Input: While the individual apparent K (M) values of CYP2B4 and CYP2E1 for CPR are similar, the apparent K (M) of CYP2E1 for CPR in the presence of CYP2B4 decreased significantly, thus suggesting that CYP2B4 enhances the affinity of CYP2E1 for CPR and this may allow CYP2E1 to out-compete CYP2B4 for CPR.


Input: Songaricalarins A-E, cytotoxic oplopane sesquiterpenes from Ligularia songarica.

Songaricalarins A-E

oplopane sesquiterpenes


Input: Five new highly oxygenated oplopane sesquiterpenes, songaricalarins A-E (1-5), and two known analogues (6 and 7) were isolated from the roots and rhizomes of Ligularia songarica.

oxygenated oplopane sesquiterpenes

songaricalarins A-E


Input: Their structures and configurations were elucidated by spectroscopic methods, including 2D-NMR techniques, and the structure of 1 was confirmed by single-crystal X-ray diffraction.


Input: All compounds were evaluated for in vitro cytotoxic activity against cultured A-549, MCF-7, KB, and KBVIN cells, and 4 exhibited cytotoxicity with EC50 values of 4. 9, 0. 8, 3. 4, and 3. 2 mu g/mL, respectively.


Input: Angiogenesis is required for stress fracture healing in rats.


Input: Although angiogenesis and osteogenesis are critically linked, the importance of angiogenesis for stress fracture healing is unknown.


Input: In this study, mechanical loading was used to create a non-displaced stress fracture in the adult rat forelimb.


Input: Fumagillin, an anti-angiogenic agent, was used as the water soluble analogue TNP-470 (25mg/kg) as well as incorporated into lipid-encapsulated alpha (v) beta (3) integrin targeted nanoparticles (0. 25mg/kg).

Fumagillin


Input: In the first experiment, TNP-470 was administered daily for 5 days following mechanical loading, and changes in gene expression, vascularity, and woven bone formation were quantified.


Input: Although no changes in vascularity were detected 3 days after loading, treatment-related downregulation of angiogenic (Pecam1) and osteogenic (Bsp, Osx) genes was observed at this early time point.


Input: On day 7, microCT imaging of loaded limbs revealed diminished woven bone formation in treated limbs compared to vehicle treated limbs.


Input: In the second experiment, alpha (v) beta (3) integrin targeted fumagillin nanoparticles were administered as before, albeit with a 100-fold lower dose, and changes in vascularity and woven bone formation were determined.

fumagillin


Input: There were no treatment-related changes in vessel count or volume 3 days after loading, although fewer angiogenic (CD105 positive) blood vessels were present in treated limbs compared to vehicle treated limbs.


Input: This result manifested on day 7 as a reduction in total vascularity, as measured by histology (vessel count) and microCT (vessel volume).


Input: Similar to the first experiment, treated limbs had diminished woven bone formation on day 7 compared to vehicle treated limbs.


Input: These results indicate that angiogenesis is required for stress fracture healing, and may have implications for inducing rapid repair of stress fractures.


Input: Amino acid residues at the N-and C-termini are essential for the folding of active human butyrylcholinesterase polypeptide.

Amino acid


Input: Human serum butyrylcholinesterase (HuBChE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic organophosphate (OP) nerve agents.

organophosphate


Input: A dose of 200mg of HuBChE is envisioned as a prophylactic treatment that can protect humans from an exposure of up to 2 x LD50 of soman.


Input: The limited availability and administration of multiple doses of this stoichiometric bioscavenger make this pretreatment difficult.


Input: Thus, the goal of this study was to produce a smaller enzymatically active HuBChE polypeptide (HBP) that could bind to nerve agents with high affinity thereby reducing the dose of enzyme.


Input: Studies have indicated that the three-dimensional structure and the domains of HuBChE (acyl pocket, lip of the active center gorge, and the anionic substrate-binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs.

acyl


Input: Therefore, we designed three HBPs by deleting some N-and C-terminal residues of HuBChE by maintaining the folds of the active site core that includes the three active site residues (S198, E325, and H438).


Input: HBP-4 that lacks 45 residues from C-terminus but known to have BChE activity was used as a control.


Input: The cDNAs for the HBPs containing signal sequences were synthesized, cloned into different mammalian expression vectors, and recombinant polypeptides were transiently expressed in different cell lines.


Input: No BChE activity was detected in the culture media of cells transfected with any of the newly designed HBPs, and the inactive polypeptides remained inside the cells.


Input: Only enzymatically active HBP-4 was secreted into the culture medium.


Input: These results suggest that residues at the N-and C-termini are required for the folding and/or maintenance of HBP into an active stable, conformation.


Input: Overexpression of H1 calponin in osteoblast lineage cells leads to a decrease in bone mass by disrupting osteoblast function and promoting osteoclast formation.


Input: H1 calponin (CNN1) is known as a smooth muscle-specific, actin-binding protein which regulates smooth muscle contractive activity.


Input: Although previous studies have shown that CNN1 has effect on bone, the mechanism is not well defined.


Input: To investigate the role of CNN1 in maintaining bone homeostasis, we generated transgenic mice overexpressing Cnn1 under the control of the osteoblast-specific 3. 6-kb Col1a1 promoter.


Input: Col1a1-Cnn1 transgenic mice showed delayed bone formation at embryonic stage and decreased bone mass at adult stage.


Input: Morphology analyses showed reduced trabecular number, thickness and defects in bone formation.


Input: The proliferation and migration of osteoblasts were decreased in Col1a1-Cnn1 mice due to alterations in cytoskeleton.


Input: The early osteoblast differentiation of Col1a1-Cnn1 mice was increased, but the late stage differentiation and mineralization of osteoblasts derived from Col1a1-Cnn1 mice were significantly decreased.


Input: In addition to impaired bone formation, the decreased bone mass was also associated with enhanced osteoclastogenesis.


Input: Tartrate-resistant acid phosphatase (TRAP) staining revealed increased osteoclast numbers in tibias of 2-month-old Col1a1-Cnn1 mice, and increased numbers of osteoclasts co-cultured with Col1a1-Cnn1 osteoblasts.

Tartrate


Input: The ratio of RANKL to OPG was significantly increased in Col1a1-Cnn1 osteoblasts.


Input: These findings reveal a novel function of CNN1 in maintaining bone homeostasis by coupling bone formation to bone resorption.


Input: Optical imaging techniques for point-of-care diagnostics.


Input: Improving access to effective and affordable healthcare has long been a global endeavor.


Input: In this quest, the development of cost-effective and easy-to-use medical testing equipment that enables rapid and accurate diagnosis is essential to reduce the time and costs associated with healthcare services.


Input: To this end, point-of-care (POC) diagnostics plays a crucial role in healthcare delivery in both developed and developing countries by bringing medical testing to patients, or to sites near patients.


Input: As the diagnosis of a wide range of diseases, including various types of cancers and many endemics, relies on optical techniques, numerous compact and cost-effective optical imaging platforms have been developed in recent years for use at the POC.


Input: Here, we review the state-of-the-art optical imaging techniques that can have a significant impact on global health by facilitating effective and affordable POC diagnostics.


Input: Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome.


Input: The impact of glucocorticoids (GC) on skeletal development has not been established.


Input: The objective of this study was to examine changes in volumetric bone mineral density (vBMD) and cortical structure over 1 year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth.


Input: Fifty-six NS participants, aged 5 to 21 years, were enrolled a median of 4. 3 (0. 5 to 8. 1) years after diagnosis.


Input: Tibia peripheral quantitative computed tomography (pQCT) scans were obtained at enrollment and 6 and 12 months later.


Input: Sex, race, and age-specific Z-scores were generated for trabecular vBMD (TrabBMD-Z), cortical vBMD (CortBMD-Z), and cortical area (CortArea-Z) based on > 650 reference participants.


Input: CortArea-Z was further adjusted for tibia length-for-age Z-score.


Input: Quasi-least squares regression was used to identify determinants of changes in pQCT Z-scores.


Input: At enrollment, mean TrabBMD-Z (-0. 54 +/- 1. 32) was significantly lower (p = 0. 0001) and CortBMD-Z (0. 73 +/- 1. 16, p < 0. 0001) and CortArea-Z (0. 27 +/- 0. 91, p = 0. 03) significantly greater in NS versus reference participants, as previously described.


Input: Forty-eight (86%) participants were treated with GC over the study interval (median dose 0. 29 mg/kg/day).


Input: On average, TrabBMD-Z and CortBMD-Z did not change significantly over the study interval; however, CortArea-Z decreased (p = 0. 003).


Input: Greater GC dose (p < 0. 001), lesser increases in tibia length (p < 0. 001), and lesser increases in CortArea-Z (p = 0. 003) were independently associated with greater increases in CortBMD-Z.


Input: Greater increases in tibia length were associated with greater declines in CortArea-Z (p < 0. 01); this association was absent in reference participants (interaction p < 0. 02).


Input: In conclusion, GC therapy was associated with increases in CortBMD-Z, potentially related to suppressed bone formation and greater secondary mineralization.


Input: Conversely, greater growth and expansion of CortArea-Z (ie, new bone formation) were associated with declines in CortBMD-Z.


Input: Greater linear growth was associated with impaired expansion of cortical area in NS.


Input: Studies are needed to determine the fracture implications of these findings.


Input: Neuropeptide Y is a critical modulator of leptin' s regulation of cortical bone.


Input: Leptin signaling is required for normal bone homeostasis; however, loss of leptin results in differing effects on cortical and cancellous bone, as well as altered responses between the axial and appendicular regions.


Input: Local beta-adrenergic actions are responsible for the greater cancellous bone volume in leptin-deficient (ob/ob) mice; however, the mechanism responsible for the opposing reduction in cortical bone in ob/ob mice is not known.


Input: Here we show that blocking the leptin-deficient increase in neuropeptide Y (NPY) expression reverses the cortical bone loss in ob/ob mice.


Input: Mice null for both NPY and leptin (NPY (-/-) ob/ob), display greater cortical bone mass in both long-bones and vertebra, with NPY (-/-) ob/ob mice exhibiting thicker and denser cortical bone, associated with greater endocortical and periosteal mineral apposition rate (MAR), compared to ob/ob animals.


Input: Importantly, these cortical changes occurred without significant increases in body weight, with NPY (-/-) ob/ob mice showing significantly reduced adiposity compared to ob/ob controls, most likely due to the reduced respiratory exchange ratio seen in these animals.


Input: Interestingly, cancellous bone volume was not different between NPY (-/-) ob/ob and ob/ob, suggesting that NPY is not influencing the adrenergic axis.


Input: Taken together, this work demonstrates the critical role of NPY signaling in the regulation of bone and energy homeostasis, and more importantly, suggests that reduced leptin levels or leptin resistance, which occurs in obesity, could potentially inhibit cortical bone formation via increased central NPY signaling.


Input: Characterisation of acetylcholinesterase release from neuronal cells.


Input: Although acetylcholinesterase (AChE) is primarily a hydrolytic enzyme, metabolising the neurotransmitter acetylcholine in cholinergic synapses, it also has some non-catalytic functions in the brain which are far less well characterised.

acetylcholinesterase


Input: AChE was shown to be secreted or shed from the neuronal cell surface like several other membrane proteins, such as the amyloid precursor protein (APP).


Input: Since AChE does not possess a transmembrane domain, its anchorage in the membrane is established via the Proline Rich Membrane Anchor (PRiMA), a transmembrane protein.

Proline


Input: Both the subunit oligomerisation and membrane anchor of AChE are shared by a related enzyme, butyrylcholinesterase (BChE), the physiological function of which in the brain is unclear.


Input: In this work, we have assayed the relative activities of AChE and BChE in membrane fractions and culture medium of three different neuronal cell lines, namely the neuroblastoma cell lines SH-SY5Y and NB7 and the mouse basal forebrain cell line SN56.


Input: In an effort to understand the shedding process of AChE, we have used several pharmacological treatments, which showed that it is likely to be mediated in part by an EDTA-and batimastat-sensitive, but GM6001-insensitive metalloprotease, with the possible additional involvement of a thiol isomerase.

EDTA

batimastat

thiol


Input: Cellular release of AChE by SH-SY5Y is significantly enhanced by the muscarinic acetylcholine receptor (mAChR) agonists carbachol or muscarine, with the effect of carbachol blocked by the mAChR antagonist atropine.

acetylcholine

carbachol

muscarine

carbachol

atropine


Input: AChE has been implicated in the pathogenesis of Alzheimer' s disease and it has been shown that it accelerates formation and increases toxicity of amyloid fibrils, which have been closely linked to the pathology of AD.


Input: In light of this, greater understanding of AChE and BChE physiology may also benefit AD research.


Input: Cholinesterases in development: AChE as a firewall to inhibit cell proliferation and support differentiation.


Input: Acetylcholinesterase (AChE) is a most remarkable protein, not only because it is one of the fastest enzymes in nature, but also since it appears in many molecular forms and is regulated by elaborate genetic networks.


Input: AChE is expressed in many tissues during development and in mature organisms, as well as in healthy and diseased states.


Input: In search for alternative, " non-classical " functions of cholinesterases (ChEs), AChE could either work within the frame of classic cholinergic systems, but in non-neural tissues (" non-synaptic function "), or act non-enzymatically.


Input: Here, we review briefly some of the major ideas and advances of this field, and report on some recent progress from our own experimental work, e. g. that (i) non-neural ChEs have pronounced, predominantly enzymatic effects on early embryonic (limb) development in chick and mouse, that (ii) retinal R28 cells of the rat overexpressing synaptic AChE present a significantly decreased cell proliferation, and that (iii) in developing chick retina ACh-synthesizing and ACh-degrading cells originate from the same postmitotic precursor cells, which later form two locally opposing cell populations.

AChE

ACh


Input: We suggest that such distinct distributions of ChAT (+) vs. AChE (+) cells in the inner half retina provide graded distributions of ACh, which can direct cell differentiation and network formation.

AChE


Input: Thus, as corroborated by works from many labs, AChE can be considered a highly co-opting protein, which can combine enzymatic and non-enzymatic functions within one molecule.


Input: Nanoengineered colloidal probes for Raman-based detection of biomolecules inside living cells.


Input: Gold nanoparticle aggregate carbon nanotube functionalized colloidal particles serve as an efficient platform for probing the intracellular environment.

carbon


Input: The probes provide the means of effective localization of signal and detection of molecular fingerprints of biomolecules in living cells.


Input: The approach demonstrated in this work opens significant opportunities in molecular imaging as well as intracellular sensing and trafficking.


Input: Sex and dose-dependent effects of developmental exposure to bisphenol A on anxiety and spatial learning in deer mice (Peromyscus maniculatus bairdii) offspring.

bisphenol A


Input: Bisphenol A (BPA) is a widely produced, endocrine disrupting compound that is pervasive in the environment.

Bisphenol A

BPA


Input: Data suggest that developmental exposure to BPA during sexual differentiation of the brain leads to later behavioral consequences in offspring.

BPA


Input: Outbred deer mice (Peromyscus maniculatus bairdii) are an excellent animal model for such studies as they exhibit well-defined sex-and steroid-dependent behaviors.

steroid


Input: Here, dams during gestation and lactation were fed with a phytoestrogen-free control diet, the same diet supplemented with either ethinyl estradiol (0. 1 ppb), or one of the three doses of BPA (50 mg, 5 mg, 50 mu g/kg feed weight).

ethinyl estradiol

BPA


Input: After weaning, the pups were maintained on control diet until they reached sexual maturity and then assessed for both spatial learning capabilities and anxiety-like and exploratory behaviors.


Input: Relative to controls, males exposed to the two upper but not the lowest dose of BPA demonstrated similar impairments in spatial learning, increased anxiety and reduced exploratory behaviors as ethinyl estradiol-exposed males, while females exposed to ethinyl estradiol, but not to BPA, consistently exhibited masculinized spatial abilities.

BPA

ethinyl estradiol

ethinyl estradiol

BPA


Input: We also determined whether dams maintained chronically on the upper dose of BPA contained environmentally relevant concentrations of BPA in their blood.

BPA

BPA


Input: While serum concentrations of unconjugated BPA in controls were below the minimum level of detection, those from dams on the BPA diet were comparable (5. 48 +/- 2. 07 ng/ml) to concentrations that have been observed in humans.

BPA

BPA


Input: Together, these studies demonstrate that developmental exposure to environmentally relevant concentrations of BPA can disrupt adult behaviors in a dose-and sex-dependent manner.

BPA


Input: Self-propelled nanojets via template electrodeposition.


Input: In this paper, we present a rapid, high-yield, low-end and low-cost fabrication of nanojet motors using a template directed electrochemical deposition method.


Input: Using an electrochemical deposition method, the bubble-ejecting nanojets were grown within the alumina template, which is commercially available.

alumina


Input: These fabricated nanosized devices have typical dimensions of 300 nm (diameter) by 4. 5 mu m (length), and they are able to move in a hydrogen peroxide fuel solution with velocities up to approximately 40 body lengths per second.

hydrogen peroxide


Input: They are also capable of exhibiting various modes of movement such as straight, screw-like and circular motions, in a similar manner comparable to larger micro-sized jets.


Input: In addition, due to their small dimensions, the movements of these nanojets can be strongly influenced by colliding them with microbubbles.


Input: This highly parallel method which is of low-cost and requires the usage of low-end equipment that can be easily located in any laboratory opens up the doors for world-wide nanojet fabrication in the near future.


Input: Endocrine disruptors fludioxonil and fenhexamid stimulate miR-21 expression in breast cancer cells.

fludioxonil

fenhexamid


Input: Fenhexamid and fludioxonil are antifungal agents used in agricultural applications, which are present at measurable amounts in fruits and vegetables.

Fenhexamid

fludioxonil


Input: Fenhexamid and fludioxonil showed endocrine disruptor activity as antiandrogens in an androgen receptor reporter assay in engineered human breast cancer cells.

Fenhexamid

fludioxonil


Input: Little is known about how environmental chemicals regulate microRNA (miRNA) expression.


Input: This study examined the effect of fenhexamid and fludioxonil on the expression of the oncomiR miR-21 in MCF-7, T47D, and MDA-MB-231 human breast cancer cells and downstream targets of miR-21 in MCF-7 cells.

fenhexamid

fludioxonil


Input: Fenhexamid and fludioxonil stimulated miR-21 expression in a concentration-dependent manner and reduced the expression of miR-21 target Pdcd4 protein.

Fenhexamid

fludioxonil


Input: Antisense to miR-21 blocked the increase in Pdcd4 protein by fenhexamid and fludioxonil.

fenhexamid

fludioxonil


Input: Fenhexamid and fludioxonil reduced miR-125b and miR-181a, demonstrating specificity of miRNA regulation.

Fenhexamid

fludioxonil


Input: Induction of miR-21 was inhibited by the estrogen receptor antagonist fulvestrant, by androgen receptor antagonist bicalutamide, by actinomycin D and cycloheximide, and by inhibitors of the mitogen-activated protein kinases and phosphoinositide 3-kinase pathways.

estrogen

fulvestrant

androgen

bicalutamide

actinomycin D

cycloheximide

phosphoinositide


Input: Fenhexamid activation was inhibited by the arylhydrocarbon receptor antagonist alpha-napthoflavone.

Fenhexamid

arylhydrocarbon

alpha-napthoflavone


Input: Fenhexamid and fludioxonil did not affect dihydrotestosterone-induced miR-21 expression.

Fenhexamid

fludioxonil

dihydrotestosterone


Input: Fludioxonil, but not fenhexamid, inhibited MCF-7 cell viability, and both inhibited estradiol-induced cell proliferation and reduced cell motility.

Fludioxonil

fenhexamid

estradiol


Input: Together these data indicate that fenhexamid and fludioxonil use similar and distinct mechanisms to increase miR-21 expression with downstream antiestrogenic activity.

fenhexamid

fludioxonil


Input: Benzo [a] pyrene-induced transcriptomic responses in primary hepatocytes and in vivo liver: toxicokinetics is essential for in vivo-in vitro comparisons.

Benzo [a] pyrene


Input: The traditional 2-year cancer bioassay needs replacement by more cost-effective and predictive tests.


Input: The use of toxicogenomics in an in vitro system may provide a more high-throughput method to investigate early alterations induced by carcinogens.


Input: Recently, the differential gene expression response in wild-type and cancer-prone Xpa (-/-) p53 (+/-) primary mouse hepatocytes after exposure to benzo [a] pyrene (B [a] P) revealed downregulation of cancer-related pathways in Xpa (-/-) p53 (+/-) hepatocytes only.

benzo [a] pyrene

B [a] P


Input: Here, we investigated pathway regulation upon in vivo B [a] P exposure of wild-type and Xpa (-/-) p53 (+/-) mice.

B [a] P


Input: In vivo transcriptomics analysis revealed a limited gene expression response in mouse livers, but with a significant induction of DNA replication and apoptotic/anti-apoptotic cellular responses in Xpa (-/-) p53 (+/-) livers only.


Input: In order to be able to make a meaningful in vivo-in vitro comparison we estimated internal in vivo B [a] P concentrations using DNA adduct levels and physiologically based kinetic modeling.

B [a] P


Input: Based on these results, the in vitro concentration that corresponded best with the internal in vivo dose was chosen.


Input: Comparison of in vivo and in vitro data demonstrated similarities in transcriptomics response: xenobiotic metabolism, lipid metabolism and oxidative stress.


Input: However, we were unable to detect cancer-related pathways in either wild-type or Xpa (-/-) p53 (+/-) exposed livers, which were previously found to be induced by B [a] P in Xpa (-/-) p53 (+/-) primary hepatocytes.

B [a] P


Input: In conclusion, we showed parallels in gene expression responses between livers and primary hepatocytes upon exposure to equivalent concentrations of B [a] P.

B [a] P


Input: Furthermore, we recommend considering toxicokinetics when modeling a complex in vivo endpoint with in vitro models.


Input: Environmentally relevant concentrations of a common insecticide increase predation risk in a freshwater gastropod.


Input: Ecological receptors are faced with a multitude of stressors that include abiotic and biotic factors creating a challenge for assessing risk of chemical exposure.


Input: Of particular interest and importance are the effects of contaminants on inter-species interactions such as competition and predator-prey relationships.


Input: The objective of this study was to determine whether environmentally relevant concentrations of the commonly used insecticide, malathion, would alter predator avoidance behavior in a freshwater gastropod that could translate to increased predation risk.

malathion


Input: We exposed adult Physa pomilia snails to 0, 0. 25, or 1. 0 mg/L malathion for 2, 24, or 48 h and evaluated predator avoidance using a behavioral assay in which snails were exposed to cues from predatory crayfish.

malathion


Input: We found a significant reduction in predator avoidance in snails exposed to both concentrations of malathion after 48 h of exposure.

malathion


Input: To evaluate whether observed effects of malathion on predator avoidance actually increased susceptibility of snails to predators, we conducted a predator challenge experiment.

malathion


Input: Snails exposed to 0. 25 mg/L malathion for 48 h were significantly more susceptible to predation.

malathion


Input: That increased predation risk was evident 48 h after initial malathion exposures is a unique result because most studies have evaluated behavioral responses soon after (< 12 h) initiation of pesticide exposure.

malathion


Input: The extent to which the observed interactions affect natural populations, and the mechanisms through which they are mediated are largely unexplored.


Input: However, our study is the first to show that a commonly used insecticide decreases predator avoidance and may actually increase predation susceptibility in gastropods at concentrations several orders of magnitude below acute toxicity levels.


Input: Contamination by metals and pharmaceuticals in northern Taihu Lake (China) and its relation to integrated biomarker response in fish.


Input: Taihu Lake is the largest shallow freshwater lake in eastern China and is suffering not only from an increasingly serious threat of eutrophication but also potential ecological risk due to the input of emerging contaminants.


Input: Active biomonitoring was conducted in Taihu Lake using transplanted goldfish (Carassius auratus) to determine the contamination by pharmaceuticals and metals and to assess the potential ecological risk.


Input: A suite of biomarkers including acetylcholinesterase, ethoxyresorufin O-deethylase, glutathione S-transferase, glutathione peroxidase and superoxide dismutase activities in fish after 7, 14, 21 and 28 days of exposure in situ, as well as pharmaceuticals and metals in water, were determined during the field exposure period.

ethoxyresorufin O

glutathione S

glutathione

superoxide


Input: The results indicate that pharmaceuticals exist mainly in Zhushan Bay and Meiliang Bay, while metals are present mainly in Gong Bay.


Input: An integrated biomarker response (IBR) was calculated and used to evaluate the ecological risk of the polluted area of Taihu Lake.


Input: It was found that Zhushan Bay might present higher risk to fish, followed by Meiliang Bay.


Input: IBR values were in good agreement with copper and caffeine concentrations.

copper

caffeine


Input: New markers of apoptosis in children on chronic dialysis.


Input: Enhanced apoptosis is characteristic for chronic kidney disease (CKD).


Input: A specific type of apoptosis, anoikis, is connected with the extracellular matrix turnover and cell detachment.


Input: Although E-cadherin, extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP)-8 may play an important role in this process, they have not been analyzed in any nephrological aspect, either in CKD.


Input: The aim of study was to evaluate the serum concentrations of E-cadherin, EMMPRIN and their potential regulators (MMP-8, MMP-7, TIMP-1, TIMP-2), with relevance to apoptosis/cell damage markers (sFas, sFasL, Hsp27), in children with CKD.


Input: 39 CKD children stages 3-4, 26 CKD children stage 5 still on conservative treatment, 19 patients on hemodialysis (HD), 22 children on automated peritoneal dialysis (APD) and 30 controls were examined.


Input: Serum concentrations of those parameters were assessed by ELISA.


Input: Median E-cadherin, EMMPRIN and MMP-8 values were significantly increased in patients on dialysis versus those in pre-dialysis period and versus controls.


Input: The highest values were noticed in the HD subjects.


Input: Regression analysis revealed that EMMPRIN and MMP-8 predicted various apoptosis markers, whereas E-cadherin turned out the best predictor of both apoptosis (Hsp27, sFas, sFasL) and matrix turnover (MMP-7, TIMP-1, TIMP-2) indexes in dialyzed patients.


Input: Children with CKD are prone to E-cadherin, EMMPRIN and MMP-8 elevation, aggravated by the dialysis commencement and most evident on hemodialysis.


Input: Correlations between parameters suggest their role as indexes of apoptosis in children on dialysis.


Input: E-cadherin seems the most accurate marker of anoikis in this population.


Input: Regulation of hepatic phase II metabolism in pregnant mice.


Input: Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo-and xenobiotics.


Input: In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30.


Input: Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams.


Input: Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice.

bisphenol A


Input: Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed.


Input: Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions.

acetaminophen


Input: Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPAR alpha, and PXR and their target genes were downregulated, whereas ER alpha mRNA was upregulated.


Input: Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPAR alpha, PXR, and ER alpha signaling pathways may be candidate signaling pathways responsible for these changes.


Input: Dendritic arbor of neurons in the hypothalamic ventromedial nucleus in female prairie voles (Microtus ochrogaster).


Input: Female mating behavior in rats is associated with hormone-induced changes in the dendritic arbor of neurons in the ventromedial nucleus of the hypothalamus (VMH), particularly the ventrolateral portion.


Input: Regulation of mating behavior in female prairie voles differs substantially from that in rats; therefore, we examined the dendritic morphology of VMH neurons in this species.


Input: Sexually na i ve adult female prairie voles were housed with a male to activate the females' reproductive endocrine system.


Input: Following 48 h of cohabitation, females were tested for evidence of reproductive activation by assessing the level of male sexual interest, after which their brains were processed using Golgi impregnation, which allowed ventrolateral VMH neurons to be visualized and analyzed.


Input: Dendritic arborization in the female prairie vole VMH neurons was strikingly similar to that of female rats.


Input: The key difference was that in the prairie voles the long primary dendrites extended considerably further than those observed in rats.


Input: Although most female voles paired with males exhibited sexual activation, some females did not.


Input: These two groups displayed specific differences in their VMH dendrites.


Input: In particular, the long primary dendrites were longer in the reproductively active females compared with those in the non-activated females.


Input: Overall, dendrite lengths were positively correlated with plasma estradiol levels in females exposed to males, but not in unpaired females.

estradiol


Input: Although causal relationships between the neuroendocrine events, dendrite length, and the outward, behavioral manifestation of reproductive activation cannot be determined from this study, these results suggest an association between ventrolateral VMH dendrite morphology and female mating behavior in prairie voles, akin to what has been observed in female rats.


Input: Hormesis: its impact on medicine and health.


Input: This article offers a broad assessment of the hormetic dose response and its relevance to biomedical researchers, physicians, the pharmaceutical industry, and public health scientists.


Input: This article contains a series of 61 questions followed by relatively brief but referenced responses that provides support for the conclusion that hormesis is a reproducible phenomenon, commonly observed, with a frequency far greater than other dose-response models such as the threshold and linear nonthreshold dose-response models.


Input: The article provides a detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how hormesis is currently being used within medicine and identifying how this concept could be further applied in the development of new therapeutic advances and in improved public health practices.


Input: APP independent and dependent effects on neurite outgrowth are modulated by the receptor associated protein (RAP).


Input: Amyloid precursor protein (APP) and its secreted form, sAPP, contribute to the development of neurons in hippocampus, a brain region critical for learning and memory.


Input: Full-length APP binds the low-density lipoprotein receptor-related protein (LRP), which stimulates APP endocytosis.


Input: LRP also contributes to neurite growth.


Input: Furthermore, the receptor associated protein (RAP) binds LRP in a manner that blocks APP-LRP interactions.


Input: To elucidate APP contributions to neurite growth for full-length APP and sAPP, we cultured wild type (WT) and APP knockout (KO) neurons in sAPP alpha and/or RAP and measured neurite outgrowth at 1 day in vitro.


Input: Our data reveal that WT neurons had less axonal outgrowth including less axon branching.


Input: RAP treatment potentiated the inhibitory effects of APP.


Input: KO neurons had significantly more outgrowth and branching, especially in response to RAP, effects which were also associated with ERK2 activation.


Input: Our results affirm a major inhibitory role by full-length APP on all aspects of axonal and dendritic outgrowth, and show that RAP-LRP binding stimulated axon growth independently of APP.


Input: These findings support a major role for APP as an inhibitor of neurite growth and reveal novel signaling functions for LRP that may be disrupted by Alzheimer' s pathology or therapies aimed at APP processing.


Input: Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design.

ether


Input: The human ether-a-go-go-related gene (hERG) is a K + channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death.

ether

K +


Input: In this present review, we have focused the physicochemical properties responsible for the hERG blocking activity of structurally different compounds.


Input: The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the hERG blocking activity along with topological and electronic properties.


Input: The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine carry the common molecular structure of O = C = N-C-C-C-N that possessed positive ionotropic effect and hERG blocking activity.

quinolizidine alkaloids

oxymatrine

sophoridine

sophocarpine

matrine

O = C = N-C-C-C-N


Input: Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial.

Acehytisine hydrochloride

Guangfu base A


Input: The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7. 419 MM).

isoquinoline alkaloid

neferine

Nef


Input: Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity.


Input: Recent research works revealed that Eag and hERG channels are expressed by a variety of cancer cell lines and tissues.


Input: The Eag channel showed an oncogenic potential while hERG channels are associated with more aggressive tumors and have a role in mediating invasion.


Input: This review concluded that the consideration of physicochemical properties necessary for the hERG blocking activity will guide to develop novel drugs with less cardiotoxicity.


Input: In vitro synergistic interaction between amide piplartine and antimicrobial peptide dermaseptin against Schistosoma mansoni schistosomula and adult worms.

amide piplartine


Input: Schistosomiasis is one of the world' s major public health problems, and praziquantel is the only available drug to treat this notable neglected disease.

praziquantel


Input: Drug combinations have been considered an important strategy for treatment of infectious diseases, which might enhance therapeutic efficacy and delaying resistance.


Input: In this study, we have examined the in vitro activities of the amide piplartine and the antimicrobial peptide dermaseptin 01 administered singly or in combination against Schistosoma mansoni of different ages including 3-hour-old and 7-day-old schistosomula and 49-day-old adult schistosomes as well as on egg output by adult worms.

amide piplartine


Input: We calculated the median lethal concentrations (LC (50)) of 7. 87 and 17. 99 mu M on 49-day-old adults, 11. 02 and 71. 58 mu M on 7-day-old schistosomula, and 70. 87 and 98. 42 mu M on 3-hour-old schistosomula for piplartine and dermaseptin, respectively.

piplartine


Input: Most Piplartine/dermaseptin combinations showed synergistic effect, with combination index (CI) values less than 0. 9 when S. mansoni adults or schistosomula were simultaneously incubated with both drugs in vitro; synergy between these two compounds was also indicated using isobolograms.

Piplartine


Input: Additionally, we observed alterations on the tegumental surface of schistosomula and adult schistosomes by means of laser scanning confocal microscopy.


Input: Furthermore, egg laying of surviving worms was considerably more reduced when exposed to the piplartine/dermaseptin combinations than each drug alone, and this inhibition was irreversible.

piplartine


Input: This is the first report on the synergistic effect between piplartine and dermaseptin against S. mansoni and opens the route to further studies (e. g. in vivo) to characterize this combination in greater detail.

piplartine


Input: Physiological effects of waterborne lead exposure in spiny dogfish (Squalus acanthias).


Input: To broaden our knowledge about the toxicity of metals in marine elasmobranchs, cannulated spiny dogfish (Squalus acanthias) were exposed to 20 mu M and 100 mu M lead (Pb).

Pb


Input: Since we wanted to focus on sub lethal ion-osmoregulatory and respiratory disturbances, arterial blood samples were analysed for pH (a), PaO (2), haematocrit and total CO (2) values at several time points.

CO (2)


Input: Plasma was used to determine urea, TMAO, lactate and ion concentrations.

urea

TMAO

lactate


Input: After 96 h, Pb concentrations were determined in a number of tissues, such as gill, rectal gland, skin and liver.

Pb


Input: To further investigate ion and osmoregulation, Na (+)/K (+)-ATPase activities in gill and rectal gland were analysed as well as rates of ammonia and urea excretion.

Na (+)

K (+)

ammonia

urea


Input: Additionally, we studied the energy reserves in muscle and liver.


Input: Pb strongly accumulated in gills and especially in skin.

Pb


Input: Lower accumulation rates occurred in gut, kidney and rectal gland.


Input: A clear disturbance in acid-base status was observed after one day of exposure indicating a transient period of hyperventilation.


Input: The increase in pH (a) was temporary at 20 mu M, but persisted at 100 mu M.


Input: After 2 days, plasma Na and Cl concentrations were reduced compared to controls at 100 mu M Pb and urea excretion rates were elevated.

Cl

Pb

urea


Input: Pb caused impaired Na (+)/K (+)-ATPase activity in gills, but not in rectal gland.

Pb

Na (+)

K (+)


Input: We conclude that spiny dogfish experienced relatively low ion-osmoregulatory and respiratory distress when exposed to lead, particularly when compared to effects of other metals such as silver.

silver


Input: These elasmobranchs appear to be able to minimize the disturbance and maintain physiological homeostasis during an acute Pb exposure.

Pb


Input: An omics based assessment of cadmium toxicity in the green alga Chlamydomonas reinhardtii.

cadmium


Input: The effects of cadmium were assessed in the freshwater alga Chlamydomonas reinhardtii.

cadmium


Input: Algae were exposed to concentrations of 0, 8. 1 or 114. 8 mu M of cadmium and growth rates, gene transcription and metabolite profiles were examined after 48 and 72 h of exposure.

cadmium


Input: In algae exposed to 8. 1 mu M Cd, several genes were differentially transcribed after 48 h but no adverse growth related effects were detected.

Cd


Input: A transient effect on both gene transcription patterns and metabolite profiles could be discerned after 48 h of exposure but the majority of these changes disappeared after 72 h.


Input: In contrast, all effects were more pronounced at the 114. 8 mu M cadmium exposure.

cadmium


Input: Here growth was clearly reduced and transcription of a large number of genes involved in oxidative stress defense mechanisms was differentially increased.


Input: Metabolites involved in the glutathione synthesis pathway (an important antioxidant defense) were also affected but the effects of cadmium were found to be more pronounced at the transcript level than in the metabolome, suggesting that the former exhibits greater sensitivity toward cadmium exposure.

glutathione

cadmium

cadmium


Input: Establishment of a robust hepatitis C virus replicon cell line over-expressing P-glycoprotein that facilitates analysis of P-gp drug transporter effects on inhibitor antiviral activity.


Input: P-glycoprotein (P-gp) is an active efflux pump affecting the pharmacokinetic (PK) profiles of drugs that are P-gp substrates.


Input: The Caco-2 bi-directional assay is widely used to identify drug-P-gp interactions in vitro.


Input: For molecules exhibiting non-classical drug properties however, ambiguous results limit its use in lead optimization.


Input: The goal of this study was to develop a robust cell-based assay system to directly measure the role of P-gp-driven efflux in reducing the potency of hepatitis C virus (HCV) replication inhibitors.


Input: Vinblastine (Vin) was employed to select for a Vin-resistant HCV replicon (313-11) from the parental cell line (377-2).

Vinblastine

Vin

Vin


Input: The 313-11 cell line was > 50-fold resistant to Vin and over-expressed P-gp, as determined by Western immunoblots.

Vin


Input: Increased expression of P-gp was mediated by up-regulation of the MDR1 transcript.


Input: The reduced potency of different classes of HCV replication inhibitors in the 313-11 P-gp cell line was restored in the presence of known P-gp inhibitors.


Input: Addition of the P-gp inhibitor, tariquidar, increased the uptake of a radiolabeled HCV replication inhibitor by 14-fold in the 313-11 replicon cell line.

tariquidar


Input: Finally, a positive correlation was demonstrated between potency in the 313-11 replicon and the bi-directional Caco-2 efflux ratio for a panel of HCV protease inhibitors.


Input: In conclusion, a robust P-gp HCV replicon cell-based assay has been developed to measure the effect of the P-gp efflux pump on the potency of different classes of HCV replication inhibitors.


Input: This system establishes a direct correlation between antiviral activity and the effect of P-gp efflux in a single cell line.


Input: Multifunctional targets of dietary polyphenols in disease: a case for the chemokine network and energy metabolism.

polyphenols


Input: Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms.


Input: The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism.


Input: The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease.

AMP


Input: Several effects of polyphenols are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators.

polyphenols


Input: Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating.


Input: If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements.


Input: We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy.


Input: Hence, improvement in food through enrichment with polyphenols with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value.

polyphenols


Input: Emerging Fusarium mycotoxins in organic and conventional pasta collected in Spain.


Input: One of the main sources of emerging Fusarium mycotoxins in human nutrition is the cereals and cereal products.


Input: In this study, an analytical method to determine enniatins A, A1, B and B1 (ENs), beauvericin (BEA) and fusaproliferin (FUS) based on Ultra-Turrax extraction followed by liquid chromatography coupled to triple quadrupole mass spectrometer detector (MS/MS QqQ), was applied for the analysis of pasta.

enniatins A, A1, B and B1

beauvericin

BEA

fusaproliferin

FUS


Input: For this purpose, 114 commercial samples of pasta were acquired from supermarkets located in Valencia.


Input: The results showed higher frequencies of contamination in organic pasta than in conventional pasta, while the concentration levels were variable for both types of pasta.


Input: In positive samples, BEA levels varied from 0. 10 to 20. 96 mu g/kg and FUS levels varied from 0. 05 to 8. 02 mu g/kg.

BEA

FUS


Input: ENs levels ranged from 0. 25 to 979. 56 mu g/kg, though the majority of the values were below 25 mu g/kg.


Input: Besides, it was observed the simultaneous presence of two or more mycotoxins in a high percentage of the samples.


Input: Finally, an evaluation of the dietary exposure of the emerging Fusarium mycotoxins was performed in the Spanish population.


Input: The prevalence of ENs, BEA and FUS in cereal products suggests that the toxins may pose a health risk to Spanish population.

BEA

FUS


Input: Structure-based design and synthesis of novel pseudosaccharine derivatives as antiproliferative agents and kinase inhibitors.

pseudosaccharine


Input: This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity.

pseudosaccharine


Input: This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases.

quinazoline


Input: Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels.


Input: Compound 9b displayed broad spectrum antiproliferative activity on NCI 60-cell lines panel with mean GI50 of 5. 4 mu M.


Input: Investigation of the molecular mechanism showed probable inhibitory activity against Src kinase.


Input: Giant cell tumor of bone: a basic science perspective.


Input: Comprehending the pathogenesis of giant cell tumor of bone (GCT) is of critical importance for developing novel targeted treatments for this locally-aggressive primary bone tumor.


Input: GCT is characterized by the presence of large multinucleated osteoclast-like giant cells distributed amongst mononuclear spindle-like stromal cells and other monocytes.


Input: The giant cells are principally responsible for the extensive bone resorption by the tumor.


Input: However, the spindle-like stromal cells chiefly direct the pathology of the tumor by recruiting monocytes and promoting their fusion into giant cells.


Input: The stromal cells also enhance the resorptive ability of the giant cells.


Input: This review encompasses many of the attributes of GCT, including the process of giant cell formation and the mechanisms of bone resorption.


Input: The significance of the receptor activator of nuclear factor-kappa B ligand (RANKL) in the development of GCT and the importance of proteases, including numerous matrix metalloproteinases, are highlighted.


Input: The mesenchymal lineage of the stromal cells and the origin of the hematopoietic monocytes are also discussed.


Input: Several aspects of GCT that require further understanding, including the etiology of the tumor, the mechanisms of metastases, and the development of an appropriate animal model, are also considered.


Input: By exploring the current status of GCT research, this review accentuates the significant progress made in understanding the biology of the tumor, and discusses important areas for future investigation.


Input: NCTC 2544 and IL-18 production: a tool for the identification of contact allergens.


Input: Progress in understanding the mechanisms of skin sensitization, provides us with the opportunity to develop in vitro tests as an alternative to in vivo sensitization testing.


Input: Keratinocytes play a key role in all phases of skin sensitization.


Input: We have recently identified interleukin-18 (IL-18) production in keratinocyte as a potentially useful endpoint for determination of contact sensitization potential of low molecular weight chemicals.


Input: The aim of the present article is to further exploit the performance of the NCTC 2544 assay.


Input: NCTC 2544 is a commercially available skin epithelial-like cell line originating from normal human skin, which posses a good expression of cytochrome P450-dependent enzymatic activities.


Input: Cells were exposed to contact allergens (2-bromo-2-bromomethyl glutaronitrile, cinnamaldehyde, citral, diethylmaleate, dinitrochlorobenzene, glyoxal, 2-mercaptobenzothiazole, nickel sulfate, 4-nitrobenzylbromide, oxazolone, penicillin G, resorcinol, tetramethylthiuram disulfide), to pre-pro-haptens (cinnamyl alcohol, eugenol, isoeugenol, p-phenylediamine), to respiratory allergens (ammonium hexachloroplatinate, diphenylmethane diisocyanate, glutaraldehyde, hexamethylenediisocyanate, maleic anhydride, trimellitic anhydride) and to irritants (benzaldehyde, cholorobenzene, diethylphtalate, hydrobenzoic acid, lactic acid, octanoic acid, phenol, salicylic acid, sodium lauryl sulphate, sulfamic acid).

2-bromo-2-bromomethyl glutaronitrile

cinnamaldehyde

citral

diethylmaleate

dinitrochlorobenzene

glyoxal

nickel sulfate

oxazolone

penicillin G

resorcinol

tetramethylthiuram disulfide

cinnamyl alcohol

eugenol

isoeugenol

p-phenylediamine

ammonium hexachloroplatinate

diphenylmethane diisocyanate

glutaraldehyde

hexamethylenediisocyanate

maleic anhydride

trimellitic anhydride

benzaldehyde

cholorobenzene

diethylphtalate

hydrobenzoic acid

lactic acid

octanoic acid

phenol

salicylic acid

sodium lauryl sulphate

sulfamic acid


Input: Cell associated IL-18 was evaluated 24 later by ELISA.


Input: At not-cytotoxic concentrations (cell viability higher of 80%, as assessed by MTT reduction assay), all contact sensitizers, including pre-pro-haptens, induced a dose-related increase in IL-18, whereas both irritants, with the exception of sulfamic acid, and respiratory allergens failed.

MTT

sulfamic acid


Input: A total of 33 chemicals were tested, with an overall accuracy of 97%.


Input: Overall, results obtained indicated that cell-associated IL-18 might provide an in vitro tool for identification and discrimination of contact vs. respiratory allergens and/or irritants.


Input: Application of the acquired knowledge and implementation of the Sens-it-iv toolbox for identification and classification of skin and respiratory sensitizers.


Input: The contribution of the Sens-it-iv project to the reduction and replacement of animal experimentation is 3-fold.


Input: The funding of basic research has expanded the existing scientific knowledge thereby strengthening the understanding of the cellular and molecular mechanisms driving skin and respiratory sensitization.


Input: Examples are given on how a better understanding was used to improve existing test concepts.


Input: This knowledge was also applied to develop novel test systems.


Input: While some of test systems did not reach sufficient maturity for being considered for pre-validation others did and entered into the Sens-it-iv toolbox.


Input: In the process, developments outside the Sens-it-iv orbit were carefully followed and assessed in order to avoid duplication and to assure synergy between the ongoing activities (e. g. Cosmetics Europe Task Force for Sensitization).


Input: Tests from the Sens-it-iv toolbox were submitted to the European Reference Laboratory for Alternative Methods (EuRL-ECVAM) to initiate the rigid procedures for regulatory acceptance by national and international authorities.


Input: In spite of not being validated yet, selected tests were already applied in a weight-of-evidence approach in the context of REACH.


Input: Furthermore, several chemical, pharmaceutical, cosmetic and consumer product companies are currently assessing selected tests and testing strategies for their value as tools for screening and hazard identification using in house compounds and mixtures.


Input: The main points of concern related to transfer to and implementation by industry were cost, through-put and applicability domain, rather than regulatory acceptance.


Input: These issues are currently addressed in applied research projects which are financially supported by individual companies, or consortia of companies, representing the various industry sectors.


Input: Assay of vtg, ERs and PPARs as endpoint for the rapid in vitro screening of the harmful effect of Di-(2-ethylhexyl)-phthalate (DEHP) and phthalic acid (PA) in zebrafish primary hepatocyte cultures.

DEHP

phthalic acid


Input: In the last years the concern about the negative effects of phthalates on reproduction significantly increased.

phthalates


Input: Considering that, at date data available dealing with the adverse outcome of Di-(2-ethylhexyl)-phthalate (DEHP) on the reproduction of several species are still contrasting, in this study, the effects induced by DEHP (0. 05, 0. 1, 1, 10 and 100 nM) and its active metabolite, phthalic acid (PA) (0. 01, 0. 1, 1 and 10 mu M), were analyzed in zebrafish, Danio rerio, primary hepatocyte cultures, using target molecules involved in fish reproduction (vitellogenin--vtg and estrogen receptors--ER alpha, beta 1 and beta 2) and metabolism (peroxisome proliferators activated receptors--PPAR alpha, beta, gamma).

DEHP

DEHP

phthalic acid

estrogen


Input: The use of in vitro culture, in fact, has the potential to significantly reduce the number of animals sacrificed for research allowing a precise control of the physical and chemical parameters that is often not possible in vivo.


Input: Moreover, since many toxicological studies revealed a sex specific response to toxicants, male and female primary hepatocyte cultures were set up to elucidate the possible gender specific effects of two common environmental phthalates.

phthalates


Input: The increase of vtg levels observed in the culture media of male or female hepatocytes strongly evidenced the phthalates E2-like action.

phthalates


Input: Moreover, the data obtained suggested that the observed different ERs isoforms modulation is otherwise associated with the vtg increase, depending on fish gender.


Input: Regarding PPARs, a similar trend of expression was found in both males and females.


Input: In conclusion, this study enforces the role of vtg as biomarker for evaluate the presence of environmental doses of DEHP and PA.

DEHP


Input: Considering the similar gender modulation observed for vtg and PPARs, these molecules could be used for the rapid screening of the presence of DEHP and PA.

DEHP


Input: Noteworthy the gender specific modulation observed for ERs opens a debate on the estrogenic mechanism of action of DEHP and PA and their role on vtg induction.

DEHP


Input: Inhibition of EGF/EGFR activation with naphtho [1, 2-b] furan-4, 5-dione blocks migration and invasion of MDA-MB-231 cells.

naphtho [1, 2-b] furan-4, 5-dione


Input: Naphtho [1, 2-b] furan-4, 5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity.

Naphtho [1, 2-b] furan-4, 5-dione

NFD


Input: Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma.


Input: We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion.

NFD


Input: NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity.

NFD


Input: NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt.

NFD

phosphatidylinositol


Input: The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion.

wortmannin


Input: Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation.


Input: These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression.

NFD


Input: These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells.

NFD


Input: The association of serum 25-hydroxyvitamin D and vertebral fractures in patients with type 2 diabetes.

25-hydroxyvitamin D


Input: Vitamin D is an important regulator of bone health.

Vitamin D


Input: Previous studies examining the association between vitamin D deficiency and osteoporotic fractures have reported conflicting results.

vitamin D


Input: The relationship between vitamin D status and risk of vertebral fractures in diabetic patients is unknown.

vitamin D


Input: The objective of this study was to examine whether low serum 25-hydroxyvitamin D [25 (OH) D] levels were associated with vertebral fractures in patients with type 2 diabetes.

25-hydroxyvitamin D

25 (OH) D


Input: This cross-sectional study was conducted among 161 postmenopausal women and 180 men with type 2 diabetes.


Input: Serum concentrations of 25 (OH) D were measured and the presence of vertebral fracture was assessed using lateral plain radiographs of the thoracolumbar spine.

25 (OH) D


Input: Women had lower 25 (OH) D levels than men (31. 3 +/- 17. 7 vs. 41. 3 +/- 26. 5 ng/mL, p < 0. 001).

25 (OH) D


Input: Vertebral fractures were found in 16% of patients.


Input: Men with a serum 25 (OH) D concentration greater than 30 ng/mL showed a lower prevalence of vertebral fractures compared to those with 20-29. 9 ng/mL or those with less than 20 ng/mL (9. 4% vs. 17. 9% vs. 21. 7%, p for trend = 0. 036).

25 (OH) D


Input: However, there was no significant association between vitamin D status and the prevalence of vertebral fractures in women (14. 4% vs. 19. 2% vs. 26. 6%, p for trend = 0. 111).

vitamin D


Input: After adjusting for multiple confounding factors, men with a serum 25 (OH) D concentration of less than 20 ng/mL were associated with an increased risk of vertebral fractures (OR 7. 87; 95% CI 1. 69-36. 71), but not women.

25 (OH) D


Input: In conclusion, serum 25 (OH) D levels below 20 ng/mL were associated with an increased vertebral fracture risk in men with type 2 diabetes.

25 (OH) D


Input: Chiral and chemical oscillations in a simple dimerization model.


Input: We consider the APED model (activation-polymerization-epimerization-depolymerization) for describing the emergence of chiral solutions within a non-catalytic framework for chiral polymerization.


Input: The minimal APED model for dimerization can lead to the spontaneous appearance of chiral oscillations and we describe in detail the nature of these oscillations in the enantiomeric excess, which are the consequence of oscillations of the concentrations of the associated chemical species.


Input: Ketamine-induced neuronal damage and altered N-methyl-D-aspartate receptor function in rat primary forebrain culture.

Ketamine

N-methyl-D-aspartate


Input: Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is frequently used in pediatric general anesthesia.

Ketamine

N-methyl-D-aspartate

NMDA


Input: Accumulating evidence from animal experiments has demonstrated that ketamine causes neuronal cell death during the brain growth spurt.

ketamine


Input: To elucidate the underlying mechanisms associated with ketamine-induced neuronal toxicity and search for approaches or agents to prevent ketamine' s adverse effects on the developing brain, a primary nerve cell culture system was utilized.

ketamine

ketamine


Input: Neurons harvested from the forebrain of newborn rats were maintained under normal control conditions or exposed to either ketamine (10 micro M) or ketamine plus L-carnitine (an antioxidant; 1-100 micro M) for 24h, followed by a 24-h withdrawal period.

ketamine

ketamine

L-carnitine


Input: Ketamine exposure resulted in elevated NMDA receptor (NR1) expression, increased generation of reactive oxygen species (ROS) as indicated by higher levels of 8-oxoguanine production, and enhanced neuronal damage.

Ketamine

NMDA

oxygen


Input: Coadministration of L-carnitine significantly diminished ROS generation and provided near complete protection of neurons from ketamine-induced cell death.

L-carnitine

ketamine


Input: NMDA receptors regulate channels that are highly permeable to calcium, and calcium imaging data demonstrated that neurons exposed to ketamine had a significantly elevated amplitude of calcium influx and higher intracellular free calcium concentrations ([Ca (2 +)] i) evoked by NMDA (50 micro M), compared with control neurons.

NMDA

calcium

calcium

ketamine

calcium

calcium

Ca (2 +)

NMDA


Input: These findings suggest that prolonged ketamine exposure produces an increase in NMDA receptor expression (compensatory upregulation), which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to elevated ROS generation and neuronal cell death.

ketamine

NMDA

calcium

ketamine


Input: L-Carnitine appears to be a promising agent in preventing or reversing ketamine' s toxic effects on neurons at an early developmental stage.

L-Carnitine

ketamine


Input: Resonance Raman spectral imaging of intracellular uptake of beta-carotene loaded poly (D, L-lactide-co-glycolide) nanoparticles.

beta-carotene

poly (D, L-lactide-co-glycolide)


Input: The use of nanoparticles for drug delivery has been drawing considerable attention in pharmaceutical research.


Input: With increasing diversity and potential of various carrier systems, it is important to study the impact of nanocarriers on sub-cellular metabolic processes and organelles, since the delivery of a drug usually involves intra-cellular internalization.


Input: Herein, we employ Raman microscopy as a non-invasive method for cellular and sub-cellular imaging, to monitor the uptake and translocation patterns of particles based on poly (D, L-lactide-co-glycolide) over time.

poly (D, L-lactide-co-glycolide)


Input: As the technique detects inherent signals from the molecules of interest, it does not rely on external labels or dyes, which is an advantage over fluorescence labeling.


Input: For this purpose, the particles were loaded with beta-carotene.

beta-carotene


Input: The conjugated pi-system of the molecule has a large Raman scattering cross-section and gives rise to resonance Raman effects, which can enhance the sensitivity by orders of magnitude.


Input: beta-Carotene as a provitamin is not soluble in water and is thus usually of low bioavailability, which is enhanced by encapsulation into the nanoparticles.

beta-Carotene


Input: Activation of group I metabotropic glutamate receptors potentiates heteromeric kainate receptors.

glutamate

kainate


Input: Kainate receptors (KARs), a family of ionotropic glutamate receptors, are widely expressed in the central nervous system and are critically involved in synaptic transmission.

Kainate

glutamate


Input: KAR activation is influenced by metabotropic glutamate receptor (mGlu) signaling, but the underlying mechanisms are not understood.

glutamate


Input: We undertook studies to examine how mGlu modulation affects activation of KARs.


Input: Confocal immunohistochemistry of rat hippocampus and cultured rat cortex revealed colocalization of the high-affinity KAR subunits with group I mGlu receptors.


Input: In hippocampal and cortical cultures, the calcium signal caused by activation of native KARs was potentiated by activation of group I mGlu receptors.

calcium


Input: In Xenopus laevis oocytes, activation of group I mGlu receptors potentiated heteromeric but not homomeric KAR-mediated currents, with no change in agonist potency.


Input: The potentiation of heteromeric KARs by mGlu1 activation was attenuated by GDP beta S, blocked by an inhibitor of phospholipase C or the calcium chelator 1, 2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid (BAPTA), prolonged by the phosphatase inhibitor okadaic acid, but unaffected by the tyrosine kinase inhibitor lavendustin A.

calcium

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

BAPTA

okadaic acid

tyrosine

lavendustin A


Input: Protein kinase C (PKC) inhibition reduced the potentiation by mGlu1 of GluK2/GluK5, and conversely, direct activation of PKC by phorbol 12-myristate, 13-acetate potentiated GluK2/GluK5.

phorbol 12-myristate, 13-acetate


Input: Using site-directed mutagenesis, we identified three serines (Ser833, Ser836, and Ser840) within the membrane proximal region of the GluK5 C-terminal domain that, in combination, are required for mGlu1-mediated potentiation of KARs.

serines

C


Input: Together, these data suggest that phosphorylation of key residues in the C-terminal domain changes the overall charge of this domain, resulting in potentiated agonist responses.

C


Input: beta-Adrenergic agonists mediate enhancement of beta 1-adrenergic receptor N-terminal cleavage and stabilization in vivo and in vitro.

N


Input: The beta (1)-adrenergic receptor (beta (1) AR) is the predominant beta AR in the heart and is the main target for beta-adrenergic antagonists, widely used in the treatment of cardiovascular diseases.


Input: Previously, we have shown that the human (h) beta (1) AR is cleaved in its N terminus by a metalloproteinase, both constitutively and in a receptor activation-dependent manner.

N


Input: In this study, we investigated the specific events involved in beta (1) AR regulation, focusing on the effects of long-term treatment with beta-adrenergic ligands on receptor processing in stably transfected human embryonic kidney 293 (i) cells.


Input: The key findings were verified using the transiently transfected h beta (1) AR and the endogenously expressed receptor in neonatal rat cardiomyocytes.


Input: By using flow cytometry and Western blotting, we demonstrated that isoproterenol, S-propranolol, CGP-12177 [4-[3-[(1, 1-dimethylethyl) amino] 2-hydroxypropoxy]-1, 3-dihydro-2H-benzimidazol-2-one], pindolol, and timolol, which displayed agonistic properties toward the beta (1) AR in either the adenylyl cyclase or the mitogen-activated protein kinase signaling pathways, induced cleavage of the mature cell-surface receptor.

isoproterenol

S-propranolol

4-[3-[(1, 1-dimethylethyl) amino] 2-hydroxypropoxy]-1, 3-dihydro-2H-benzimidazol-2-one

pindolol

timolol

adenylyl


Input: In contrast, metoprolol, bisoprolol, and CGP-20712 [1-[2-((3-carbamoyl-4-hydroxy) phenoxy) ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-2-propanol], which showed no agonistic activity, had only a marginal or no effect.

metoprolol

bisoprolol

1-[2-((3-carbamoyl-4-hydroxy) phenoxy) ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl) phenoxy]-2-propanol


Input: Importantly, the agonists also stabilized intracellular receptor precursors, possibly via their pharmacological chaperone action, and they stabilized the receptor in vitro.


Input: The opposing effects on the two receptor forms thus led to an increase in the amount of cleaved receptor fragments at the plasma membrane.


Input: The results underscore the pluridimensionality of beta-adrenergic ligands and extend this property from receptor activation and signaling to the regulation of beta (1) AR levels.


Input: This phenomenon may contribute to the exceptional resistance of beta (1) ARs to downregulation and tendency toward upregulation following long-term ligand treatments.


Input: The biarylpyrazole compound AM251 alters mitochondrial physiology via proteolytic degradation of ERR alpha.

biarylpyrazole


Input: The orphan nuclear receptor estrogen-related receptor alpha (ERR alpha) directs the transcription of nuclear genes involved in energy homeostasis control and the regulation of mitochondrial mass and function.

estrogen


Input: A crucial role for controlling ERR alpha-mediated target gene expression has been ascribed to the biarylpyrazole compound 1-(2, 4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) through direct binding to and destabilization of ERR alpha protein.

biarylpyrazole

1-(2, 4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide


Input: Here, we provide evidence that structurally related AM251 analogs also have negative impacts on ERR alpha protein levels in a cell-type-dependent manner while having no deleterious actions on ERR gamma.


Input: We show that these off-target cellular effects of AM251 are mediated by proteasomal degradation of nuclear ERR alpha.


Input: Cell treatment with the nuclear export inhibitor leptomycin B did not prevent AM251-induced destabilization of ERR alpha protein, whereas proteasome inhibition with MG132 stabilized and maintained its DNA-binding function, indicative of ERR alpha being a target of nuclear proteasomal complexes.

leptomycin B


Input: NativePAGE analysis revealed that ERR alpha formed a ~ 220-kDa multiprotein nuclear complex that was devoid of ERR gamma and the coregulator peroxisome proliferator-activated receptor gamma coactivator-1.


Input: AM251 induced SUMO-2, 3 incorporation in ERR alpha in conjunction with increased protein kinase C activity, whose activation by phorbol ester also promoted ERR alpha protein loss.

phorbol ester


Input: Down-regulation of ERR alpha by AM251 or small interfering RNA led to increased mitochondria biogenesis while negatively impacting mitochondrial membrane potential.


Input: These results reveal a novel molecular mechanism by which AM251 and related compounds alter mitochondrial physiology through destabilization of ERR alpha.


Input: Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells.

Metformin

AMP


Input: The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals.

Metformin


Input: Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin.

Metformin


Input: To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined.

Metformin

Metformin

adenosine monophosphate


Input: Metformin significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C.

Metformin

compound C


Input: Furthermore, the AMPK activator 5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion.

5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide

AICAR


Input: Additionally, ghrelin cells were shown to express AMPK.


Input: Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) AMPK.

Metformin


Input: Our results show that Metformin directly inhibits stomach ghrelin production and secretion through AMPK.

Metformin


Input: This reduction in ghrelin secretion may be one of the key components in Metformin' s mechanism of weight loss.

Metformin


Input: A hybrid method employing breakdown anodization and electrophoretic deposition for superhydrophilic surfaces.


Input: A fabrication method is developed for superhydrophilic surfaces with high capillary pressure and fast spreading speed.


Input: The fabrication method consists of electrophoretic deposition (EPD) and breakdown anodization (BDA).


Input: Nanopores and micropores were produced on titanium plates by EPD and BDA, respectively.

titanium


Input: In EPD, TiO (2) nanoparticles were used to enhance the surface energy and create nanoporous structures, while BDA was employed to produce microporous structures.

TiO (2)


Input: Capillary rise measurements (CRM) were utilized to characterize superhydrophilic surfaces in terms of capillary pressure and spreading speed.


Input: From CRM, it was revealed that microporous structures play a dominant role in determining transport properties, and nanoporous structures affect local wettability without significantly reducing spreading speed.


Input: By combining BDA and EPD into a hybrid method, dual-scale (nano and micro) porous structures were produced on titanium plates.

titanium


Input: The methods presented offer the potential to vary the transport characteristics of superhydrophilic surfaces by altering the nanoscale and microscale features independently.


Input: As an example, surfaces with unconventional capillary flows were produced by the hybrid method.


Input: This method provides additional opportunities to investigate wetting phenomena while offering a potentially low cost process for industrial applications.


Input: Genetic approaches in Drosophila for the study neurodevelopmental disorders.


Input: The fruit fly Drosophila melanogaster is one of the premier genetic model organisms used in biomedical research today owing to the extraordinary power of its genetic tool-kit.


Input: Made famous by numerous seminal discoveries of basic developmental mechanisms and behavioral genetics, the power of fruit fly genetics is becoming increasingly applied to questions directly relevant to human health.


Input: In this review we discuss how Drosophila research is applied to address major questions in neurodevelopmental disorders.


Input: This article is part of the Special Issue entitled' Neurodevelopmental Disorders'.


Input: Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats.

nandrolone decanoate


Input: Chronic exposure to the anabolic androgenic steroids (AAS) nandrolone decanoate (ND) in supra-physiological doses is associated with learning and memory impairments.

steroids

nandrolone decanoate


Input: Given the well-known beneficial effects of voluntary exercise on cognitive functions, we examined whether voluntary exercise would improve the cognitive deficits induced by chronic administration of ND.


Input: We also investigated the effects of ND and voluntary exercise on hippocampal BDNF levels.


Input: The rats were randomly distributed into 4 experimental groups: the vehicle-sedentary group, the ND-sedentary group, the vehicle-exercise group, and the ND-exercise group.


Input: The vehicle-exercise and the ND-exercise groups were allowed to freely exercise in a running wheel for 15 days.


Input: The vehicle-sedentary and the ND-sedentary groups were kept sedentary for the same period.


Input: Vehicle or ND injections were started 14 days prior to the voluntary exercise and continued throughout the 15 days of voluntary exercise.


Input: After the 15-day period, the rats were trained and tested on a water maze spatial task using four trials per day for 5 consecutive days followed by a probe trial two days later.


Input: Exercise significantly improved performance during both the training and retention of the water maze task, and enhanced hippocampal BDNF.


Input: ND impaired spatial learning and memory, and this effect was not rescued by exercise.


Input: ND also potentiated the exercise-induced increase in hippocampal BDNF levels.


Input: These results seem to indicate that voluntary exercise is unable to improve the disruption of cognitive functions by chronic ND.


Input: Moreover, increased levels of BDNF may play a role in ND-induced impairments in learning and memory.


Input: The harmful effects of ND and other AAS on learning and memory should be taken into account when athletes decide to use AAS for performance or body image improvement.


Input: Rosiglitazone disrupts endosteal bone formation during distraction osteogenesis by local adipocytic infiltration.

Rosiglitazone


Input: Rosiglitazone (Rosi) is a drug in the thiazolidinedione class for treatment of type 2 diabetes mellitus (T2DM), which binds and activates PPAR gamma nuclear receptor in fat cells, sensitizing them to insulin.

Rosiglitazone

Rosi

thiazolidinedione


Input: Despite proven antidiabetic efficacy, Rosi therapy may be associated with trabecular bone loss and an increased risk of fractures.

Rosi


Input: To examine the potential side effects of Rosi treatment on bone formation, we delivered Rosi to mice using a combined model of distraction osteogenesis (DO) and type 2 diabetes mellitus (T2DM).

Rosi

Rosi


Input: DO provides a unique method to isolate the sequence of intramembranous bone formation, an important component of both fracture healing and bone homeostasis.


Input: Four groups of n = 6 mice were used to compare the effects of Rosi on bone formation and cellular composition in both diabetic (Avy/a strain) and non-diabetic mice (a/a strain).

Rosi


Input: New bone formation was examined by high resolution radiographs, micro-computed tomography, and histology.


Input: Precursor cells in the distraction gap were quantitated using immunohistochemical stains for proliferating cell nuclear antigen.


Input: Committed osteoblasts and adipocytes in the gap were identified and quantitated by immunostaining for osteocalcin and FABP4/aP2, respectively.


Input: The diabetic model developed obesity, hyperglycemia, hyperinsulinemia and insulin resistance, while the control littermates remained lean, normoglycemic and insulin sensitive.


Input: Rosi treatment decreased levels of non-fasted glucose and insulin and improved insulin sensitivity in the A (vy)/a mice, but had no effect in a/a mice, indicating antidiabetic efficacy of Rosi at the tested dose.

Rosi

glucose

Rosi


Input: Despite the diabetic, obese mice having twice the number of fat cells in their marrow than the non-diabetic mice, bone formation using DO was not adversely affected by the diabetes itself.


Input: However, Rosi treatment significantly diminished intramembranous endosteal bone formation, while increasing adipogenesis in and adjacent to the distraction gap up to 3. 5-to 3. 8-fold in both diabetic and non-diabetic models.

Rosi


Input: This effect was independent of the anti-diabetic therapeutic response.


Input: These results raise the question of whether osteoblast precursors are inhibited in their development or actually converted to adipocytic phenotypes, possibly via marrow fat PPAR gamma nuclear receptor.


Input: Pharmacological management of ocular hypertension: current approaches and future prospective.


Input: Elevated eye pressure is the main risk factor for glaucoma, and intraocular pressure rises when the balance between aqueous humor formation and outflow resistance is compromised.


Input: In a normal eye there is a precise tune of aqueous outflow under the fine control of ciliary body and trabecular meshwork.


Input: Current pharmacological therapies for lowering the intraocular pressure in glaucoma include increasing aqueous humor outflow and suppression of aqueous humor production.


Input: However, most of antiglaucoma drugs currently on the market do not target the trabecular meshwork that represents the site of the pathology.


Input: This review focuses on pharmacological management of ocular hypertension with a particular attention to the future pharmacotherapy scenario.


Input: Perfluorooctane sulfonate (PFOS) affects hormone receptor activity, steroidogenesis, and expression of endocrine-related genes in vitro and in vivo.

Perfluorooctane sulfonate

PFOS


Input: Perfluorooctane sulfonate (PFOS) is a widespread and persistent chemical in the environment.

Perfluorooctane sulfonate

PFOS


Input: We investigated the endocrine-disrupting effects of PFOS using a combination of in vitro and in vivo assays.

PFOS


Input: Reporter gene assays were used to detect receptor-mediated (anti-) estrogenic, (anti-) androgenic, and (anti-) thyroid hormone activities.

thyroid hormone


Input: The effect of PFOS on steroidogenesis was assessed both at hormone levels in the supernatant and at expression levels of hormone-induced genes in the H295R cell.

PFOS


Input: A zebrafish-based short-term screening method was developed to detect the effect of PFOS on endocrine function in vivo.

PFOS


Input: The results indicate that PFOS can act as an estrogen receptor agonist and thyroid hormone receptor antagonist.

PFOS

estrogen

thyroid hormone


Input: Exposure to PFOS decreased supernatant testosterone (T), increased estradiol (E2) concentrations in H295R cell medium and altered the expression of several genes involved in steroidogenesis.

PFOS

testosterone

estradiol


Input: In addition, PFOS increased early thyroid development gene (hhex and pax8) expression in a concentration-dependent manner, decreased steroidogenic enzyme gene (CYP17, CYP19a, CYP19b) expression, and changed the expression pattern of estrogen receptor production genes (esr1, esr2b) after 500 micro g/L PFOS treatment in zebrafish embryos.

PFOS

estrogen

PFOS


Input: These results indicate that PFOS has the ability to act as an endocrine disruptor both in vitro and in vivo by disrupting the function of nuclear hormone receptors, interfering with steroidogenesis, and altering the expression of endocrine-related genes in zebrafish embryo.

PFOS


Input: Solid-state nanopore detection of protein complexes: applications in healthcare and protein kinetics.


Input: Protein conjugation provides a unique look into many biological phenomena and has been used for decades for molecular recognition purposes.


Input: In this study, the use of solid-state nanopores for the detection of gp120-associated complexes are investigated.


Input: They exhibit monovalent and multivalent binding to anti-gp120 antibody monomer and dimers.


Input: In order to investigate the feasibility of many practical applications related to nanopores, detection of specific protein complexes is attempted within a heterogeneous protein sample, and the role of voltage on complexed proteins is researched.


Input: It is found that the electric field within the pore can result in unbinding of a freely translocating protein complex within the transient event durations measured experimentally.


Input: The strong dependence of the unbinding time with voltage can be used to improve the detection capability of the nanopore system by adding an additional level of specificity that can be probed.


Input: These data provide a strong framework for future protein-specific detection schemes, which are shown to be feasible in the realm of a' real-world' sample and an automated multidimensional method of detecting events.


Input: Multicenter precision of cortical and trabecular bone quality measures assessed by high-resolution peripheral quantitative computed tomography.


Input: High-resolution peripheral quantitative computed tomography (HR-pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality.


Input: The utility of this technology to address important skeletal health questions requires translation to standardized multicenter data pools.


Input: Our goal was to evaluate the feasibility of pooling data in multicenter HR-pQCT imaging trials.


Input: Reproducibility imaging experiments were performed using structure and composition-realistic phantoms constructed from cadaveric radii.


Input: Single-center precision was determined by repeat scanning over short-term (< 72 hours), intermediate-term (3-5 months), and long-term intervals (28 months).


Input: Multicenter precision was determined by imaging the phantoms at nine different HR-pQCT centers.


Input: Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters.


Input: Single-center short-term RMSCVs were < 1% for all parameters except cortical thickness (Ct. Th) (1. 1%), spatial variability in cortical thickness (Ct. Th. SD) (2. 6%), standard deviation of trabecular separation (Tb. Sp. SD) (1. 8%), and porosity measures (6% to 8%).


Input: Intermediate-term RMSCVs were generally not statistically different from short-term values.


Input: Long-term variability was significantly greater for all density measures (0. 7% to 2. 0%; p < 0. 05 versus short-term) and several structure measures: cortical thickness (Ct. Th) (3. 4%; p < 0. 01 versus short-term), cortical porosity (Ct. Po) (15. 4%; p < 0. 01 versus short-term), and trabecular thickness (Tb. Th) (2. 2%; p < 0. 01 versus short-term).


Input: Multicenter RMSCVs were also significantly higher than short-term values: 2% to 4% for density and micro-finite element analysis (micro FE) measures (p < 0. 0001), 2. 6% to 5. 3% for morphometric measures (p < 0. 001), whereas Ct. Po was 16. 2% (p < 0. 001).


Input: In the absence of subject motion, multicenter precision errors for HR-pQCT parameters were generally less than 5%.


Input: Phantom-based multicenter precision was comparable to previously reported in in vivo single-center precision errors, although this was approximately two to five times worse than ex vivo short-term precision.


Input: The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multicenter study designs.


Input: Pharmacokinetics and metabolism of [(14) C] anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans.

[(14) C] anagliptin


Input: 1. The disposition of anagliptin, an orally active, highly selective dipeptidyl peptidase-4 inhibitor, was investigated after a single oral dose of 100 mg/1. 92 MBq [(14) C] anagliptin to six healthy men.

anagliptin

[(14) C] anagliptin


Input: Almost all the dose (98. 2%) was recovered within 168 h: 73. 2% in urine and 25. 0% in faeces.


Input: 2. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug attained at a mean time of 1. 8-h postdose.

Anagliptin


Input: Mean fraction of the dose absorbed was > 73%.


Input: Unchanged drug and a carboxylate metabolite (M1) were the major components in plasma, accounting for 66. 0 and 23. 4% of total plasma radioactivity area under the curve, respectively.

carboxylate


Input: 3. Anagliptin was incompletely metabolized, with about 50% dose eliminated as unchanged drug (46. 6% in urine and 4. 1% in faeces).

Anagliptin


Input: Metabolism to M1 accounted for 29. 2% of the dose.


Input: No other metabolite accounted for > 1% dose in excreta or yielded measurable systemic exposure.


Input: Terminal half-life of anagliptin and M1 was 4. 37 and 9. 88 h, respectively.

anagliptin


Input: Renal clearance of unbound anagliptin and unbound M1 far exceeded glomerular filtration rate, indicating active renal elimination: that might reflect the fact that anagliptin may be a substrate of OAT1, OAT3, MDR1 and MRP2, and M1 a substrate of OAT3, BCRP, MRP2 and MRP4.

anagliptin

anagliptin


Input: Substrate effect on the plasmonic sensing ability of hollow nanoparticles of different shapes.


Input: Gold hollow nanospheres (AuHSs) and gold hollow nanocubes (AuHCs) were synthesized by the galvanic replacement technique using silver nano templates.

silver


Input: Colloidal AuHSs are found to have a higher sensitivity factor than that of AuHCs.


Input: This value decreases for both shapes when the nanoparticles are assembled on a quartz substrate by using the Langmuir-Blodgett technique.

quartz


Input: AuHSs are observed to have the larger effect.


Input: It is observed that as the separation gap between AuHCs nanoparticles decreases, their localized surface plasmon resonance band red shifts more than AuHSs.


Input: This is accounted for by the discrete dipole approximation (DDA) calculations.


Input: The coupling between the plasmon fields of the AuHCs pair is stronger than that between AuHSs pair.


Input: Using the DDA calculation, this is found to be due to geometric factors, as well as to the difference in the plasmonic field intensity.


Input: The calculation also showed that the plasmon field distributions of both AuHCs and AuHSs were distorted by the quartz substrate in a different manner.

quartz


Input: It is also observed that the surface-enhanced Raman spectrum of thiophenol is stronger when measured on AuHCs than on AuHSs.

thiophenol


Input: This is due to the difference in the plasmon field distribution as well as the fact that the AuHCs have a higher scattering/absorption yield ratio.


Input: Noncanonical suppression of GH-dependent isoforms of cytochrome P450 by the somatostatin analog octreotide.

somatostatin

octreotide


Input: Octreotide is a potent somatostatin analog therapeutically used to treat several conditions including hyper GH secretion in patients with acromegaly.

Octreotide

somatostatin


Input: We infused, over 30 s, octreotide into male rats every 12 h for 6 days at levels considerably greater than typical human therapeutic doses.

octreotide


Input: Unexpectedly, resulting circulating GH profile was characterized by pulses of higher amplitudes, longer durations, and greater total content than normal, but still contained an otherwise male-like episodic secretory profiles.


Input: In apparent disaccord, the normally elevated masculine expression levels (protein and/or mRNA) of CYP2C11 (accounting for > 50% of the total hepatic cytochrome P450 content), CYP3A2, CYP2C7, and IGF1, dependent on the episodic GH profile, were considerably downregulated.


Input: We explain this contradiction by proposing that the requisite minimal GH-devoid interpulse durations in the masculine profile that solely regulate expression of at least CYP2C11 and IGF1 may be sufficiently reduced to suppress transcription of the hepatic genes.


Input: Alternatively, we observed that octreotide infusion may have acted directly on the hepatocytes to induce expression of immune response factors postulated to suppress CYP transcription and/or upregulate expression of several negative regulators (e. g. phosphatases and SOCS proteins) of the JAK2/STAT5B signaling pathway that normally mediates the upregulation of CYP2C11 and IGF1 by the masculine episodic GH profile.

octreotide


Input: Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models.


Input: Agonists and positive allosteric modulators (PAMs) of alpha 7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for managing cognitive deficits in schizophrenia and Alzheimer' s disease.

acetylcholine


Input: Though alpha 7 agonists were recently found to possess antinociceptive and anti-inflammatory properties in rodent models of chronic neuropathic pain and inflammation, the effects of alpha 7 nAChRs PAMs on chronic pain and inflammation remain largely unknown.


Input: The present study investigated whether PAMs, by increasing endogenous cholinergic tone, potentiate alpha 7 nAChRs function to attenuate inflammatory and chronic neuropathic pain in mice.


Input: We tested two types of PAMS, type I (NS1738) and type II (PNU-120596) in carrageenan-induced inflammatory pain and chronic constriction injury (CCI) neuropathic pain models.


Input: We found that both NS1738 and PNU-120596 significantly reduced thermal hyperalgesia, while only PNU-120596 significantly reduced edema caused by a hind paw infusion of carrageenan.


Input: Importantly, PNU-120596 reversed established thermal hyperalgesia and edema induced by carrageenan.


Input: In the CCI model, PNU-120596 had long-lasting (up to 6 h), dose-dependent anti-hyperalgesic and anti-allodynic effects after a single injection, while NS1738 was inactive.


Input: Systemic administration of the alpha 7 nAChR antagonist MLA reversed PNU-120596' s effects, suggesting the involvement of central and peripheral alpha 7 nAChRs.

MLA


Input: Furthermore, PNU-120596 enhanced an ineffective dose of selective agonist PHA-543613 to produce anti-allodynic effects in the CCI model.


Input: Our results indicate that the type II alpha 7 nAChRs PAM PNU-120596, but not the type I alpha 7 nAChRs PAM NS1738, shows significant anti-edematous and anti-allodynic effects in inflammatory and CCI pain models in mice.


Input: Tandem inverse-electron-demand hetero-/retro-Diels-Alder reactions for aromatic nitrogen heterocycle synthesis.

nitrogen


Input: The merged inverse-electron-demand hetero-Diels-Alder (ihDA)/retro-Diels-Alder (rDA) reaction sequence can be used to rapidly synthesise highly functionalised nitrogen heteroaromatics.

nitrogen


Input: The reaction offers many advantages: high atom economy, high levels of regioselectivity, it rarely requires a catalyst and, in some cases, can be performed in the absence of solvent.


Input: In this tutorial review we discuss the range of commonly used dienophiles and aza-dienes for this process whilst highlighting the reactivity trends, and illustrating their applications.

aza-dienes


Input: Use of transgenic GFP reporter strains of the nematode Caenorhabditis elegans to investigate the patterns of stress responses induced by pesticides and by organic extracts from agricultural soils.


Input: As a free-living nematode, C. elegans is exposed to various pesticides used in agriculture, as well as to persistent organic residues which may contaminate the soil for long periods.


Input: Following on from our previous study of metal effects on 24 GFP-reporter strains representing four different stress-response pathways in C. elegans (Anbalagan et al. Ecotoxicology 21: 439-455, 2012), we now present parallel data on the responses of these same strains to several commonly used pesticides.


Input: Some of these, like dichlorvos, induced multiple stress genes in a concentration-dependent manner.

dichlorvos


Input: Unusually, endosulfan induced only one gene (cyp-34A9) to very high levels (8-10-fold) even at the lowest test concentration, with a clear plateau at higher doses.

endosulfan


Input: Other pesticides, like diuron, did not alter reporter gene expression detectably even at the highest test concentration attainable, while others (such as glyphosate) did so only at very high concentrations.

diuron

glyphosate


Input: We have also used five responsive GFP reporters to investigate the toxicity of soil pore water from two agricultural sites in south-east Spain, designated P74 (used for cauliflower production, but significantly metal contaminated) and P73 (used for growing lettuce, but with only background levels of metals).


Input: Both soil pore water samples induced all five test genes to varying extents, yet artificial mixtures containing all major metals present had essentially no effect on these same transgenes.


Input: Soluble organic contaminants present in the pore water were extracted with acetone and dichloromethane, then after evaporation of the solvents, the organic residues were redissolved in ultrapure water to reconstitute the soluble organic components of the original soil pore water.

acetone

dichloromethane


Input: These organic extracts induced transgene expression at similar or higher levels than the original pore water.


Input: Addition of the corresponding metal mixtures had either no effect, or reduced transgene expression towards the levels seen with soil pore water only.


Input: We conclude that the main toxicants present in these soil pore water samples are organic rather than metallic in nature.