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Dose accumulation

Sher Ali, Tao Xu, Xiaolan Xu
Ca(2+) release-activated Ca(2+) (CRAC) channels play an essential role in the immune system. The pore-forming subunit, Orai1, is an important pharmacological target. Here, we summarize the recent discoveries on the structure-function relationship of Orai1, as well as its interaction with the native channel opener STIM1 and chemical modulator 2-aminoethoxydiphenyl borate (2-APB). We first introduce the critical structural elements of Orai1, which include a Ca(2+) accumulating region (CAR), ion selectivity filter, hydrophobic centre, basic region, extended transmembrane orai1 N-terminal (ETON), transmembrane (TM) regions 2 and 3, P245 bend, (263) SHK(265) hinge linker and L273-L276 hydrophobic patch...
October 18, 2016: Journal of Physiology
Bishoy Kamel, Garry G Graham, Kenneth M Williams, Kevin D Pile, Richard O Day
Febuxostat is a xanthine oxidoreductase inhibitor that has been developed to treat chronic gout. In healthy subjects, the pharmacokinetic parameters of febuxostat after multiple oral dose administration include an oral availability of about 85 %, an apparent oral clearance (CL/F) of 10.5 ± 3.4 L/h and an apparent volume of distribution at steady state (V ss/F) of 48 ± 23 L. The time course of plasma concentrations follows a two-compartment model. The initial half-life (t ½) is approximately 2 h and the terminal t ½ determined at daily doses of 40 mg or more is 9...
October 17, 2016: Clinical Pharmacokinetics
Ricardo Alcántara-de la Cruz, Pablo T Fernández-Moreno, Carmen V Ozuna, Antonia M Rojano-Delgado, Hugo E Cruz-Hipolito, José A Domínguez-Valenzuela, Francisco Barro, Rafael De Prado
In 2014 hairy beggarticks (Bidens pilosa L.) has been identified as being glyphosate-resistant in citrus orchards from Mexico. The target and non-target site mechanisms involved in the response to glyphosate of two resistant populations (R1 and R2) and one susceptible (S) were studied. Experiments of dose-response, shikimic acid accumulation, uptake-translocation, enzyme activity and 5-enolpyruvyl shikimate-3-phosphate synthase (EPSPS) gene sequencing were carried out in each population. The R1 and R2 populations were 20...
2016: Frontiers in Plant Science
Nnamdi Norbert Jibiri, Tawakalitu Oluwatoyin Akintunde, Musa Yusuf Dambele, Christopher Jimoh Olowookere
OBJECTIVE: The practice of regular dose measurement helps to ascertain the level of occupational dose delivered to the staff involved in diagnostic procedures. This study was carried out to evaluate the dose exposed to the hands of radiologists and a radiologic technologist carrying out HSG and radionuclide bone scan examinations in several hospitals in Nigeria. METHODS: Radiation doses exposed to the hands of radiologists and a technician carrying out hysterosalpingography (HSG) and bone scan procedures were measured using calibrated thermo-luminescent dosimeters...
October 5, 2016: Molecular Imaging and Radionuclide Therapy
H Calvete-Sogo, I González-Fernández, H García-Gómez, R Alonso, S Elvira, J Sanz, V Bermejo-Bermejo
Ozone (O3) critical levels (CLe) are still poorly developed for herbaceous vegetation. They are currently based on single species responses which do not reflect the multi-species nature of semi-natural vegetation communities. Also, the potential effects of other factors like the nitrogen (N) input are not considered in their derivation, making their use uncertain under natural conditions. Exposure- and dose-response relationships were derived from two open-top chamber experiments exposing a mixture of 6 representative annual Mediterranean pasture species growing in natural soil to 4 O3 fumigation levels and 3 N inputs...
October 14, 2016: Environmental Pollution
Patrícia Manuela Ribeiro Pereira, Sandrina Silva, Mafalda Bispo, Mónica da Rocha Zuzarte, Célia Gomes, Henrique Girão, José A S Cavaleiro, Carlos A Fontes Ribeiro, Joao P C Tome, Rosa Fernandes
Here we report the rational design of a new third-generation photosensitizer (PS), a chlorin conjugated with galactodendritic units, ChlGal8, to improve the effectiveness of bladder cancer treatment. ChlGal8 shows better photo-chemical and -physical properties than a recently reported homologous porphyrin, PorGal8. In addition to inheriting excellent photostability, ability to generate singlet oxygen and to interact with the proteins galectin-1 and human serum albumin (HSA), ChlGal8 exhibits high absorption in the red region of the electromagnetic spectrum...
October 17, 2016: Bioconjugate Chemistry
Cheng-Hua Zhou, Ming-Xing Zhang, Sha-Sha Zhou, Huan Li, Jian Gao, Lei Du, Xiao-Xing Yin
Accumulating evidence has demonstrated that epigenetic modification-mediated changes in pain-related gene expressions play an important role in the development and maintenance of neuropathic pain. Sirtuin 1 (SIRT1), anicotinamide adenosine dinucleotide (NAD)-dependent deacetylase, is involved in the development of chronic pain. Moreover, SIRT1 may be a novel therapeutic target for the prevention of type 2 diabetes mellitus (T2DM). But the role of SIRT1 in T2DM-induced neuropathic pain remains unknown. In this study, we found that spinal SIRT1 expression and activity were down-regulated significantly in high-fat-fed/low-dose STZ-induced neuropathic pain rats...
September 29, 2016: Pain
Nursel Gül, Nuri Yiğit, Fulya Saygılı, Ebru Demirel, Ceren Geniş
We used transmission electron microscopy to examine the cytotoxic effects of the second-generation anticoagulant rodenticides difenacoum and brodifacoum on rat liver. A single dose of difenacoum or brodifacoum was administered to rats by gastric gavage and liver samples were taken after 24 h, four days or seven days. In the livers of rats treated with difenacoum for 24 h, hepatocytes typically showed increased numbers of lysosomes, as well as enlargement of both the perinuclear space and the cisternae of the rough endoplasmic reticulum (RER), while sinusoids were irregularly shaped and contained Kupffer cells...
September 1, 2016: Arhiv za Higijenu Rada i Toksikologiju
Anna Polomska, Marc A Gauthier, Jean-Christophe Leroux
Drug nanocrystals (NCs) are colloidal dispersions composed almost entirely of drug. As such, there is substantial interest in targeting them to diseased tissues, where they can locally deliver high doses of the therapeutic. However, because of their uncontrolled dissolution characteristics in vivo and uptake by the monomolecular phagocyte system, achieving tumor accumulation is challenging. To address these issues, a layer-by-layer approach is adopted to coat paclitaxel NCs with alternating layers of oppositely charged polyelectrolytes, using a PEGylated copolymer as the top layer...
October 17, 2016: Small
Guangyong Chen, Yangdong Han, Wang He, Feng Liang
In the present study, we evaluated the protective effects of amentoflavone (AMF) against high-fat (HF) diet-induced metabolic dysfunction and focused on the influence of AMF on adipogenic differentiation during 3T3-L1 adipocyte differentiation. For this purpose, male Wistar rats were fed a HF diet or a HF diet with AMF (10 or 50 mg/kg). We found that AMF protected against HF diet-induced metabolic dysfunction in a dose-dependent manner, as evidenced by a decrease in the fasting blood glucose levels, fasting insulin levels and the homeostatic model assessment-insulin resistance index (HOMA‑IR), as well as by a decrease in the glucose level, as shown by the intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test...
October 14, 2016: International Journal of Molecular Medicine
Ha Ryong Kim, Da Young Shin, Kyu Hyuck Chung
Polyhexamethylene biguanide (PHMB) is a member of the polymeric guanidine family, which is used as a biocide and preservative in industrial, medicinal, and consumer products. Some studies reported that polyhexamethylene guanidine phosphate, which is also a member of the guanidine family, induced severe inflammation and fibrosis in the lungs. However, limited studies have evaluated the pulmonary toxicity of PHMB associated with inflammatory responses. The aim of this study was to elucidate the inflammatory responses and its mechanisms induced by PHMB in lung cells...
October 13, 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Cody S Shirriff, John J Heikkila
Endoplasmic reticulum (ER) stress can result in the accumulation of unfolded/misfolded protein in the ER lumen, which can trigger the unfolded protein response (UPR) resulting in the activation of various genes including immunoglobulin-binding protein (BiP; also known as glucose-regulated protein 78 or HSPA5). BiP, an ER heat shock protein 70 (HSP70) family member, binds to unfolded protein, inhibits their aggregation and re-folds them in an ATP-dependent manner. While cadmium, an environmental contaminant, was shown to induce the accumulation of HSP70 in vertebrate cells, less information is available regarding the effect of this metal on BiP accumulation or function...
October 13, 2016: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Radoslava Vlčková, Drahomíra Sopková, Zuzana Andrejčáková, Igor Valocký, Attila Kádasi, Abdel Halim Harrath, Vladimír Petrilla, Alexander V Sirotkin
Yucca (Yucca schidigera) is a popular medicinal plant due to its many positive effects on animal and human physiology, including their reproductive systems. To examine the effect of supplemental yucca feeding on sheep reproduction, including ovarian functions and their hormonal regulators, ewes were fed (or not fed, control) yucca powder (1.5 g/head/day, 30 days). Macromorphometric indexes of the oviduct, ovary, and ovarian folliculogenesis were measured. Reproductive hormone levels in the blood were measured using a radioimmunoassay...
September 21, 2016: Theriogenology
K Kramkowski, A Leszczynska, K Przyborowski, B Proniewski, N Marcinczyk, U Rykaczewska, D Jarmoc, E Chabielska, S Chlopicki
In humans, short-term supplementation with nitrate is hypotensive and inhibits platelet aggregation via an nitric oxide (NO)-dependent mechanism. In the present work, we analyzed whether short-term treatment with nitrate induces antithrombotic effects in rats and mice. Arterial thrombosis was evoked electrically in a rat model in which renovascular hypertension was induced by partial ligation of the left renal artery. In mice expressing green fluorescent protein, laser-induced thrombosis was analyzed intravitally by using confocal microscope...
October 14, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
Marianne Uteng, Andreas Mahl, Nicolau Beckmann, Alessandro Piaia, David Ledieu, Valerie Dubost, Elaine Tritto, Armin Wolf, Pierre Moulin, Li Li, Salah-Dine Chibout, Francois Pognan
The aim of this study was to determine the relative safety of four antiviral drugs (telbivudine, tenofovir, adefovir, entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Spraque-Dawley rats. The antiviral drugs were administered once daily for four weeks by oral gavage at about 10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology and electron microscopic examination...
October 13, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Qiao Wang, Xinyu Chen, Yiping Ren, Qing Chen, Zhen Meng, Jun Cheng, Yunyan Zheng, Weijiang Zeng, Qingning Zhao, Yu Zhang
Acrylamide is classified as a probable carcinogen to humans and generated from Maillard reaction. Currently, the short-term exposure to acrylamide was evaluated via external diet sources in vitro or two main mercapturic acid metabolites: N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) in vivo. In the present work, we comprehensively profiled four mercapturic acid metabolites and evaluated their internal exposure in rats and Chinese adolescents. The cumulative excretion of mercapturic acid metabolites contributes 38...
October 13, 2016: Archives of Toxicology
Saeed Mohammed Imran Hosen, Dipesh Das, Rupkanowar Kobi, Dil Umme Salma Chowdhury, Md Jibran Alam, Bashudev Rudra, Muhammad Abu Bakar, Saiful Islam, Zillur Rahman, Mohammad Al-Forkan
BACKGROUND: In the present study, we investigated the arsenic accumulation in different parts of rice irrigated with arsenic contaminated water. Besides, we also evaluated the protective effects of Corchorus olitorius leaves against arsenic contaminated rice induced toxicities in animal model. METHODS: A pot experiment was conducted with arsenic amended irrigation water (0.0, 25.0, 50.0 and 75.0 mg/L As) to investigate the arsenic accumulation in different parts of rice...
October 14, 2016: BMC Pharmacology & Toxicology
Danyue Zhao, Nagendra P Shah
Black tea (BT) has been positively linked to improved redox status, while its efficacy is limited due to the low bioavailability of BT flavonoids. In addition to the direct antioxidant activity, flavonoids regulate redox balance via inducing endogenous antioxidants, particularly glutathione (GSH) and GSH-dependent antioxidant enzymes. This work first examined the effect of lactic acid bacteria (LAB) and BT alone or in combination on flavonoid bioavailability and metabolism; next, the effect of LAB-fermented BT diet in attenuating oxidative stress in mice and the underlying mechanisms were studied...
September 18, 2016: Journal of Nutritional Biochemistry
Juanjuan Wang, Qingshui Shi, Chunyong Wu, Fang Feng
Zhi-Zi-Da-Huang decoction (ZZDHD) has been used for treatment of alcoholic liver disease in China for thousands of years. In order to reveal the dynamic biotransformation of the decoction in vivo, a high-throughout, sensitive and special method based on high performance liquid chromatography coupled with diode array detection and time-of-flight mass spectrometry (HPLC-DAD-TOF/MS) and high performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC-QqQ/MS) was developed and validated...
October 4, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Steven A Lacy, Dale R Miles, Linh T Nguyen
Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq(®)) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC)...
October 12, 2016: Clinical Pharmacokinetics
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