Input: In contrast, 8-oxoG repair in Ogg1-proficient airway epithelium was coupled to an increase in DNA single-strand break (SSB) levels and exacerbation of allergen challenge-dependent inflammation.


Input: Decreased expression of the Nei-like glycosylases Neil1 and Neil2 that preferentially excise ring-opened purines and 5-hydroxyuracil, respectively, did not alter the above parameters of allergic immune responses to RWPE.


Input: These results show that DNA SSBs formed during Ogg1-mediated repair of 8-oxoG augment antigen-driven allergic immune responses.


Input: A transient modulation of OGG1 expression/activity in airway epithelial cells could have clinical benefits.


Input: Nano-and microscaled particles for drug targeting to inflamed intestinal mucosa: a first in vivo study in human patients.


Input: Most of the drugs used in the treatment of inflammatory bowel disease (IBD) become systemically bioavailable and potentially bear strong adverse effects.


Input: Targeting the inflamed areas of the intestine and keeping the drug localised at its site of action can reduce adverse effects.


Input: In animal studies, luminal uptake into inflamed mucosal areas has been shown to be size dependent.


Input: We investigated the potential of nano-and microparticle uptake into the rectal mucosa of human IBD patients.


Input: Fluorescently labelled placebo nanoparticles (NP) 250nm in size and microparticles (MP) 3. 0 mu m in size were prepared.


Input: 2h after rectal application to patients with Crohn' s disease (CD) or ulcerative colitis (UC), confocal laser endomicroscopy was performed to visualise the particles in inflamed mucosal areas.


Input: In biopsies, ex vivo mucosal transport processes were investigated in miniaturised Ussing chambers.


Input: We examined 33 patients with IBD (19 patients with CD, 14 patients with UC) and 6 healthy controls.


Input: A significantly enhanced accumulation of MP in ulcerous lesions was observed (covered area = 1. 28% (range 0. 83%-3. 45%) vs. 0% in controls; p = 0. 011), while NP were visible only in traces on mucosal surfaces of all patients.


Input: The Ussing chamber experiments suggest persorption of particles through cellular voids; statistical significance was only reached for NP.


Input: Drug-containing particles may have great potential to more specifically target intestinal lesions to maximise therapeutic efficacy and minimise potential side effects.


Input: Nanoparticles may not be required for local drug delivery to intestinal lesions in humans, thereby minimising the risk of unintended translocation into the blood system.


Input: Sulfur fumigation, a better or worse choice in preservation of Traditional Chinese Medicine?

Sulfur


Input: Sulfur fumigation (SF) in Traditional Chinese Medicine (TCM) is a highly efficient and important traditional preservation method in China.

Sulfur


Input: This method has generated a great deal of concern and has been disputed in the last few years because of its uncertain safety.


Input: SF can alter the quality of TCMs by damaging the bioactive compounds, changing chemical profiles, and generating detrimental exogenous materials.


Input: However, SF is still widely used in the herbal medicinal industry because of its various benefits, such as its pesticidal and anti-bacterial effects, easy operation, and low-cost.


Input: This review contains the current situation, chemical mechanism and reactions during SF, the pharmacological and pharmacokinetic research, and the influence of quality caused by SF.


Input: In addition, a quantification-operation sulfur fumigation device (QOSFD), which can maintain the quality of TCMs by controlling the SF processing parameters, has been designed and introduced.

sulfur


Input: The key technologies of this device involve controlling the O (2) content and the temperature of SO (2) as well as the quantification of sulfur in SF.

O (2)

SO (2)

sulfur


Input: This device can reduce the possibility of reaction between bioactive compounds and sulfur/sulfurous acid, as well as control the limitation of SO (2) residues.

sulfur

sulfurous acid

SO (2)


Input: The QOSFD is regarded as a promising preservation technique in the field of TCM, medicinal materials, agriculture, and fruit industry.


Input: Nerium oleander derived cardiac glycoside oleandrin is a novel inhibitor of HIV infectivity.

oleandrin


Input: We evaluated the effectiveness of Anvirzel (TM), an aqueous extract of Nerium oleander on HIV infection of human peripheral blood mononuclear cells.


Input: Oleandrin, the principle cardiac glycoside (CG) in Anvirzel (TM) has been shown to exhibit anti-cancer properties but its efficacy against HIV is unknown.

Oleandrin


Input: Treatment with Anvirzel (TM) significantly reduced the infectivity of virus produced from infected cells without any change in the total amount of virus produced.


Input: This is in contrast to treatment with AZT, a potent inhibitor of HIV replication that has been shown to significantly reduce virus production.

AZT


Input: Relative to untreated cultures, virus in cultures treated with oleandrin had significantly reduced expression of the envelope protein gp120, the sole determinant of virus infectivity, suggesting a novel mechanism underlying the impaired infectivity.

oleandrin


Input: These results support the potential utility of the Nerium oleander aqueous extract, containing the CG oleandrin as a novel candidate anti-HIV therapeutic.

oleandrin


Input: Protective effect of cinnamon polyphenols against STZ-diabetic mice fed high-sugar, high-fat diet and its underlying mechanism.

polyphenols

STZ


Input: This study was designed to investigate the potential effects of 14days' intragastrically given of cinnamon polyphenols (CPS) in treating diabetic mice induced by intraperitoneal injection of streptozotocin (150mgkg (-1)) and fed high-sugar, high-fat diet.

polyphenols

streptozotocin

sugar


Input: The diabetic mice model was successfully established through determining on fasting blood-glucose (FBG) test.

glucose


Input: As revealed by glucose oxidase (GOD) and radioimmunoassay (RIA), both dimethyldiguanide (DC, 0. 6gkg (-1) d (-1)) and CPS (0. 3, 0. 6, 1. 2gkg (-1) d (-1)) treatments significantly resulted in down-regulation of blood glucose and insulin levels in serum, while the levels of oxidative stress markers were markedly lowered through ELISA assay.

glucose

dimethyldiguanide

glucose


Input: Meanwhile, the pathological damage in islet with pancreatic beta cells was ameliorated by treatment of CPS at different doses, as shown in HE stain.


Input: At the same time, the treatments also caused notable reduction of iNOS, NF-kappa B expressions showing in Western blot analysis.


Input: These findings demonstrate that cinnamon polyphenols can exert the hypoglycemic and hypolipidemic effects through the mechanisms that may be associated with repairing pancreatic beta cells in diabetic mice and improving its anti-oxidative capacity, as well as attenuating cytotoxicity via inhibition of iNOS, NF-kappa B activation.

polyphenols


Input: Nine new steroidal glycosides from the roots of Cynanchum stauntonii.

steroidal glycosides


Input: Nine new steroidal glycosides, named as stauntosides C-K (2, 5, 7-10, 13, 14, and 16), along with seven known compounds (1, 3, 4, 6, 11, 12, and 15) were isolated from the 95% ethanol extract of the roots of Cynanchum stauntonii.

steroidal glycosides

stauntosides C-K

ethanol


Input: The structures of these new compounds were elucidated on the basis of extensive spectroscopic analyses, mainly 1D and 2D NMR, and HRESI-MS, and qualitative chemical methods.


Input: Their significance in terms of the chemotaxonomy of C. stauntonii is discussed.


Input: Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy.

imatinib


Input: The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST.

imatinib

tyrosine


Input: Response to imatinib mainly depends from KIT and PDGFR alpha mutational status.

imatinib


Input: Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations.

imatinib


Input: This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available.


Input: We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400mg daily as first line therapy.

imatinib

imatinib


Input: Included in this analysis were polymorphisms in the transporters' family SLC22, SLCO, ABC, and in the metabolizing genes CYP-3A4 and-3A5.


Input: Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372).


Input: Importantly, multivariate analysis, adjusting for age, gender, KIT/PDGFR alpha mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance.


Input: In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy.

imatinib


Input: Further investigations are required in an attempt to further personalize GIST therapy.


Input: Postexposure application of Fas receptor small-interfering RNA to suppress sulfur mustard-induced apoptosis in human airway epithelial cells: implication for a therapeutic approach.

sulfur


Input: Sulfur mustard (SM) is a vesicant chemical warfare and terrorism agent.

Sulfur


Input: Besides skin and eye injury, respiratory damage has been mainly responsible for morbidity and mortality after SM exposure.


Input: Previously, it was shown that suppressing the death receptor (DR) response by the dominant-negative Fas-associated death domain protein prior to SM exposure blocked apoptosis and microvesication in skin.


Input: Here, we studied whether antagonizing the Fas receptor (FasR) pathway by small-interfering RNA (siRNA) applied after SM exposure would prevent apoptosis and, thus, airway injury.


Input: Normal human bronchial/tracheal epithelial (NHBE) cells were used as an in vitro model with FasR siRNA, FasR agonistic antibody CH11, and FasR antagonistic antibody ZB4 as investigative tools.


Input: In NHBE cells, both SM (300 micro M) and CH11 (100 ng/ml) induced caspase-3 activation, which was inhibited by FasR siRNA and ZB4, indicating that SM-induced apoptosis was via the Fas response.


Input: FasR siRNA inhibited SM-induced caspase-3 activation when added to NHBE cultures up to 8 hours after SM.


Input: Results using annexin V/propidium iodide-stained cells showed that both apoptosis and necrosis were involved in cell death due to SM; FasR siRNA decreased both apoptotic and necrotic cell populations.

propidium iodide


Input: Bronchoalveolar lavage fluid (BALF) of rats exposed to SM (1 mg/kg, 50 minutes) revealed a significant (P < 0. 05) increase in soluble Fas ligand and active caspase-3 in BALF cells.


Input: These findings suggest an intervention of Fas-mediated apoptosis as a postexposure therapeutic strategy with a therapeutic window for SM inhalation injury and possibly other respiratory diseases involving the Fas response.


Input: Fat body dSir2 regulates muscle mitochondrial physiology and energy homeostasis nonautonomously and mimics the autonomous functions of dSir2 in muscles.


Input: Sir2 is an evolutionarily conserved NAD (+)-dependent deacetylase which has been shown to play a critical role in glucose and fat metabolism.

NAD (+)

glucose


Input: In this study, we have perturbed Drosophila Sir2 (dSir2) expression, bidirectionally, in muscles and the fat body.


Input: We report that dSir2 plays a critical role in insulin signaling, glucose homeostasis, and mitochondrial functions.

glucose


Input: Importantly, we establish the nonautonomous functions of fat body dSir2 in regulating mitochondrial physiology and insulin signaling in muscles.


Input: We have identified a novel interplay between dSir2 and dFOXO at an organismal level, which involves Drosophila insulin-like peptide (dILP)-dependent insulin signaling.


Input: By genetic perturbations and metabolic rescue, we provide evidence to illustrate that fat body dSir2 mediates its effects on the muscles via free fatty acids (FFA) and dILPs (from the insulin-producing cells [IPCs]).

fatty acids


Input: In summary, we show that fat body dSir2 is a master regulator of organismal energy homeostasis and is required for maintaining the metabolic regulatory network across tissues.


Input: Steady-state of an enzymatic reaction is dependent on the density of reactant.


Input: The post-translational modification of proteins is controlled by the relative activities of two opposing enzymes.


Input: For example, the extent of phosphorylation of tyrosine residues reflects the balance of a kinase and a phosphatase enzyme.

tyrosine


Input: The present article uses as a model system a self-assembled monolayer that presents a peptide that can be phosphorylated by Abl kinase and subsequently dephosphorylated by Lambda phosphatase.


Input: Treatment of monolayers with a reaction mixture containing both enzymes reveals that the steady-state level of peptide phosphorylation is dependent on the density of the peptide.


Input: Using identical reaction mixtures, surfaces that presented the substrate at high density led to a phosphorylated peptide at steady-state, whereas surfaces that presented the substrate at low density led to unphosphorylated peptide at steady-state.


Input: This dependence owes to an autocatalytic phosphorylation reaction that operates at high densities of substrate.


Input: This work provides an example of an interfacial reaction that has properties that have no analogue in the corresponding solution phase reaction.


Input: It also provides a model system that is relevant to understanding mechanisms that regulate signaling at the cellular membrane.


Input: Alkaline phosphatase as a treatment of sepsis-associated acute kidney injury.


Input: Currently there are no pharmacological therapies licensed to treat sepsis-associated acute kidney injury (AKI).


Input: Considering the high incidence and mortality of sepsis-associated AKI, there is an urgent medical need to develop effective pharmacological interventions.


Input: Two phase II clinical trials recently demonstrated beneficial effects of the enzyme alkaline phosphatase (AP).


Input: In critically ill patients with sepsis-associated AKI, treatment with AP reduced the urinary excretion of tubular injury biomarkers and plasma markers of inflammation, which was associated with improvement of renal function.


Input: The dephosphorylating enzyme, AP, is endogenously present in the renal proximal tubule apical membrane but becomes depleted during ischemia-induced AKI, thereby possibly contributing to further renal damage.


Input: The exact mechanism of action of AP in AKI is unknown, but might be related to detoxification of circulating lipopolysaccharide and other proinflammatory mediators that lose their proinflammatory effects after dephosphorylation.


Input: Alternatively, tissue damage associated with systemic inflammation might be attenuated by an AP-mediated effect on adenosine metabolism.

adenosine


Input: Adenosine is a signaling molecule that has been shown to protect the body from inflammation-induced tissue injury, which is derived through dephosphorylation of ATP.

Adenosine

ATP


Input: In this Perspectives article, we discuss the clinical activity of AP and its putative molecular modes of action, and we speculate on its use to treat and possibly prevent sepsis-associated AKI.


Input: Unambiguous structure elucidation of heterocyclic products from condensation-cyclisation reactions of enaminones by 2D INADEQUATE and 15N NMR.

enaminones


Input: The reaction of enaminones with 3-amino-2-cyanopent-2-enedinitrile can lead to an array of 12 possible products, depending on the reaction pathway and tautomerization.

enaminones


Input: The use of 2D INADEQUATE and (15) N NMR for the unambiguous structure elucidation of the reaction products is discussed in this manuscript.

(15) N


Input: An ion-induced low-oil-adhesion organic/inorganic hybrid film for stable superoleophobicity in seawater.


Input: Superoleophobicity under seawater: An ion-induced low-oil-adhesion film with underwater superoleophobicity is prepared by a typical layer-by-layer (LBL) method.


Input: Under an artificial marine environment with high ion-strength, the prepared polyelectrolytes/AuNPs hybrid film becomes rougher and possesses a higher water ratio, which in turn endows the film with superoleophobicity and low underwater oil adhesion.


Input: The as-prepared film shows excellent environmental stability in artificial seawater.


Input: This study provides a new strategy for controlling the self-cleaning property and accelerating the development of stable underwater superoleophobic films.


Input: p21-Activated kinase 6 (PAK6) inhibits prostate cancer growth via phosphorylation of androgen receptor and tumorigenic E3 ligase murine double minute-2 (Mdm2).

androgen


Input: The androgen receptor (AR) signaling pathway plays a crucial role in the development and growth of prostate malignancies.

androgen


Input: Regulation of AR homeostasis in prostate tumorigenesis has not yet been fully characterized.


Input: In this study, we demonstrate that p21-activated kinase 6 (PAK6) inhibits prostate tumorigenesis by regulating AR homeostasis.


Input: First, we demonstrated that in normal prostate epithelium, AR co-localizes with PAK6 in the cytoplasm and translocates into the nucleus in malignant prostate.


Input: Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli.

Ser

androgen


Input: We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation.

Thr

Ser


Input: Moreover, we found that Thr-158 collaborates with Ser-186 for AR-Mdm2 association and AR ubiquitin-mediated degradation as it facilitates PAK6-mediated AR homeostasis.

Thr

Ser


Input: PAK6 knockdown promotes prostate tumor growth in vivo.


Input: Interestingly, we found a strong inverse correlation between PAK6 and AR expression in the cytoplasm of prostate cancer cells.


Input: These observations indicate that PAK6 may be important for the maintenance of androgen-induced AR signaling homeostasis and in prostate malignancy, as well as being a possible new therapeutic target for AR-positive and hormone-sensitive prostate cancer.

androgen


Input: ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT.


Input: The objective of this study was to establish the role of apoA-IV, ABCA1, and LCAT in the biogenesis of apoA-IV-containing HDL (HDL-A-IV) using different mouse models.


Input: Adenovirus-mediated gene transfer of apoA-IV in apoA-I (-/-) mice did not change plasma lipid levels.


Input: ApoA-IV floated in the HDL2/HDL3 region, promoted the formation of spherical HDL particles as determined by electron microscopy, and generated mostly alpha-and a few pre-beta-like HDL subpopulations.


Input: Gene transfer of apoA-IV in apoA-I (-/-) x apoE (-/-) mice increased plasma cholesterol and triglyceride levels, and 80% of the protein was distributed in the VLDL/IDL/LDL region.

cholesterol

triglyceride


Input: This treatment likewise generated alpha-and pre-beta-like HDL subpopulations.


Input: Spherical and alpha-migrating HDL particles were not detectable following gene transfer of apoA-IV in ABCA1 (-/-) or LCAT (-/-) mice.


Input: Coexpression of apoA-IV and LCAT in apoA-I (-/-) mice restored the formation of HDL-A-IV.


Input: Lipid-free apoA-IV and reconstituted HDL-A-IV promoted ABCA1 and scavenger receptor BI (SR-BI)-mediated cholesterol efflux, respectively, as efficiently as apoA-I and apoE.

cholesterol


Input: Our findings are consistent with a novel function of apoA-IV in the biogenesis of discrete HDL-A-IV particles with the participation of ABCA1 and LCAT, and may explain previously reported anti-inflammatory and atheroprotective properties of apoA-IV.


Input: Efficacy of the levonorgestrel intrauterine system (LNG-IUS) in the prevention of the atypical endometrial hyperplasia and endometrial cancer: retrospective data from selected obese menopausal symptomatic women.

levonorgestrel

LNG


Input: The aim of this retrospective study was to evaluate the efficacy of levonorgestrel intrauterine system-releasing (LNG-IUS) insertion in preventing atypical endometrial hyperplasia (AH) and endometrial cancer (EC) in symptomatic postmenopausal overweight/obese women.

levonorgestrel

LNG


Input: A total of 34 overweight/obese postmenopausal women, presenting abnormal uterine bleeding (AUB) and endometrial hyperplasia (EH), and who were submitted to LNG-IUS insertion, were identified from registry data.

LNG


Input: Endometrial histology at LNG-IUS insertion showed simple EH in 20 cases (58. 8%), complex EH in 14 cases (41. 2%).

LNG


Input: At 36 months, 91% of patients showed no recurrence of AUB and a significant reduction in the mean endometrial thickness (from 8. 2 +/- 2. 2 to 3. 2 +/- 1. 5 mm, p < 0. 05) was observed.


Input: Histologic regression of EH was observed in 27 (79. 4%) and 33 (97. 5%) cases at 12 and 36 months, respectively.


Input: None of the women in which EH persisted, reported cellular atypia or cancer progression at 12 and 36 months of follow-up.


Input: LNG-IUS represents an effective treatment option to manage postmenopausal obese women affected by AUB and EH.

LNG


Input: The device seems to be able to prevent the onset of AH and EC in women at high risk.


Input: Further prospective controlled studies in a well selected group of women are needed.


Input: Investigating the roles of different monoamine transmitters and impulse control using the 5-choice serial reaction time task.

monoamine


Input: Previous studies have shown that drugs which block the reuptake of catecholamine neurotransmitters improve impulse control in diseases such as attention deficit hyperactivity disorder (ADHD).

catecholamine


Input: Serotonin-specific reuptake inhibitors (SSRI) lack efficacy in ADHD and have been linked to increased suicide risk.

Serotonin


Input: The present study investigated drugs with affinity for one or more of the monoamine reuptake transporters using the 5-choice serial reaction time task, a model of attention and impulsivity in rodents.

monoamine


Input: We also tested the effects of the alpha (2)-adreoceptor antagonist, idazoxan and novel antidepressant, agomelatine, which both increase cortical noradrenaline concentrations through non-reuptake mechanisms.

idazoxan

agomelatine

noradrenaline


Input: Improvements in impulse control were observed with venlafaxine, a serotonin and noradrenaline re-uptake inhibitor (SNRI) but not bupropion (dopamine and noradrenaline re-uptake inhibitor).

venlafaxine

serotonin

noradrenaline

bupropion

dopamine

noradrenaline


Input: Sibutramine (SNRI) reduced premature responses by ~ 50% at the highest dose tested but this was not significant.

Sibutramine


Input: All three of the SSRIs tested reduced premature responding in a dose-dependent manner, although also slowed response and collection latencies.


Input: Neither idazoxan nor agomelatine significantly reduced premature responding, suggesting a lack of efficacy at the doses tested.

idazoxan

agomelatine


Input: None of the drugs tested improved attention in this task but sibutramine (SNRI), fluoxetine (SSRI) and paroxetine (SSRI) all increased omissions at the highest dose tested.

sibutramine

fluoxetine

paroxetine


Input: These data suggest that the SNRIs and SSRIs reduce premature responding but tend to be less specific than noradrenaline specific reuptake inhibitors in this model.

noradrenaline


Input: SSRIs did not induce any specific impairment in impulse control in this model.


Input: The metallohormone cadmium modulates AhR-associated gene expression in the small intestine of rats similar to ethinyl-estradiol.

cadmium

ethinyl-estradiol


Input: Cadmium (Cd) affects the expression of estrogen receptor (ER) and aryl hydrocarbon receptor (AhR)-associated genes in rat uterus and elicits estrogen-like activity in vitro.

Cadmium

Cd

estrogen

aryl hydrocarbon

estrogen


Input: The small intestine is highly exposed to dietary Cd which may mimic or antagonize estrogen action in this tissue.

Cd

estrogen


Input: We investigated the effects of Cd and 17-alpha-ethinylestradiol (EE 2) on AhR-associated gene expression after oral exposure of ovariectomized female Wistar rats, and metallothionein (Mt1a) expression as a typical metal-response marker.

Cd

EE 2


Input: Mt1a in the small intestine was strongly induced by co-treatment with CdCl 2 at 2 mg/kg b. wt (Cd 2) and 0. 1 mg/kg b. wt EE2 than by the single compound (3-day gavage).

CdCl 2

Cd


Input: The Cd 2-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was not antagonized by pure anti-estrogen (2. 5 mg/kg b. wt ZK191703 s. c., ZK).

Cd

estrogen


Input: Interestingly, the EE 2-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was antagonized by Cd 2 in vivo and in colon cancer cell lines (HT-29 and CaCo-2, treated 5 days with Cd 1 micro M and/or E 2 0. 01 micro M) with low or no ER-beta expression.

EE 2

Cd

Cd


Input: Dose dependency was studied after Cd exposure with drinking water (5 and 50 ppm CdCl 2 equivalent to 0. 4 and 4 mg/kg b. wt; Cd 0. 4, Cd 4) for 28 days and EE 2 as reference.

Cd

CdCl 2

Cd

Cd

EE 2


Input: Intestinal Mt1a expression was dose dependently induced, while AhR target genes were down-regulated by Cd 0. 4 similar to EE 2 and more pronounced than by Cd 4.

Cd

EE 2

Cd


Input: We propose that Cd modulates intestinal AhR-associated gene expression similar to estrogens, but (contrary to its effects in uterus) via ER-independent and/or ER-beta-mediated mechanisms.

Cd

estrogens


Input: Our new data suggest interference of Cd with estrogen and AhR signaling in the small intestine.

Cd

estrogen


Input: Interactions between chemical and climate stressors: a role for mechanistic toxicology in assessing climate change risks.


Input: Incorporation of global climate change (GCC) effects into assessments of chemical risk and injury requires integrated examinations of chemical and nonchemical stressors.


Input: Environmental variables altered by GCC (temperature, precipitation, salinity, pH) can influence the toxicokinetics of chemical absorption, distribution, metabolism, and excretion as well as toxicodynamic interactions between chemicals and target molecules.


Input: In addition, GCC challenges processes critical for coping with the external environment (water balance, thermoregulation, nutrition, and the immune, endocrine, and neurological systems), leaving organisms sensitive to even slight perturbations by chemicals when pushed to the limits of their physiological tolerance range.


Input: In simplest terms, GCC can make organisms more sensitive to chemical stressors, while alternatively, exposure to chemicals can make organisms more sensitive to GCC stressors.


Input: One challenge is to identify potential interactions between nonchemical and chemical stressors affecting key physiological processes in an organism.


Input: We employed adverse outcome pathways, constructs depicting linkages between mechanism-based molecular initiating events and impacts on individuals or populations, to assess how chemical-and climate-specific variables interact to lead to adverse outcomes.


Input: Case examples are presented for prospective scenarios, hypothesizing potential chemical-GCC interactions, and retrospective scenarios, proposing mechanisms for demonstrated chemical-climate interactions in natural populations.


Input: Understanding GCC interactions along adverse outcome pathways facilitates extrapolation between species or other levels of organization, development of hypotheses and focal areas for further research, and improved inputs for risk and resource injury assessments.


Input: How is (68) Ga labeling of macrocyclic chelators influenced by metal ion contaminants in (68) Ge/(68) Ga generator eluates?

(68) Ga

(68) Ge

(68) Ga


Input: To assess the influence of Zn (2 +), Cu (2 +), Fe (3 +), Al (3 +), Ti (IV), and Sn (IV) on incorporation of (68) Ga (3 +) into pendant-arm macrocyclic chelators, the (68) Ga labeling of 1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA), 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA), 1, 4, 7-triazacyclononane-1, 4, 7-tris [methyl (2-carboxyethyl) phosphinic acid]) (TRAP), and 1, 4, 7-triazacyclononane-1-[methyl (2-carboxyethyl) phosphinic acid]-4, 7-bis [methyl (2-hydroxymethyl) phosphinic acid] (NOPO), as well as their peptide conjugates, was investigated in the presence of varying concentrations of these metal ions.

Zn (2 +)

Cu (2 +)

Fe (3 +)

Al (3 +)

Ti (IV)

Sn (IV)

(68) Ga (3 +)

(68) Ga

1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid

NOTA

1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid

DOTA

1, 4, 7-triazacyclononane-1, 4, 7-tris [methyl (2-carboxyethyl) phosphinic acid])

TRAP

1, 4, 7-triazacyclononane-1-[methyl (2-carboxyethyl) phosphinic acid]-4, 7-bis [methyl (2-hydroxymethyl) phosphinic acid]

NOPO


Input: The (68) Ga labeling yield for carboxylate-type chelators NOTA and DOTA is decreased at lower metal ion contaminant concentrations compared with phosphinate-type chelators TRAP and NOPO.

(68) Ga

carboxylate

NOTA

DOTA

phosphinate

TRAP

NOPO


Input: The latter are able to rapidly exchange coordinated Zn (II) with (68) Ga (3 +), as confirmed by mass spectrometry and (31) P NMR spectroscopy.

Zn (II)

(68) Ga (3 +)

(31) P


Input: (68) Ga labeling of Zn (II) complexes of TRAP and NOPO proceeds as efficient as labeling of neat NOTA; this applies also to the corresponding peptide conjugates of these chelators.

(68) Ga

Zn (II)

TRAP

NOPO

NOTA


Input: This behavior results in substantially improved selectivity for Ga (3 +) and, therefore, in more robust and reliable (68) Ga labeling procedures.

Ga (3 +)

(68) Ga


Input: In addition, none of the investigated chelators binds (68) Ge, rendering post-labeling purification protocols, for example, solid-phase extraction, a reliable means of removal of (68) Ge contamination from (68) Ga radiopharmaceuticals.

(68) Ge

(68) Ge

(68) Ga


Input: Influence of global climate change on chemical fate and bioaccumulation: the role of multimedia models.


Input: Multimedia environmental fate models are valuable tools for investigating potential changes associated with global climate change, particularly because thermodynamic forcing on partitioning behavior as well as diffusive and nondiffusive exchange processes are implicitly considered.


Input: Similarly, food-web bioaccumulation models are capable of integrating the net effect of changes associated with factors such as temperature, growth rates, feeding preferences, and partitioning behavior on bioaccumulation potential.


Input: For the climate change scenarios considered in the present study, such tools indicate that alterations to exposure concentrations are typically within a factor of 2 of the baseline output.


Input: Based on an appreciation for the uncertainty in model parameters and baseline output, the authors recommend caution when interpreting or speculating on the relative importance of global climate change with respect to how changes caused by it will influence chemical fate and bioavailability.


Input: The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function.


Input: Haploinsufficiency of Progranulin (PGRN), a gene encoding a secreted glycoprotein, is a major cause of frontotemporal lobar degeneration with ubiquitin (FTLD-U) positive inclusions.


Input: Single nucleotide polymorphisms in the TMEM106B gene were recently discovered as a risk factor for FTLD-U, especially in patients with PGRN mutations.

nucleotide


Input: TMEM106B is also associated with cognitive impairment in amyotrophic lateral sclerosis patients.


Input: Despite these studies, little is known about TMEM106B at molecular and cellular levels and how TMEM106B contributes to FTLD.


Input: Here, we show that TMEM106B is localized in the late endosome/lysosome compartments and TMEM106B levels are regulated by lysosomal activities.


Input: Ectopic expression of TMEM106B induces morphologic changes of lysosome compartments and delays the degradation of endocytic cargoes by the endolysosomal pathway.


Input: Furthermore, overexpression of TMEM106B correlates with elevated levels of PGRN, possibly by attenuating lysosomal degradation of PGRN.


Input: These results shed light on the cellular functions of TMEM106B and the roles of TMEM106B in the pathogenesis of FTLD-U with PGRN mutations.


Input: The binding of multiple nuclear receptors to a single regulatory region is important for the proper expression of EDG84A in Drosophila melanogaster.


Input: Nuclear receptor transcription factor family members share target sequence similarity; however, little is known about how these factors exert their specific regulatory control.


Input: Here, we examine the mechanism regulating the expression of the Drosophila EDG84A gene, a target gene of the orphan nuclear receptor beta FTZ-F1, as a model to study the cooperative behavior among nuclear receptors.


Input: We show that the three nuclear receptors beta FTZ-F1, DHR3, and DHR39 bind to a common element in the EDG84A promoter.


Input: The expression level of the EDG84A promoter-lacZ reporter genes in DHR39-induced and mutant animals, respectively, suggests that DHR39 works as a repressor.


Input: The activity of a reporter gene carrying a mutation preventing DHR3 binding was reduced in ftz-f1 mutants and rescued by the induced expression of beta FTZ-F1, suggesting that DHR3 and beta FTZ-F1 activate the EDG84A gene in a redundant manner.


Input: A reporter gene carrying a mutation that abolishes DHR39 and FTZ-F1 binding was prematurely expressed, and the expression level of the reporter gene carrying a mutation preventing DHR3 binding was reduced.


Input: These findings suggest that the temporal expression of this gene is mainly controlled by beta FTZ-F1 but that the binding of DHR3 is also important.


Input: Comparison of the binding site sequence among Drosophila species suggests that DHR3 binding ability was gained after the melanogaster subgroup evolved, and this ability may contribute to the robust expression of this gene.


Input: These results show the complicated regulatory mechanisms utilized by multiple nuclear receptors to properly regulate the expression of their target gene through a single target site.


Input: High-dose sodium selenite toxicity cannot be prevented by the co-administration of pharmacological levels of epigallocatechin-3-gallate which in turn aggravates the toxicity.

sodium selenite


Input: Selenium, an essential trace element, can also be toxic at higher levels of exposure.

Selenium


Input: Several lines of evidence show epigallocatechin-3-gallate (EGCG), a predominant component of green tea catechins with numerous health benefits, can ameliorate the toxicity of many agents.

EGCG

catechins


Input: A proof-in-principle experiment was conducted to determine if EGCG would ameliorate sodium selenite-induced growth suppression.

EGCG

sodium selenite


Input: Mice were intraperitioneally injected with selenite once daily for five days at a dose of 3 mg Se/kg, which fully suppressed animal growth but did not cause death.

selenite

Se


Input: Surprisingly the co-administration of the selenite and nontoxic doses of EGCG (10, 20 and 40 mg/kg, intraperitioneally) resulted in the mortality of treated mice in a dose and time-dependent manner (33. 3%, 100% and 100%, respectively).

selenite

EGCG


Input: EGCG-selenite induced lethality did not result from enhanced selenium accumulation but appeared to involve the suppression of a selenite-induced adaptive response as evidenced by hepatic glutathione S-transferase activity.

EGCG

selenite

selenium

selenite

glutathione S


Input: While EGCG has been reported to ameliorate the toxicity of some agents, the induction of mortality by combined treatment with pharmacological doses of selenium and EGCG is a previously unrecognized synergism that must be considered not only in the remediation of high environmental selenium exposures but also in the development of pharmaceuticals and nutriceuticals.

EGCG

selenium

EGCG

selenium


Input: Investigation of peripubertal expression of Lin28a and Lin28b in C57BL/6 female mice.


Input: Genome-wide association studies recently identified 32 loci that associate with the age at menarche (AAM) in humans.


Input: Because the locus most robustly associated with AAM is in/near LIN28B, the goal of this study was to investigate how the Lin28 pathway might modulate pubertal timing by examining expression of Lin28b, and its homologue, Lin28a, across the pubertal transition in female mice.


Input: Quantitative reverse-transcriptase PCR data indicate that, prior to the onset of puberty, expression of both Lin28b and Lin28a decreases in the ovary, while expression of only Lin28a decreases in the hypothalamus; the expression of Lin28a increases after the onset of puberty in the pituitary.


Input: Immunohistochemistry in ovarian tissue verified that Lin28a protein levels decreased in parallel with gene expression.


Input: Although these data do not demonstrate cause and effect, they do suggest that decreased expression of Lin28a/Lin28b may facilitate the transition into puberty, consistent with previous data showing that overexpression of Lin28a in transgenic mice leads to delayed puberty.


Input: In addition, although Lin28b and/or Lin28a expression significantly decreased prior to puberty, neither Let-7a nor Let-7g miRNA levels changed significantly, raising the possibility that some effects of Lin28b and Lin28a within the hypothalamic-pituitary-gonadal (HPG) axis may be Let-7 miRNA independent.


Input: Subsequent studies, such as tissue and age specific modulation of Lin28b and Lin28a expression, could determine whether the expression patterns observed are responsible for modulating the onset of puberty and delineate further the role of this pathway in the HPG axis.


Input: Chinese medicine formula " Weikang Keli " induces autophagic cell death on human gastric cancer cell line SGC-7901.


Input: Weikang Keli (constitutes of Root of Codonopsis pilosula, Rhizoma Atractylodis Macrocephalae, Rhizoma Curcumae Aeruginosae, Rhizoma Pinelliae, Actinidia chinensis Planch, and Rhodiola rosea) is a well known Chinese herbal formula for gastric cancer therapy in clinical treatment.


Input: However, the detailed molecular mechanisms involved are still not fully understood.


Input: In this study, we found that Weikang Keli could induce patterns of autophagy in SGC-7901 cells, including intracellular vacuole formation, microtubule-associated protein 1 light chain 3 (LC3) conversion.


Input: Hoechst 33258 staining and Western blot analysis of apoptosis-related proteins showed that WK induced SGC-7901 cell death was not through apoptosis.

Hoechst 33258


Input: In vivo study also revealed that i. g. administration of Weikang Keli once a day for 25 days could significantly reduce tumor volumes by about 50%.


Input: Collectively, the current data indicated that Weikang Keli induced gastric cancer cell death by autophagy effects.


Input: Relieving visceral hyperalgesia effect of Kangtai capsule and its potential mechanisms via modulating the 5-HT and NO level in vivo.

NO


Input: Kangtai capsule (KT) is one type of traditional Chinese medicine preparation derived from the proved recipe, which was frequently applied as an effective clinical treatment of IBS.


Input: However, there still lack the reasonable and all-round analytical approach and the scientific studies on its underlying mechanisms.


Input: Therefore, our study aimed to develop the novel method for evaluating its quality as well as to interpret the potential mechanisms.


Input: In our study, high performance liquid chromatography (HPLC) fingerprint was applied to provide a chemical profile of KT.


Input: The neonatal maternal separation (NMS) on Sprague-Dawley pups was employed to evaluate the therapeutic effect of KT by virtue of various parameters including visceral hyperalgesia, serum nitric oxide (NO) level, and tissue 5-hydroxytryptamine (5-HT) level.

nitric oxide

NO


Input: Consequently, a chromatographic condition, which was carried at 30 degrees C with a flow rate of 0. 5 ml/min on AQUA 3 mu C18 column with mobile phase of acetonitrile and water-phosphoric acid (100: 0. 1, v/v), was established to give a common fingerprint chromatography under 254 nm with a similarity index of 0. 963 within ten batches of KT samples.

acetonitrile

phosphoric acid


Input: On the NMS model, KT markedly elevated the pain threshold of NMS rats.


Input: Furthermore, KT at three doses significantly decreased 5-HT content from distal colon of visceral hyperalgesia rats induced by NMS, while the significant decrease of 5-HT content in serum was only observed in the group with KT at high dose.


Input: However, compared with that in NMS rats without KT, there was no apparent difference of 5-HT level from brain issue in the rats with various doses.


Input: Besides, KT could substantially elevate the concentration of NO in the serum.

NO


Input: The results showed our study developed the simple, rapid, accurate, reproducible qualitative and quantitative analysis by HPLC fingerprint for the quality control for KT.


Input: Data from the pharmacological investigation suggested that the curative effect of KT to the visceral hypersensitivity may be concerned with the level of 5-HT and NO in vivo, promising its potential in irritable bowel syndrome treatment.

NO


Input: First report of the use of a saxitoxin-protein conjugate to develop a DNA aptamer to a small molecule toxin.

saxitoxin


Input: Saxitoxin (STX) is a low molecular weight neurotoxin mainly produced by certain marine dinoflagellates that, along with its family of similarly related paralytic shellfish toxins, may cause the potentially fatal intoxication known as paralytic shellfish poisoning.

Saxitoxin

STX


Input: Illness and fatality rates are low due to the effective monitoring programs that determine when toxins exceed the established regulatory action level and effectuate shellfish harvesting closures accordingly.


Input: Such monitoring programs rely on the ability to rapidly screen large volumes of samples.


Input: Many of the screening assays currently available employ antibodies or live animals.


Input: This research focused on developing an analytical recognition element that would eliminate the challenges associated with the limited availability of antibodies and the use of animals.


Input: Here we report the discovery of a DNA aptamer that targets STX.

STX


Input: Concentration-dependent and selective binding of the aptamer to STX was determined using a surface plasmon resonance sensor.

STX


Input: Not only does this work represent the first reported aptamer to STX, but also the first aptamer to any marine biotoxin.

STX


Input: A novel strategy of using a toxin-protein conjugate for DNA aptamer selection was successfully implemented to overcome the challenges associated with aptamer selection to small molecules.


Input: Taking advantage of such an approach could lead to increased diversity and accessibility of aptamers to low molecular weight toxins, which could then be incorporated as analytical recognition elements in diagnostic assays for foodborne toxin detection.


Input: The selected STX aptamer sequence is provided here, making it available to any investigator for use in assay development for the detection of STX.

STX

STX


Input: Nanomedicine for the treatment of retinal and optic nerve diseases.

retinal


Input: The earliest impact of nanomedicine in ophthalmology is likely to involve the areas of biopharmaceuticals, implantable materials (e. g. tissue regeneration scaffolds, bioresorbable materials), implantable devices (e. g. glaucoma drainage valves), and diagnostic tools (e. g. intraocular pressure (IOP) monitors).


Input: Nanotechnology will bring about the development of regenerative medicine (i. e. replacement and improvement of cells, tissues, and organs) and artificial vision.


Input: In this chapter, we review ophthalmic applications of nanotechnology in the following areas: drug and trophic factor therapy for glaucoma, retinal degenerative, and retinal vascular disease; gene therapy for retinal degenerative disease; regenerative medicine, including optogenetics and optic nerve regeneration; and diagnostics (minimally invasive IOP monitoring).

retinal


Input: Nanotechnology will play an important role in both early-stage and late-stage intervention in the management of blinding diseases.


Input: Evaluation of presumptive biomarkers of oxidative stress, immune response and apoptosis in primary open-angle glaucoma.


Input: There is growing interest on the correlation among oxidative stress, inflammation, apoptosis and primary open-angle glaucoma initiation and progression.


Input: Reactive oxygen species are formed in the eyes following a wide variety of stressors, and are largely implicated in glaucoma pathogenesis.

oxygen


Input: Immune-inflammatory response mediators have recently become a target of ophthalmologic concern, including glaucoma.


Input: Much attention has been derived to the role of specific pro and anti-apoptotic molecules in glaucoma.


Input: This article reviews the early evidence suggesting that reactive oxygen species, immune inflammatory response mediators, and apoptogenic molecules are engaged in glaucoma disease.

oxygen


Input: Moreover, further research concerning the functions, effectors and signaling pathways of the above molecules and their interactions, may lead to specifically develop targeted screening tools based on presumptive biomarkers and surrogate endpoints against primary open-angle glaucoma progression and blindness.


Input: Pushing short DNA fragments to the limit: Phylogenetic relationships of' hydrobioid' gastropods (Caenogastropoda: Rissooidea).


Input: Although phylogenetic studies are increasingly utilizing multi-locus datasets, a review of GenBank data for the Gastropoda indicates a strong bias towards a few short gene fragments (most commonly COI, LSU rRNA, and SSU rRNA).


Input: This is particularly the case for the Rissooidea, one of the largest and most taxonomically difficult gastropod superfamilies.


Input: Here we analyze fragments of these three genes from 90 species to determine whether they can well resolve higher relationships within this superfamily, whether structurally aligned sequence datasets increase phylogenetic signal, and whether the inclusion of highly variable regions introduces noise.


Input: We also used the resulting phylogenetic data in combination with morphological/anatomical evidence to re-evaluate the taxonomic status of' hydrobioid' family-level groups.


Input: Our results indicate that all three of the alignment strategies that were used resulted in phylogenies having similar signal levels.


Input: However, there was a slight advantage to using structural alignment for inferring family-level relationships.


Input: Moreover, the set of' standard' gastropod genes supported recognition of many previously recognized families and provides new insight into the systematics of several problematic groups.


Input: However, some family-group taxa were unresolved and the relationships among families were also poorly supported, suggesting a need for more extensive sampling and inclusion of additional genes.


Input: Divergence in androgen sensitivity contributes to population differences in sexual dimorphism of electrocommunication behavior.

androgen


Input: Weakly-electric fish (Apteronotidae) produce highly diverse electrocommunication signals.


Input: Electric organ discharges (EODs) vary across species, sexes, and in the magnitude and direction of their sexual dimorphism.


Input: Gonadal steroid hormones can modulate EODs, and differences in androgen sensitivity are hypothesized to underlie variation in the degree of sexual dimorphism across species.

androgen


Input: In this study, we asked whether variation in androgen sensitivity explained variation in sexual dimorphism of EODs within species, at the population level.

androgen


Input: We examined two populations of black ghost knifefish (Apteronotus albifrons), one from the Orinoco and the other from the Amazon River Basin.


Input: EOD frequency (EODf) and chirp rates were measured to characterize diversity in sexual dimorphism across populations.


Input: The magnitude of sexual dimorphism in EODf differed significantly across populations, and was more pronounced in the Orinoco population than in the Amazon population.


Input: Chirp rates were sexually monomorphic in both populations.


Input: 11-Ketotestosterone (11-kT) was administered over a two-week period to assess population differences in sensitivity to androgens.

androgens


Input: 11-kT masculinized EODf significantly more in the population with the greater degree of sexual dimorphism.


Input: 11-kT had no effect on the sexually monomorphic chirping rates.


Input: We conclude that population divergence in androgen sensitivity contributes to variation in sexual dimorphism of EODf in A. albifrons.

androgen


Input: Effects of phospholipase A2 and metalloprotease fractions of Russell' s viper venom on cytokines and renal hemodynamics in dogs.


Input: Several enzymes in Russell' s viper (Daboia siamensis) venom are involved in the venom effects and renal injury.


Input: The effects of fractional components of Russell' s viper venom, phospholipase A (2) and metalloprotease fractions, were examined in two groups of four experimental dogs each.


Input: Animals received an intravenous injection of 140 mu g/kg of each venom fraction.


Input: The inflammatory effects and renal hemodynamic changes were assessed.


Input: Plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and PGE2 were elevated by both phospholipase A (2) (PLA (2)) and metalloprotease (MP) fractions.


Input: The plasma level of nitric oxide was increased after PLA (2) fraction injection but not with MP fraction injection.

nitric oxide


Input: Leukocytosis with increase in lymphocytes, monocytes and granulocytes was observed after both PLA (2) and MP injections.


Input: Results from this study suggested that both PLA (2) and MP were inflammatory.


Input: Increased red blood cell count, hematocrit and hemoglobin concentration were observed in animals injected with PLA (2) fraction, but not with MP fraction.


Input: Hemodynamically, PLA (2) fraction induced marked decrease in mean arterial pressure with decreased renal vascular resistance initially followed later by increased renal vascular resistance.


Input: MP fraction caused less decrease of mean arterial pressure but increased renal vascular resistance throughout the experiment.


Input: Both enzymes decreased renal blood flow, glomerular filtration rate and urine flow.


Input: The findings indicate vasodilating effect of PLA (2) fraction and vasoconstricting effect and decreased cardiac function of MP fraction.


Input: Heteromtoxin (HmTx), a novel heterodimeric phospholipase A (2) from Heterometrus laoticus scorpion venom.


Input: Heteromtoxin (HmTx) is a group III phospholipase A (2) produced in Heterometrus laoticus, in Thailand.


Input: In this study, HmTx was purified from venom by separation chromatography, and the PLA (2) activity of the fractions was determined by lecithin agar assay.


Input: The enzyme is an acidic protein with a pI of 5. 6 and an apparent molecular weight of 14018. 4 Da.


Input: The nucleotide sequence of HmTx contains 649 bp, and the mature protein is predicted to have 131 amino acid residues-104 of which make up the large subunit, and 27 of which make up the small subunit.

nucleotide

amino acid


Input: The subunit structure of HmTx is highly similar to that of the other toxin, Pandinus imperator imperatoxin I (IpTx (i)) and to Mesobuthus tamulus phospholipase A (2) (MtPLA (2)).


Input: The 3D-structure of HmTx consists of three conserved alpha-helices: h1 (Lys24-His34), h2 (Cys59-Asp71), and h3 (Ala80-Phe89).


Input: The beta-sheet consisted of a single stranded anti-parallel beta-sheet (b1. 1 at Glu43-Lys45 and b1. 2 at Lys48-Asn50) that was highly similar to the conserved sequences (-CGXG-,-CCXXHDXC-and CXCEXXXXXC-) of Apis mellifera (bee) phospholipases.


Input: A non-catalytic function of Rev1 in translesion DNA synthesis and mutagenesis is mediated by its stable interaction with Rad5.


Input: DNA damage tolerance consisting of template switching and translesion synthesis is a major cellular mechanism in response to unrepaired DNA lesions during replication.


Input: The Rev1 pathway constitutes the major mechanism of translesion synthesis and base damage-induced mutagenesis in model cell systems.


Input: Rev1 is a dCMP transferase, but additionally plays non-catalytic functions in translesion synthesis.

dCMP


Input: Using the yeast model system, we attempted to gain further insights into the non-catalytic functions of Rev1.


Input: Rev1 stably interacts with Rad5 (a central component of the template switching pathway) via the C-terminal region of Rev1 and the N-terminal region of Rad5.

C

N


Input: Supporting functional significance of this interaction, both the Rev1 pathway and Rad5 are required for translesion synthesis and mutagenesis of 1, N (6)-ethenoadenine.

1, N (6)-ethenoadenine


Input: Furthermore, disrupting the Rev1-Rad5 interaction by mutating Rev1 did not affect its dCMP transferase, but led to inactivation of the Rev1 non-catalytic function in translesion synthesis of UV-induced DNA damage.

dCMP


Input: Deletion analysis revealed that the C-terminal 21-amino acid sequence of Rev1 is uniquely required for its interaction with Rad5 and is essential for its non-catalytic function.

C

amino acid


Input: Deletion analysis additionally implicated a C-terminal region of Rev1 in its negative regulation.

C


Input: These results show that a non-catalytic function of Rev1 in translesion synthesis and mutagenesis is mediated by its interaction with Rad5.


Input: TNF-alpha-induced CXCL8 production by A549 cells: involvement of the non-neuronal cholinergic system.


Input: It was recently suggested that the non-neuronal cholinergic system has a regulatory role in pulmonary inflammation.


Input: We investigated this system' s involvement in the control of cytokine production by the A549 human alveolar epithelial cell line.


Input: CXCL8 and acetylcholine (ACh) concentrations were measured using ELISA and LC-MS/MS, respectively.

acetylcholine

ACh


Input: The mRNA expression of muscarinic receptor (MR) subtypes was determined using RT-PCR.


Input: In A549 cells, TNF-alpha increased the release of CXCL8 and ACh and the expression of the subtype 3 MR (M3R).

ACh


Input: Furthermore, TNF-alpha-induced CXCL8 secretion was (i) inhibited by the MR antagonist tiotropium and the M3R antagonist 4-DAMP and (ii) enhanced by the M1/M3R agonist pilocarpine and the cholinesterase inhibitor physostigmine.

tiotropium

pilocarpine

physostigmine


Input: Taken as a whole, these results suggest that ACh release by A549 cells enhances TNF-alpha-induced CXCL8 secretion through activation of the M3R.

ACh


Input: Western blot analysis revealed that pilocarpine and physostigmine enhanced the TNF-alpha-induced phosphorylation of ERK1/2 and p38 MAPK and the degradation of I kappa B alpha.

pilocarpine

physostigmine


Input: Inhibition of these pathways with specific inhibitors abrogated the pilocarpine-induced CXCL8 release.

pilocarpine


Input: Our results suggest that the TNF-alpha-induced secretion of CXCL8 in A549 cells is regulated by the release of ACh, the latter' s binding to the M3R and the downstream activation of NF-kappa B and the ERK1/2 and p38 MAPK signaling pathways.

ACh


Input: Our findings suggest that MR antagonists may have anti-inflammatory effects by preventing pro-inflammatory events driven by endogenous, non-neuronal ACh.

ACh


Input: Inhibition of vitellogenin gene induction by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin is mediated by aryl hydrocarbon receptor 2 (AHR2) in zebrafish (Danio rerio).

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin

aryl hydrocarbon


Input: Vitellogenins are hepatically derived yolk-protein precursors required for oogenesis in all oviparous teleosts.


Input: Altered gene-regulation of vitellogenesis by environmental contaminants can have profound effects on reproductive success, and ultimately population sustainability.


Input: To better understand chemical effects on vitellogenin gene regulation, we tested the hypothesis that activation of the aryl hydrocarbon receptor 2 (AHR2) by dioxin inhibits the estrogen receptor pathway regulation of 3 vitellogenin genes (vtg1-3) in vivo, using zebrafish (Danio rerio) as a model teleost.

aryl hydrocarbon

dioxin

estrogen


Input: Using an embryo-larval bioassay, embryos were either treated with 1000 pptr (parts-per-trillion, pg/mL) 17 alpha-ethynylestradiol (EE2) alone from 6h post fertilization (hpf) to 4 days post fertilization (dpf), or pre-treated with dioxin (4-5 hpf) prior to EE2.

17 alpha-ethynylestradiol


Input: Pre-treatment with 400 pptr 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (2, 3, 7, 8-TCDD) or 1, 2, 3, 7, 8-pentachlorodibenzo-p-dioxin inhibited the EE2 induction of vtg1, vtg2 and vtg3 by > 95% (p <= 0. 05).

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin

2, 3, 7, 8-TCDD

1, 2, 3, 7, 8-pentachlorodibenzo-p-dioxin


Input: In comparison, a splice-blocking AHR2 morpholino used to down-regulate ahr2 expression significantly reduced the inhibition of vtg1, vtg2 and vtg3 by 400 pptr 2, 3, 7, 8-TCDD (20. 7-27. 4% rescue).

2, 3, 7, 8-TCDD


Input: These studies demonstrate that 2, 3, 7, 8-TCDD directly inhibits the vitellogenin pathway in vivo through activation of the AHR2.

2, 3, 7, 8-TCDD


Input: This work provides evidence for AHR2 dependent cross-talk inhibition of vitellogenin genes and offers insight into anti-estrogenic reproductive effects observed in oviparous species exposed to AHR agonist contaminants.


Input: Developing and advancing dry powder inhalation towards enhanced therapeutics.


Input: Enhanced therapeutics are drug products derived from existing generic drugs that provide additional benefits to the patients and the healthcare system.


Input: Enhanced therapeutics are considered to be an important and relatively low risk source of innovation.


Input: Pulmonary drug delivery is the major delivery route to treat chronic respiratory diseases and has been proven as a potential delivery route for complex drugs that cannot be delivered orally.


Input: Development of dry powder inhalation systems targets the delivery of fine drug particles to the deep lung surface by a combination of drug formulation, primary packaging and a device, whereby each contributes to the overall performance.


Input: Various methodologies for the non-clinical and clinical performance testing of orally inhaled products have been proposed and applied with variable success.


Input: Regulatory pathways have been developed and applied since.


Input: Considerable efforts have been made during the past decade to understand and optimize pulmonary drug delivery including their efficient commercial manufacturing.


Input: Pulmonary drug delivery remains an area of future innovation in the effective treatment of pulmonary diseases as well as the systemic delivery of systemically active complex drugs.


Input: Toxicity in mice of lectin ebulin f present in dwarf Elderberry (Sambucus ebulus L.).


Input: Dwarf elder fruits (Sambucus ebulus) contain the ribosome-inactivating lectin ebulin f structurally related to ricin.


Input: We investigated intraperitoneal toxicity of ebulin f in mice and found that it triggers specific derangement of the intestines.


Input: Ebulin f was much less toxic than ricin to mice when administered intraperitoneally.


Input: The targets were cells of the intestinal crypts, which underwent apoptosis.


Input: Small intestine crypts were more sensitive than large intestine crypts.


Input: Effects of octylphenol and bisphenol A on the expression of calcium transport genes in the mouse duodenum and kidney during pregnancy.

octylphenol

bisphenol A

calcium


Input: Octylphenol (OP) is the degradative product of alkylphenol ethoxylates that are widely used to produce rubber, pesticides, and paints.

Octylphenol

alkylphenol ethoxylates


Input: Bisphenol A (BPA) is an organic compound with two functional phenol groups, and used for manufacturing polycarbonate plastic and epoxy resins, as well as other applications.

Bisphenol A

BPA

phenol

polycarbonate

epoxy


Input: OP and BPA are known as endocrine disruptors (EDs) with estrogenic activities, and may disturb natural calcium (Ca) metabolism.

BPA

calcium

Ca


Input: In the present study, the effects of OP and BPA on Ca levels in the serum and expression of Ca transport genes in the duodenum, and kidney were investigated in pregnant mice.

BPA

Ca

Ca


Input: Calbindin refers to several Ca-binding proteins originally described as vitamin D-dependent Ca-binding factors in the intestine, and kidney of birds and mammals.

Calbindin

vitamin D

Ca


Input: Transient receptor potential cation channel, subfamily V, member 6 (TRPV6) and transient receptor potential cation channel, subfamily V, member 5 (TRPV5) are Ca entry channels responsible for Ca absorption in the kidney and intestine, respectively.

Ca

Ca


Input: From 6. 5 to 16. 5 day post coitus (dpc), pregnant mice were given oral doses of 17 alpha-ethynylestradiol (EE, 0. 2mg/kg/day), BPA (5 or 50mg/kg/day), or OP (3, 12, or 48 mg/kg/day) dissolved in corn oil.

17 alpha-ethynylestradiol

BPA


Input: Samples of the duodenum, kidney, and blood were obtained from the mice on day 17. 5 of pregnancy.


Input: Serum Ca levels were decreased in the groups treated with OP and BPA.

Ca

BPA


Input: The expression levels of Ca transport genes, TRPV5 and calbindin-D9k (CaBP-9k), in the kidney were decreased after treatment with OP and BPA.

Ca

BPA


Input: Duodenal expression of TRPV6 was also reduced by BPA and OP administration.

BPA


Input: CaBP-9k expression was differentially regulated by BPA and OP.

BPA


Input: Transcriptional and translational levels of CaBP-9k were decreased by EE and BPA but increased by a high dose of OP.

BPA


Input: Taken together, our findings demonstrate that OP and BPA regulated the expression of genes associated with Ca transport in the pregnant mice, which may result in the decreased serum Ca levels.

BPA

Ca

Ca


Input: Anesthetics interacting with lipid rafts.


Input: The exact mechanism by which anesthetics induce cell membrane-mediated modifications is still an open question.


Input: Although the fluidization effect of the anesthetic molecules on the cellular membrane is widely recognized, it is not known if anesthetics show any preference for specific membrane domains, namely the lipid rafts.


Input: The importance of these membrane micro-domains derives from the fact that they have been associated with cell signaling pathways, as well as with specific drug interactions.


Input: The objective of this work is to contribute for the elucidation of this question through the comparison of the anesthetic interactions with membranes of various lipid compositions.


Input: Liposomes prepared with an equimolar mixture of POPC, sphingomyelin and cholesterol, were chosen as models for lipid rafts.

POPC

sphingomyelin

cholesterol


Input: The interactions of these liposomes with two local anesthetics, tetracaine and lidocaine, and one general anesthetic, propofol, were studied.

tetracaine

lidocaine

propofol


Input: The effect of cholesterol was investigated by comparing anesthetic interactions with POPC/SM liposomes and POPC/SM/CHOL liposomes.

cholesterol

POPC

POPC

CHOL


Input: The following experimental techniques were used: quartz crystal microbalance with dissipation, differential scanning calorimetry and phosphorus nuclear magnetic resonance.

quartz

phosphorus


Input: Although the liposomes investigated by the different techniques are not in the same conditions, it is possible to assemble the information obtained from all experimental techniques employed to reach a general conclusion.


Input: Tetracaine interacts more with raftlike domains, lidocaine induces stronger modifications on POPC/SM liposomes and the results for propofol are not fully conclusive but it seems to be the least prone to lipid interactions.

Tetracaine

lidocaine

POPC

propofol


Input: The results were compared with those obtained with DMPC-containing liposomes, reported in a previous work.

DMPC


Input: Gene transcription and biomarker responses in the clam Ruditapes philippinarum after exposure to ibuprofen.

ibuprofen


Input: Pharmaceuticals are a class of emerging environmental contaminants that continuously enter aquatic environments.


Input: Presently, little information is available about the effects of these substances on non-target organisms, such as bivalves.


Input: We investigated the effects of ibuprofen (IBU) on the clam Ruditapes philippinarum.

ibuprofen

IBU


Input: Clams were exposed for 1, 3, 5 and 7 days to 0, 100 and 1000 mu gIBU/L, and established biomarker responses (haemolymph lysozyme, gill acetylcholinesterase and digestive gland superoxide dismutase activities) as well as digestive gland transcriptome were evaluated.

superoxide


Input: A two-way ANOVA revealed significant effects of both " IBU concentration " and " exposure duration " on biomarker responses.

IBU


Input: Overall, the enzyme activities were generally lower in IBU-exposed clams than in controls.

IBU


Input: Although limited knowledge of the mollusc transcriptome makes it difficult to interpret the effects of IBU on clams, the gene transcription analysis using DNA microarrays enabled the identification of the putative molecular mode of action of the IBU.

IBU

IBU


Input: The functional analysis of differentially transcribed genes suggests that IBU can interfere with various signalling pathways in clams, such as arachidonic acid metabolism, apoptosis, peroxisomal proliferator-activated receptors, and nuclear factor-kappa B.

IBU

arachidonic acid


Input: In addition, several genes involved in the metabolism of xenobiotics (e. g., glutathione S-transferase, sulfotransferase, cytochrome P450) were also found to be significantly affected by IBU exposure.

glutathione S

IBU


Input: In summary, the integrated approach of gene transcription analysis and biomarker responses facilitated the elucidation of the putative mechanisms of action of IBU in non-target species.

IBU


Input: O2-independent formation of the inactive states of NiFe hydrogenase.

NiFe


Input: We studied the mechanism of aerobic inactivation of Desulfovibrio fructosovorans nickel-iron (NiFe) hydrogenase by quantitatively examining the results of electrochemistry, EPR and FTIR experiments.

nickel-iron

NiFe


Input: They suggest that, contrary to the commonly accepted mechanism, the attacking O (2) is not incorporated as an active site ligand but, rather, acts as an electron acceptor.

O (2)


Input: Our findings offer new ways toward the understanding of O (2) inactivation and O (2) tolerance in NiFe hydrogenases.

O (2)

O (2)

NiFe


Input: Multi-cell type human liver microtissues for hepatotoxicity testing.


Input: Current 2-dimensional hepatic model systems often fail to predict chemically induced hepatotoxicity due to the loss of a hepatocyte-specific phenotype in culture.


Input: For more predictive in vitro models, hepatocytes have to be maintained in a 3-dimensional environment that allows for polarization and cell-cell contacts.


Input: Preferably, the model will reflect an in vivo-like multi-cell type environment necessary for liver-like responses.


Input: Here, we report the characterization of a multi-cell type microtissue model, generated from primary human hepatocytes and liver-derived non-parenchymal cells.


Input: Liver microtissues were stable and functional for 5 weeks in culture enabling, for example, long-term toxicity testing of acetaminophen and diclofenac.

acetaminophen

diclofenac


Input: In addition, Kupffer cells were responsive to inflammatory stimuli such as LPS demonstrating the possibility to detect inflammation-mediated toxicity as exemplified by the drug trovafloxacin.

trovafloxacin


Input: Herewith, we present a novel 3D liver model for routine testing in 96-well format capable of reducing the risk of unwanted toxic effects in the clinic.


Input: Thyroid disruption in the lizard Podarcis bocagei exposed to a mixture of herbicides: a field study.


Input: Pesticide exposure has been related with thyroid disrupting effects in different vertebrate species.


Input: However, very little is known about the effects of these compounds in reptiles.


Input: In the Mediterranean area, lacertid lizards are the most abundant vertebrate group in agroecosystems, and have been identified as potential model species for reptile ecotoxicology.


Input: The aim of this study was to understand if the herbicides applied in corn fields have thyroid disruptive effects in the lizard Podarcis bocagei.


Input: Adult male lizards were captured in north-western Portugal in corn fields treated with herbicides (exposed sites), and in organic agricultural fields (reference sites).


Input: Thyroid and male gonad morphology and functionality, and testosterone levels were investigated through histological, immunohistochemical and biochemical techniques.

testosterone


Input: Lizards from exposed locations displayed thyroid follicular lumens with more reabsorption vacuoles and significantly larger follicular area than those from reference fields.


Input: Furthermore, testes of lizards from exposed locations had significantly larger seminiferous tubule diameters, significantly higher number of spermatogenic layers and displayed an up-regulation of thyroid hormone receptors when compared with lizards from reference areas.


Input: These findings strongly suggest that the complex mixture of herbicides that lizards are exposed to in agricultural areas have thyroid disrupting effects which ultimately affect the male reproductive system.


Input: Alachlor, which has demonstrated thyroid effects in mammals, may be largely responsible for the observed effects.

Alachlor


Input: Effects of pyrene exposure and temperature on early development of two co-existing Arctic copepods.

pyrene


Input: Oil exploration is expected to increase in the near future in Western Greenland.


Input: At present, effects of exposure to oil compounds on early life-stages of the ecologically important Calanus spp. are unknown.


Input: We investigated the effects of the oil compound pyrene, on egg hatching and naupliar development of the calanoid copepods Calanus glacialis and C. finmarchicus, two key species in the Disko Bay, Western Greenland.

pyrene


Input: At low temperature the nauplii of C. glacialis experienced reduced growth when exposed to pyrene, and survival in both species decreased.

pyrene


Input: Naupliar mortality increased with temperature at high pyrene concentration in C. finmarchicus.

pyrene


Input: Both Calanus species were affected by pyrene exposure but C. finmarchicus was more sensitive compared to C. glacialis.

pyrene


Input: Lowered growth rate and increased mortality of the naupliar stages entail reduced recruitment to copepod populations.


Input: Exposure to pyrene from an oil spill may reduce the standing stock of Calanus, which can lead to less energy available to higher trophic levels in the Arctic marine food web.

pyrene


Input: A perspective on the contribution of metabolites to drug-drug interaction potential: the need to consider both circulating levels and inhibition potency.


Input: The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at > 25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and > 10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential.


Input: This commentary attempts to rationalize the clinically relevant levels of metabolite (s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite.


Input: A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment.


Input: When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite (s).


Input: When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro.


Input: The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC.


Input: It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e. g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e. g., mechanism-based inhibition).


Input: A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety.


Input: Metal-supported aluminosilicate ultrathin films as a versatile tool for studying the surface chemistry of zeolites.

aluminosilicate

zeolites


Input: The application of a variety of " surface-science " techniques to elucidate surface structures and mechanisms of chemical reactions at zeolite surfaces has long been considered as almost impossible because of the poor electrical and thermal conductivity of those materials.

zeolite


Input: Here, we show that the growth of a thin aluminosilicate film on a metal single crystal under controlled conditions results in adequate and well-defined model systems for zeolite surfaces.

aluminosilicate

zeolite


Input: In principle, silicate films that contain metals other than Al (e. g. Ti, Fe, etc) may be prepared in a similar way.

silicate

Al

Ti

Fe


Input: We believe that this approach opens up a new playground for experimental and theoretical modeling of zeolites, aimed at a fundamental understanding of structure-reactivity relationships in such materials.

zeolites


Input: In vitro exposure of precision-cut lung slices to 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole lysylamide dihydrochloride (NSC 710305, Phortress) increases inflammatory cytokine content and tissue damage.

2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole lysylamide dihydrochloride

NSC 710305

Phortress


Input: The anticancer drug (2-[4-amino-3-methylphenyl]-5-fluorobenzothiazole lysylamide dihydrochloride) (NSC 710305, Phortress) is a metabolically activated prodrug that causes DNA adduct formation and subsequent toxicity.

2-[4-amino-3-methylphenyl]-5-fluorobenzothiazole lysylamide dihydrochloride

NSC 710305

Phortress


Input: Preclinically, it was found that hepatic, bone marrow, and pulmonary toxicity presented challenges to developing this drug.


Input: An ex vivo precision-cut lung slice (PCLS) model was used to search for concentration dependent effects of NSC 710305 (10, 25, 50, and 100 micro M) on cytokine content, protein content, and immuno/histological endpoints.

NSC 710305


Input: Preparation and culture of PCLS caused an initial spike in proinflammatory cytokine expression and therefore treatment with NSC 710305 was delayed until 48 h after initiating the slice cultures to avoid confounding the response to slicing with any drug response.

NSC 710305


Input: PCLSs were evaluated after 24, 48, and 72 h exposures to NSC 710305.

NSC 710305


Input: Reversibility of toxicity due to the 72-h treatment was evaluated after a 24-h recovery period.


Input: NSC 710305 caused a concentration-dependent cytokine response, and only the toxicity caused by a 72-h exposure to 25 micro M reversed during the 24-h recovery period.

NSC 710305


Input: Immuno/histological examination and quantitation of tissue protein levels indicated that tissue destruction, ED-1 (activated macrophage) staining, and protein levels were associated with the levels of proinflammatory cytokines in the tissue.


Input: In conclusion, the concentration-and time-dependent inflammatory response of PCLS to NSC 710305 preceded relevant tissue damage by a few days.

NSC 710305


Input: The no-observable adverse effect level (NOAEL) for 24, 48, and 72 h exposures was established as 10 micro M NSC 710305.

NSC 710305


Input: Gender difference of childhood overweight and obesity in predicting the risk of incident asthma: a systematic review and meta-analysis.


Input: The aims of our meta-analysis were (i) to quantify the predictability of childhood overweight and obesity on the risk of incident asthma; and (ii) to evaluate the gender difference on this relationship.


Input: The selection criteria included prospective cohort paediatric studies which use age-and sex-specific body mass index (BMI) as a measure of childhood overweight and the primary outcome of incident asthma.


Input: A total of 1, 027 studies were initially identified through online database searches, and finally 6 studies met the inclusion criteria.


Input: The combined result of reported relative risk from the 6 included studies revealed that overweight children conferred increased risks of incident asthma as compared with non-overweight children (relative risk, 1. 19; 95% confidence interval [CI], 1. 03-1. 37).


Input: The relationship was further elevated for obesity vs. non-obesity (relative risk, 2. 02; 95% CI, 1. 16-3. 50).


Input: A dose-responsiveness of elevated BMI on asthma incidence was observed (P for trend, 0. 004).


Input: Obese boys had a significantly larger effect than obese girls (relative risk, boys: 2. 47; 95% CI, 1. 57-3. 87; girls: 1. 25; 95% CI, 0. 51-3. 03), with significant dose-dependent effect.


Input: Proposed mechanisms of gender difference could be through pulmonary mechanics, sleep disordered breathing and leptin.


Input: Further research might be needed to better understand the exact mechanism of gender difference on the obesity-asthma relationship.


Input: Dendrimeric bowties featuring hemispheric-selective decoration of ligands for microRNA-based therapy.


Input: Dendrimers feature a defined number of terminal groups that may bind RNA or be functionalized with bioactive molecules.


Input: These competing uses of terminal groups may create an impasse if the requisite density of ligands depletes the number of terminal groups for binding sufficient RNA, or vice versa.


Input: A novel dendrimeric platform is needed that maintains high ligand density while retaining sufficient microRNA-binding terminal groups.


Input: Here we present a dendrimeric " bowtie " consisting of one-half devoted to microRNA binding and the other half to ligand presentation.


Input: We demonstrate its suitability as a transfection agent by delivering miR-126 to human vascular endothial cells (HUVECs) via polyarginine-and RGD-modified bowties and evaluating the downstream effects on proliferation and tube formation.

polyarginine


Input: Our findings indicate that the bowtie elicits desired responses and may possess superior delivery properties compared to nondecorated dendrimeric materials.


Input: The bowtie system thereby provides a new design model for developing dendrimeric delivery vehicles for RNAi therapeutics.


Input: PomZ, a ParA-like protein, regulates Z-ring formation and cell division in Myxococcus xanthus.


Input: Accurate positioning of the division site is essential to generate appropriately sized daughter cells with the correct chromosome number.


Input: In bacteria, division generally depends on assembly of the tubulin homologue FtsZ into the Z-ring at the division site.


Input: Here, we show that lack of the ParA-like protein PomZ in Myxococcus xanthus resulted in division defects with the formation of chromosome-free minicells and filamentous cells.


Input: Lack of PomZ also caused reduced formation of Z-rings and incorrect positioning of the few Z-rings formed.


Input: PomZ localization is cell cycle regulated, and PomZ accumulates at the division site at midcell after chromosome segregation but prior to FtsZ as well as in the absence of FtsZ.


Input: FtsZ displayed cooperative GTP hydrolysis in vitro but did not form detectable filaments in vitro.


Input: PomZ interacted with FtsZ in M. xanthus cell extracts.


Input: These data show that PomZ is important for Z-ring formation and is a spatial regulator of Z-ring formation and cell division.


Input: The cell cycle-dependent localization of PomZ at midcell provides a mechanism for coupling cell cycle progression and Z-ring formation.


Input: Moreover, the data suggest that PomZ is part of a system that recruits FtsZ to midcell, thereby, restricting Z-ring formation to this position.


Input: Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.

Mesalamine


Input: Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon.

Mesalamine


Input: Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking.


Input: We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background.


Input: Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29).


Input: Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and beta-catenin/Wnt signaling.


Input: PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways.


Input: We further investigated the effect of 5-ASA on cell adhesion.


Input: 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement.


Input: Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and beta-catenin.


Input: Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo.


Input: Inhibition of PAK1 by RNA interference also increased cell adhesion.


Input: PAK1 expression was elevated in APC (min) polyps and 5-ASA treatment reduced its expression.


Input: Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC (min) polyposis.

mesalamine


Input: We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis.


Input: The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action.


Input: Emodin-6-O-beta-D-glucoside inhibits HMGB1-induced inflammatory responses in vitro and in vivo.


Input: High mobility group box 1 (HMGB1) protein acts as a potent proinflammatory cytokine and is involved in the pathogenesis of several vascular diseases, such as, systemic vasculitis and sepsis.


Input: Emodin-6-O-beta-D-glucoside (EG) is a new active compound from Reynoutria japonica, and its biologic activities have not been previously investigated.


Input: In this study, we first investigated the antiinflammatory activities of EG on HMGB1-mediated proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and in a murine cecal ligation and puncture (CLP)-model of sepsis in mice.


Input: EG was found to suppress the release of HMGB1, the production of tumor necrosis factor (TNF)-alpha, and the activation of nuclear factor-kappa B (NF-kappa B) by HMGB1 in HUVECs, and to inhibit HMGB1-mediated hyperpermeability and leukocyte migration in mice.


Input: In the CLP model, HMGB1 was highly released, but this release was prevented by EG.


Input: Furthermore, EG also increased the survival times of CLP administered mice.


Input: Collectively, this study shows EG can protect barrier integrity and inhibit HMGB1-mediated inflammatory responses, which suggests a potential use as a therapy for sepsis or septic shock.


Input: Puerarin mediates hepatoprotection against CCl4-induced hepatic fibrosis rats through attenuation of inflammation response and amelioration of metabolic function.

Puerarin


Input: This study was designed to evaluate the potential effects of puerarin (PR), an effective isoflavonoid compound purified from Pueraria lobata, in treating hepatic fibrosis (HF) rats induced by carbon tetrachloride (CCl (4), 2 mL kg (-1) d (-1)).

puerarin

isoflavonoid

carbon tetrachloride

CCl (4)


Input: Compared to model control, PR treatment effectively lowered the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), total protein (TP) in HF rats.

alanine

aspartate


Input: Masson stained analysis showed that the condition of HF rats was mitigated.


Input: Meanwhile, the tumor necrosis factor alpha (TNF-alpha), nuclear factor-kappa B (NF-kappa B) expressions were significantly down-regulated at protein level by PR intervention.


Input: Additionally, the activity of superoxide dismutase (SOD) was elevated, while the content of malondialdehyde (MDA) was lessened in liver tissue.

superoxide

malondialdehyde

MDA


Input: As revealed by immunohistochemistry assay, PR therapy resulted in reduced production of transforming growth factor-beta l (TGF-beta l).


Input: Moreover, it also was attributed to decreased mRNA level of inducible nitric oxide synthase (iNOS) using RT-PCR analysis.

nitric oxide


Input: These findings demonstrate that puerarin successfully reverses hepatotoxicity in CCl (4)-induced HF rats via the underlying mechanisms of regulating serum enzymes and attenuating TNF-alpha/NF-kappa B pathway for anti-inflammation response, as well as improving metabolic function in liver tissue.

puerarin

CCl (4)


Input: Hepatoprotective effects of Gentiana asclepiadea L. extracts against carbon tetrachloride induced liver injury in rats.

carbon tetrachloride


Input: This study is an attempt to evaluate the hepatoprotective activity of Gentiana asclepiadea L. against carbon tetrachloride-induced liver injury in rats.

carbon tetrachloride


Input: Methanol extracts of aerial parts (GAA) and roots (GAR) of G. asclepiadea at doses of 100, 200, and 400mg/kg b. w. were orally administered to Wistar rats once daily for 7 days before they were treated with CCl (4).

Methanol

CCl (4)


Input: The hepatoprotective activity of the extracts in this study was compared with the reference drug silymarin.


Input: In CCl (4) treated animals, GAA and GAR significantly decreased levels of serum transaminases, alkaline phosphatase and total bilirubin, and increased the level of total protein.

CCl (4)

bilirubin


Input: Treatment with the extracts resulted in a significant increase in the levels of catalase, superoxide dismutase and reduced glutathione, accompanied with a marked reduction in the levels of malondialdehyde, as compared to CCl (4) treated group.

superoxide

reduced glutathione

malondialdehyde

CCl (4)


Input: The histopathological studies confirmed protective effects of extracts against CCl (4)-induced liver injuries.

CCl (4)


Input: No genotoxicity was observed in liver cells after GAA treatment, while GAR showed only slight genotoxic effects by comet assay.


Input: Phytochemical analysis revealed the presence of sweroside, swertiamarin and gentiopicrin in high concentrations in both extracts.

sweroside

swertiamarin

gentiopicrin


Input: It could be concluded that the use of G. asclepiadea extracts in the treatment of chemical-induced hepatotoxicity.


Input: Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals.


Input: Endocrine disrupting chemicals (EDCs) have the potential to interfere with the hormonal system and may negatively influence human health.


Input: Microarray analysis was used in this study to investigate differential gene expression in human peripheral blood cells (PBMCs) after in vitro exposure to EDCs.


Input: PBMCs, isolated from blood samples of four male and four female healthy individuals, were exposed in vitro for 18h to either a dioxin-like polychlorinated biphenyl (PCB126, 1 mu M), a non-dioxin-like polychlorinated biphenyl (PCB153, 10 mu M), a brominated flame retardant (BDE47, 10 mu M), a perfluorinated alkyl acid (PFOA, 10 mu M) or bisphenol (BPA, 10 mu M).

dioxin

polychlorinated biphenyl

dioxin

polychlorinated biphenyl

perfluorinated alkyl acid

PFOA

bisphenol

BPA


Input: ANOVA analysis revealed a significant change in the expression of 862 genes as a result of EDC exposure.


Input: The gender of the donors did not affect gene expression.


Input: Hierarchical cluster analysis created three groups and clustered: (1) PCB126-exposed samples, (2) PCB153 and BDE47, (3) PFOA and BPA.

PFOA

BPA


Input: The number of differentially expressed genes varied per compound and ranged from 60 to 192 when using fold change and multiplicity corrected p-value as filtering criteria.


Input: Exposure to PCB126 induced the AhR signaling pathway.


Input: BDE47 and PCB153 are known to disrupt thyroid metabolism and exposure influenced the expression of the nuclear receptors PPAR gamma and ESR2, respectively.


Input: BPA and PFOA did not induce significant changes in the expression of known nuclear receptors.

BPA

PFOA


Input: Overall, each compound produced a unique gene expression signature affecting pathways and GO processes linked to metabolism and inflammation.


Input: Twenty-nine genes were significantly altered in expression under all experimental conditions.


Input: Six of these genes (HSD11B2, MMP11, ADIPOQ, CEL, DUSP9 and TUB) could be associated with obesity and metabolic syndrome.


Input: In conclusion, microarray analysis identified that PBMCs altered their gene expression response in vitro when challenged with EDCs.


Input: Our screening approach has identified a number of gene candidates that warrant further study.


Input: The mechanism of carvacrol-evoked [Ca2 +] i rises and non-Ca2 +-triggered cell death in OC2 human oral cancer cells.

carvacrol

Ca2 +

Ca2 +


Input: Carvacrol is one of the main substances of essential oil which triggers intracellular Ca (2 +) mobilization and causes cytotoxicity in diverse cell models.

Carvacrol

Ca (2 +)


Input: However, the mechanism of carvacrol-induced Ca (2 +) movement and cytotoxicity is not fully understood.

carvacrol

Ca (2 +)


Input: This study examined the effect of carvacrol on cytosolic free Ca (2 +) concentrations ([Ca (2 +)] (i)), cell viability and apoptosis in OC2 human oral cancer cells.

carvacrol

Ca (2 +)

Ca (2 +)


Input: Carvacrol induced a [Ca (2 +)] (i) rise and the signal was reduced by removal of extracellular Ca (2 +).

Carvacrol

Ca (2 +)

Ca (2 +)


Input: Carvacrol-induced Ca (2 +) entry was not altered by store-operated Ca (2 +) channel inhibitors and protein kinase C (PKC) activator, but was inhibited by a PKC inhibitor.

Carvacrol

Ca (2 +)

Ca (2 +)


Input: In Ca (2 +)-free medium, treatment with the endoplasmic reticulum Ca (2 +) pump inhibitor thapsigargin (TG) or 2, 5-di-tert-butylhydroquinone (BHQ) inhibited carvacrol-induced [Ca (2 +)] (i) rise.

Ca (2 +)

Ca (2 +)

thapsigargin

2, 5-di-tert-butylhydroquinone

BHQ

carvacrol

Ca (2 +)


Input: Conversely, incubation with carvacrol inhibited TG or BHQ-induced [Ca (2 +)] (i) rise.

carvacrol

BHQ

Ca (2 +)


Input: Inhibition of phospholipase C (PLC) with U73122 abolished carvacrol-induced [Ca (2 +)] (i) rise.

carvacrol

Ca (2 +)


Input: Carvacrol decreased cell viability, which was not reversed when cytosolic Ca (2 +) was chelated with BAPTA-AM (1, 2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid-acetoxymethyl ester).

Carvacrol

Ca (2 +)

BAPTA-AM

1, 2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid-acetoxymethyl ester


Input: Carvacrol-induced apoptosis and activation of reactive oxygen species (ROS) and caspase-3.

Carvacrol

oxygen


Input: Together, carvacrol induced a [Ca (2 +)] (i) rise by inducing PLC-dependent Ca (2 +) release from the endoplasmic reticulum and Ca (2 +) entry via PKC-sensitive, non store-operated Ca (2 +) channels.

carvacrol

Ca (2 +)

Ca (2 +)

Ca (2 +)

Ca (2 +)


Input: Carvacrol-induced ROS-and caspase-3-associated apoptosis.

Carvacrol


Input: The 2, 2', 4, 4'-tetrabromodiphenyl ether hydroxylated metabolites 5-OH-BDE-47 and 6-OH-BDE-47 stimulate estradiol secretion in the ovary by activating aromatase expression.

2, 2', 4, 4'-tetrabromodiphenyl ether

estradiol


Input: The aim of the present study was to assess the effect of two hydroxylated BDE-47 metabolites, 5-OH-BDE-47 and 6-OH-BDE-47, on steroidogenesis in the ovary.

hydroxylated BDE-47


Input: Both metabolites failed to affect the production of androstenedione and testosterone but increased the secretion of estradiol at all concentrations tested.

androstenedione

testosterone

estradiol


Input: The increased secretion of estradiol was due to the stimulation of aromatase gene and protein expression.

estradiol


Input: Direct assessment of aromatase activity by dibenzylfluorescein assay and indirect assessment of aromatase activity by measurement of the conversion of testosterone to estradiol confirmed that 5-OH-BDE-47 and 6-OH-BDE-47 stimulate aromatase activity.

dibenzylfluorescein

testosterone

estradiol


Input: The aromatase inhibitor CGS 16949A abolished this stimulatory activity and reduced estradiol levels in the control and treatment groups.

CGS 16949A

estradiol


Input: Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2.

epigallocatechin gallate


Input: Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported.

Epigallocatechin gallate

EGCG


Input: Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of EGCG on bile flow and bile acid homeostasis in rats.

EGCG

bile acid


Input: Compared to controls, EGCG treatment decreased bile flow by 23%.

EGCG


Input: Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%.

bile acid

EGCG

glutathione


Input: Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level.

glutathione


Input: EGCG administration also doubled plasma bile acid levels compared to controls.

EGCG

bile acid


Input: While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by EGCG.

bile acid

bile acid

EGCG


Input: Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7 alpha-hydroxy-4-cholesten-3-one.

bile acid

7 alpha-hydroxy-4-cholesten-3-one


Input: In contrast, EGCG markedly downregulated major bile acid transporters (Asbt and Ost alpha) and regulatory molecules (Shp and Fgf15) in the ileum.

EGCG

bile acid


Input: When EGCG was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis.

EGCG

ethinylestradiol


Input: This study shows ability of EGCG to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow.

EGCG

bile acid

bile acid


Input: In conclusion, our data demonstrate that under certain conditions EGCG may induce cholestasis.

EGCG


Input: Male mating behaviour in relation to female sexual swellings, socio-sexual behaviour and hormonal changes in wild Barbary macaques.


Input: In many cercopithecine primates females display probabilistic cues of fertility to indicate the periovulatory period to males.


Input: These cues may include female behaviour, acoustic signals, and morphological signs such as the anogenital swelling.


Input: However, the extent to which males can utilise this information varies between species.


Input: We describe male sexual behaviour in relation to changes in anogenital swelling size, timing of ovulation and female socio-sexual behaviour in wild Barbary macaques (Macaca sylvanus).


Input: We further compare male sexual behaviour during conception and post-conception cycles to evaluate if males differentiate between these qualitatively different cycle types.


Input: Our results show that during conception cycles male mating behaviour was concentrated around the fertile phase implying that males inferred information from more than swelling size alone.


Input: Male mating frequency increased in line with female socio-sexual behaviour, namely female presenting and the frequency of copulations with copulation calls.


Input: Most strikingly our results show that males invested equally in mating during fertile and non-fertile, i. e. post-conception, maximum swelling phases.


Input: Whether post-conception swellings were merely a result of changes in hormone concentrations during pregnancy or part of a female reproductive strategy remains elusive.