiles of Eicosanoids and Development of Colitis in Il-10-/- Mice.

Dietary intake of linoleic acid (LA, 18:2ω-6) has risen dramatically in recent decades. Previous studies have suggested a high intake of LA could increase tissue concentrations of proinflammatory and protumorigenic ω-6-series eicosanoid metabolites, increasing risks of inflammation and associated diseases. However, the effects of a LA-rich diet on in vivo profiles of eicosanoids and development of inflammatory diseases are understudied. Here, we treated spontaneous colitis-prone (Il-10-/-) mice with a control diet (∼3 Cal% LA) or a LA-rich diet (∼9 Cal% LA) for 18 weeks and analyzed the effects of the LA-rich diet on profiles of eicosanoids and development of colitis. We found that treatment with the LA-rich diet increased the tissue level of LA: the liver levels of LA were 5.8 ± 0.6% in the control diet-treated mice versus 11.7 ± 0.7% in the LA-rich diet-treated mice (P < 0.01). The plasma concentrations of a series of LA-derived metabolites, including 9-hydroxyoctadecadienoic acid (HODE), 9,10-dihydroxyoctadecenoic acid (DiHOME), 12,13-DiHOME, and 13-HODE were significantly increased by treatment with the LA-rich diet (P < 0.05). However, the LA-rich diet had little effect on the severity of colitis in the treated Il-10-/- mice. These results suggest a limited role of increased consumption of dietary LA on promoting colitis in the Il-10-/- model.

Influence of chronic ischemic disorders in the prostate on the development of benign prostatic hyperplasia

Purpose of the study. To assess the degree of influence of ischemic disorders in the prostate on the level of androgens.Materials and methods. This was an experimental study that included 20 white non-linear sexually Mature rats. All animals were divided into 2 equal groups: main and control (intact). In the main group of animals (n=10), we created a model of chronic ischemic disorders in the prostate by partial ligation of the inferior Vena cava. After 1.5 months, we conducted a hormonal study in all rats (n=20) — determining the concentration of androgens (testosterone, dihydrotestosterone) and estrogens (estradiol) in the blood of animals and prostate tissue.Results. In the blood of animals of both groups, the level of total testosterone and estradiol did not significantly differ (p&gt;0.05). The level of dihydrotestosterone in the blood serum of rats of the main group on the background of ischemia was reduced by 18.1%, compared to the intact group (p&gt;0.05). However, we detected elevated levels of testosterone (p&lt;0.05) and dihydrotestosterone (p&gt;0.05) in prostate tissue against the background of chronic ischemia.Conclusions. Chronic ischemic disorders in the prostate can be an independent pathogenetic factor in the development of BPH. Vascular damage leads to impaired blood flow and hypoxia, with increased tissue concentration of testosterone, which potentiates the development of BPH.

Affective dimensions of pain and region -specific involvement of nitric oxide in the development of empathic hyperalgesia

Empathy for pain depends on the ability to feel, recognize, comprehend and share painful emotional conditions of others. In this study, we investigated the role of NO in a rat model of empathic pain. Pain was socially transferred from the sibling demonstrator (SD) who experienced five formalin injection to the naïve sibling observer (SO) through observation. SO rats received L-NAME (a nonspecific NO synthase inhibitor) or L-arginine (a precursor of NO) prior to observing the SD. Nociception, and concentrations of NO metabolites (NOx) in the serum, left and right hippocampus, prefrontal cortex, and cerebellum were evaluated. Nociceptive responses were significantly increased in the pain-observing groups. NOx levels measured 24 h after the last pain observation using the Griess method, were indicative of NOx concentration decreases and increases in the left hippocampus and cerebellum, respectively. There was an increase in tissue concentration of NOx in cerebellum and prefrontal cortex in both pain and observer groups 7 days after the fifth formalin injection. Our results suggest that NO is involved in development of empathic hyperalgesia, and observation of sibling’s pain can change NO metabolites in different brain regions in observer rats.

Effects of potassium nutrition and water availability on iron toxicity of rice seedlings

The aim of the study was to investigate the influence of potassium (K) nutrition and/or aeration of flooded soil through drainage on iron (Fe) toxicity of rice during the period of establishment. A hydroponic experiment with three Fe (0.1, optimal; 1, high; 2.5 mM, very high) and K levels (0.3, low; 2, optimal; 5 mM, high), and a soil experiment with two moisture levels [continuously flooded; alternate-wetting and drying (AWD)] and three Fe levels (16, low; 163, optimal; 490 mg Fe(II) kg−1 soil, high) was conducted. In the hydroponic experiment, high Fe supply increased tissue concentrations of Fe, phosphorus (P) and magnesium (Mg), and reduced manganese (Mn) concentrations. Particularly Fe, K and P were maintained at root surfaces in larger amounts than taken up by the roots. Growth of rice, photosynthesis, maximum quantum yield, effective quantum yield and electron transport rate were decreased at high and very high Fe concentrations while K application had no positive effect. In the soil experiment, growth and nutrient relations under increased Fe supply were similar to those observed in the hydroponic experiment. However, comparing both moisture levels showed that soil solution Fe concentration and plant growth were reduced and tissue P, Mg and Mn concentrations were increased in the AWD system compared to flooding. Therefore, the application of K or aeration of flooded soil cannot be generalized as promising strategies to alleviate Fe toxicity in rice at the initial crop establishment stage.

Pathophysiology of NSAID-Associated Intestinal Lesions in the Rat: Luminal Bacteria and Mucosal Inflammation as Targets for Prevention.

Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine, mainly through an involvement of enteric bacteria. This study examined the pathophysiology of NSAID-associated intestinal lesions in a rat model of diclofenac-enteropathy and evaluated the effect of rifaximin on small bowel damage. Enteropathy was induced in 40-week old male rats by intragastric diclofenac (4 mg/kg BID, 14 days). Rifaximin (delayed release formulation) was administered (50 mg/kg BID) 1 h before the NSAID. At the end of treatments, parameters dealing with ileal damage, inflammation, barrier integrity, microbiota composition, and TLR-NF-κB-inflammasome pathway were evaluated. In addition, the modulating effect of rifaximin on NLRP3 inflammasome was tested in an in vitro cell system. Diclofenac induced intestinal damage and inflammation, triggering an increase in tissue concentrations of tumor necrosis factor and interleukin-1β, higher expression of TLR-2 and TLR-4, MyD88, NF-κB and activation of caspase-1. In addition, the NSAID decreased ileal occludin expression and provoked a shift of bacterial phyla toward an increase in Proteobacteria and Bacteroidetes abundance. All these changes were counterbalanced by rifaximin co-administration. This drug was also capable of increasing the proportion of Lactobacilli, a genus depleted by the NSAID. In LPS-primed THP-1 cells stimulated by nigericin (a model to study the NLRP3 inflammasome), rifaximin reduced IL-1β production in a concentration-dependent fashion, this effect being associated with inhibition of the up-stream caspase-1 activation. In conclusion, diclofenac induced ileal mucosal lesions, driving inflammatory pathways and microbiota changes. In conclusion, rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities.

The effect of enterolactone on sphingolipid pathway and hepatic insulin resistance development in HepG2 cells

AimsObesity and type 2 diabetes mellitus, correlate with increased tissue concentration of sphingolipids, which directly interfere with insulin signaling pathway. Phytoestrogens are a group of plant-derived compounds that have been studied in the case of metabolic disorders treatment. Therefore, the aim of this study was to ascertain whether enterolactone (ENL), a commonly known phytoestrogen, may affect sphingolipid metabolism and decrease hepatic insulin resistance development in a lipid overload state. Main methodsThe study was conducted on HepG2 cells incubated with ENL and/or palmitic acid (PA) for 16 h. Intra- and extracellular sphingolipid concentrations were assessed by high performance liquid chromatography. The expression of sphingolipid pathway enzymes, apoptosis and insulin signaling pathway proteins and glucose metabolism regulators were evaluated by Western Blot. Key findingsIn HepG2 cells, a considerable augmentation of intracellular ceramide and sphingosine concentration in ENL with PA group were indicated with simultaneous increase in extracellular ceramide concentration. The ENL treatment increased expression of selected enzymes from de novo ceramide synthesis pathway with lower expression of ceramide transfer protein. We also observed a decreased expression of insulin-stimulated phosphorylation of AKT and AMPK after exposure to ENL with PA. Our research demonstrated that ENL with PA resulted in an increased expression of caspase-3. SignificanceEnterolactone, in a higher fatty acids availability, led to the development of hepatic IR in HepG2 cells. This phenomenon may be the result of elevated intracellular ceramide accumulation caused by increased de novo synthesis pathway what led to enhanced apoptosis of HepG2 cells.

Thiazolo[3,2-a]pyrimidin-5-one derivatives as a novel class of 11β-hydroxysteroid dehydrogenase inhibitors

11β-hydroxysteroid type 1 dehydrogenase (11β-HSD1) is an enzyme that increases tissue concentrations of cortisol. Selective inhibitors of this enzyme regulate the level of cortisol and thus play a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes.In this study the inhibitory activity of 29 thiazolo[3,2-a]pyrimidin-5-one derivatives on 11β-HSD1 were investigated. Studies were carried out with pooled human liver microsomes. A lot of analyzed compounds show activity for inhibiting 11β-HSD1 (up to 59.15% at concentration 10 µmol/l). Molecular docking simulation show that the molecule of the most active compound: 7-(cyclohexylmethyl)-2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one forms hydrogen bonds with Ala172, Leu171, Leu215 or Tyr177. In addition, the cycloalkane moiety can create the hydrophobic contacts with NADP+. For this compound also the most favourable Docking Score value was obtained.The most active compound only in the slight degree inhibits 11β-HSD2 activity and is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1. Consequently it can have a real effect on the regulation of the cortisol level in the body.