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Journal of Hazardous Materials Jul 2020In this work, we have investigated the stability of pindolol (PIN), a non-selective β-blocker detected in the river and wastewater of hospitals, in water solution under...
In this work, we have investigated the stability of pindolol (PIN), a non-selective β-blocker detected in the river and wastewater of hospitals, in water solution under solar irradiation. Further, detailed insights into the stability of PIN were obtained by the density functional theory (DFT) calculations and molecular dynamics simulations. The kinetics of PIN photocatalytic degradation and mineralization has been studied using four commercial photocatalysts ZnO and TiO (P25, Hombikat, and Wackherr). It was found that the major role in degradation of PIN play the reactive hydroxyl radicals. The structures of degradation intermediates were suggested by LC-ESI-MS/MS and DFT calculations. Also, DFT calculations were used to refine molecular structures of intermediates and obtain their geometries. Toxicity of PIN and its mixtures formed during photocatalytic degradation were investigated using mammalian cell lines (H-4-II-E, HT-29, and MRC-5). The H-4-II-E cell line was the most sensitive to PIN and its photodegradation mixtures. The computational results were combined with the experimental data on the amounts of degradation intermediates for determination of the intermediates that were principally responsible for the toxicity. Intermediate with two hydroxyl groups, positioned on indole ring in meta and para positions, was proposed as the one with the highest contribution to toxicity.
Topics: Animals; Catalysis; Cell Line; Humans; Kinetics; Models, Molecular; Photolysis; Pindolol; Rats; Sunlight; Titanium; Water Pollutants, Chemical; Zinc Oxide
PubMed: 32197201
DOI: 10.1016/j.jhazmat.2020.122490 -
Journal of Cachexia, Sarcopenia and... Apr 2020Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new...
BACKGROUND
Cachexia, a common manifestation of malignant cancer, is associated with wasting of skeletal muscle and fat tissue. In this study, we investigated the effects of a new first in class anabolic catabolic transforming agent on skeletal muscle in a rat model of cancer cachexia.
METHODS
Young male Wistar Han rats were intraperitoneally inoculated with 10 Yoshida hepatoma AH-130 cells and once daily treated with 0.3 mg kg , 3 mg kg MT-102, or placebo by gavage.
RESULTS
Three mg kg d MT-102 not only prevented progressive loss of fat mass (-6 ± 2 g vs -12 ± 1 g; P < 0.001); lean mass (+1 ± 10 g vs. -37 ± 2 g; P < 0.001) and body weight (+1 ± 13 g vs. -60 ± 2 g; P < 0.001) were remained. Quality of life was also improved as indicated by a higher food intake 12.9 ± 3.1 g and 4.3 ± 0.5 g, 3 mg kg d MT-102 vs. placebo, respectively, P < 0.001) and a higher spontaneous activity (52 369 ± 6521 counts/24 h and 29 509 ± 1775 counts/24 h, 3 mg·kg d MT-102 vs. placebo, respectively, P < 0.01) on Day 11. Most importantly, survival was improved (HR = 0.29; 95% CI: 0.16-0.51, P < 0.001). The molecular mechanisms behind these effects involve reduction of overall protein degradation and activation of protein synthesis, assessed by measurement of proteasome and caspase-6 activity or Western blot analysis, respectively.
CONCLUSIONS
The present study shows that 3 mg kg MT-102 reduces catabolism, while inducing anabolism in skeletal muscle leading to an improved survival.
Topics: Animals; Body Composition; Cachexia; Disease Models, Animal; Liver Neoplasms, Experimental; Male; Pindolol; Random Allocation; Rats; Rats, Wistar; Survival Analysis
PubMed: 32067370
DOI: 10.1002/jcsm.12537 -
Journal of Pharmaceutical and... Apr 2020A novel chiral stationary phase (CSP), based on a monolithic organic polymer chemically modified with teicoplanin, was fabricated within a 100 μm I.D. fused silica...
A novel chiral stationary phase (CSP), based on a monolithic organic polymer chemically modified with teicoplanin, was fabricated within a 100 μm I.D. fused silica capillary. The teicoplanin was firstly derivatized with 2-isocyanatoethyl methacrylate (ICNEML) and then thermally co-polymerized with the crosslinker ethylene dimethacrylate (EDMA) in presence of porogens (methanol and dimethylsulfoxide). The optimal experimental conditions (e.g., concentration and ratio of the reagents), considering enantioresolution and permeability, were systematically investigated. The prepared monolith was evaluated using scanning electron microscopy, and the column exhibited quite good morphology. In order to further evaluate the enantioresolving power of the poly(ICNEML-teicoplanin-co-EDMA) monolith, a series of basic and acidic chiral compounds were analyzed using an isocratic mode of polar organic solvents (methanol and acetonitrile) or the same solvents in combination with water (reversed-phase) by nano-liquid chromatography. Five mandelic acids and six derivatized amino acids were enantioresolved under reversed-phase mode (R = 1.22-3.47 and α = 1.43-6.33). This monolithic teicoplanin-CSP was also effective in the enantioseparations of 17 amino alcohol drugs employing polar-organic phase mode (MeOH/ACN/TEA/HOAc (80/20/0.03/0.055, v/v/v/v)). Ten of them were baseline enantioresolved (alprenolol, betaxolol, clenbuterol, isoproterenol, metoprolol, pindolol, propranolol, salbutamol, sotalol, tertatolol) (R = 1.55-2.48 and α = 1.21-1.55), while the others were partially enantioseparated (R = 1.14-1.48).
Topics: Amino Acids; Chromatography, Liquid; Cross-Linking Reagents; Mandelic Acids; Pharmaceutical Preparations; Polymers; Solvents; Stereoisomerism; Teicoplanin
PubMed: 32036299
DOI: 10.1016/j.jpba.2020.113129 -
Analytical Chemistry Feb 2020Capillary electrophoresis-mass spectrometry is a powerful technique for high-throughput and high efficiency separations combined with structural identification....
Capillary electrophoresis-mass spectrometry is a powerful technique for high-throughput and high efficiency separations combined with structural identification. Electrospray ionization is the primary interface used to couple capillary electrophoresis to mass analyzers; however, improved designs continue to be reported. A new interfacing method based on vibrating sharp-edge spray ionization is presented in this work to overcome the challenges of decoupling applied voltages and to enhance the compatibility with separations performed at near-neutral pH. The versatility and ease of use of this ionization source is demonstrated using β-blockers, peptides, and proteins. The cationic β-blocker pindolol was injected electrokinetically, and detected at concentrations ranging from 10 nM to 5 μM, with an estimated detection limit of 2 nM. The vibrating sharp-edge spray ionization functions with flow rates from 70 to 200 nL/min and did not perturb the capillary electrophoresis separation electroosmotic flow as evidenced by the observation that most migration times differed less than 7% ( = 3) across a lab-built system interfaced to mass spectrometry and a commercial system that utilizes absorbance detection. For cationic beta-blockers the theoretical plates achieved in the capillary electrophoresis-mass spectrometry setup were 80%-95% of that observed with a commercial capillary electrophoresis-UV absorbance detection system.
Topics: Electroosmosis; Electrophoresis, Capillary; Molecular Structure; Pindolol; Spectrometry, Mass, Electrospray Ionization
PubMed: 31971372
DOI: 10.1021/acs.analchem.9b03994 -
Pulmonary Pharmacology & Therapeutics Apr 2020The β-adrenergic receptor (β-AR) plays an important role in regulating a variety of cell and organ functions in different animal species and is an important target in...
The β-adrenergic receptor (β-AR) plays an important role in regulating a variety of cell and organ functions in different animal species and is an important target in asthma pathogenesis and therapy. The β-AR expression and function in equine bronchial epithelial cells (EBEC) were not known but innervation and significant decrease in receptor level were reported in the equine bronchial tissues from asthmatic horses. I-iodocyanopindolol (ICYP) binding studies were undertaken in primary freshly isolated and cultured EBEC to identify the presence of the β-ARs. The receptor distribution was assessed using subtype-selective β-AR antagonists (ICI 118 551 (β) and CGP 20712A (β). The β-AR function was confirmed by measuring the agonist-induced intracellular cAMP accumulation in freshly isolated and cultured EBEC. In both freshly isolated and cultured EBEC, the specific ICYP binding was saturable and of high affinity. The maximal receptor density (B) was 9763 ± 140 binding sites/cell (mean ± SEM, n = 7) and 10575 ± 194 binding sites/cell (mean ± SEM, n = 5) in freshly isolated and cultured EBEC, respectively. The receptor affinity to the ligand (K) was also not different between the two cell conditions. ICI 118.551 displaced ICYP with 25 000-fold higher affinity than CGP 20712A. Moreover, in both fresh isolated and cultured EBEC, cAMP-accumulation was stimulated with a rank-order of potency of isoproterenol > adrenaline > noradrenaline. These results highlight the β-AR to be a key subtype in both freshly isolated and cultured primary EBEC.
Topics: Adrenergic beta-Antagonists; Animals; Bronchi; Cells, Cultured; Cyclic AMP; Epithelial Cells; Horses; Imidazoles; Iodocyanopindolol; Isoproterenol; Primary Cell Culture; Propanolamines; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2
PubMed: 31962137
DOI: 10.1016/j.pupt.2020.101897 -
International Journal of Molecular... Jan 2020Altered β-adrenergic receptor (β-AR) density has been reported in cells, animals, and humans receiving β-blocker treatment. In some cases, β-AR density is...
Altered β-adrenergic receptor (β-AR) density has been reported in cells, animals, and humans receiving β-blocker treatment. In some cases, β-AR density is upregulated, but in others, it is unaffected or even reduced. Collectively, these results would imply that changes in β-AR density and β-blockade are not related. However, it has still not been clarified whether the effects of β-blockers on receptor density are related to their ability to activate different β-AR signaling pathways. To this aim, five clinically relevant β-blockers endowed with inverse, partial or biased agonism at the β-AR were evaluated for their effects on β-AR density in both human embryonic kidney 293 (HEK293) cells expressing exogenous FLAG-tagged human β-ARs and human lymphocytes expressing endogenous β-ARs. Cell surface β-AR density was measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Treatment with propranolol, carvedilol, pindolol, sotalol, or timolol did not induce any significant change in surface β-AR density in both HEK293 cells and human lymphocytes. On the contrary, treatment with the β-AR agonist isoproterenol reduced the number of cell surface β-ARs in the tested cell types without affecting β-AR-mRNA levels. Isoproterenol-induced effects on receptor density were completely antagonized by β-blocker treatment. In conclusion, the agonistic activity of β-blockers does not exert an important effect on short-term regulation of β-AR density.
Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-2 Receptor Antagonists; Cell Line; Cell Membrane; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; Organ Specificity; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 31947522
DOI: 10.3390/ijms21020512 -
Journal of Chromatography. A Apr 2020Although micellar electrokinetic chromatography-mass spectrometry (MEKC-MS) using bare silica capillary filled with molecular micelles is an advantageous hyphenated...
Establishing repeatability and ruggedness of chiral separations in micellar electrokinetic chromatography mass spectrometry: Combined use of covalently bonded capillary column and molecular micelles.
Although micellar electrokinetic chromatography-mass spectrometry (MEKC-MS) using bare silica capillary filled with molecular micelles is an advantageous hyphenated technique for chiral analysis, it is still in the developmental stage. This is mainly because of the lower repeatability of retention time and peak area associated with the difficulty in controlling electroosmotic flow on bare silica capillaries. Besides the lower robustness and electrospray erosion of the fused-silica capillary tip, the lifetime is limited for 10-15 runs per capillary column. We have tested a new MEKC-MS method to eradicate this problem using a covalently bonded 2-acrylamido-2-methyl-1-propane-sulfonic acid (AMPS) column filled with free floating molecular micelles, polysodium N-undecenoxy carbonyl-L-leucinate (poly-L-SUCL). Simultaneous enantiomeric separations and MS/MS detection of three β-blockers [atenolol (ATEN), metoprolol (METO) and, pindolol (PINDO)] was achieved within 25 min with improved column lifetime of at least 45-50 runs. Excellent repeatability of retention time was observed for β-blockers, as evidenced by the relative standard deviation of less than 2% and 3% for intra-capillary and inter-capillary column, respectively. The linear calibration range of both β-blockers was simultaneously established using enantiomers of PINDO as an internal standard. The limit of detection and the lower limit of quantitation were 0.2 μg/mL and 0.5 μg/mL, respectively, for both ATEN and METO. Acceptable recovery of the enantiomeric content of the commercial METO tablet (98-99.5%) and ATEN tablet (89-92.5%) were obtained with adequate system suitability for the precision of peak area (≤10% RSD) under optimum conditions. The developed MEKC-MS approach was extended, which provided broader repeatibility of chiral separation to a panel of primary, secondary and tertiary amines as well as one anionic chiral compound.
Topics: Adrenergic beta-Antagonists; Chromatography, Micellar Electrokinetic Capillary; Leucine; Micelles; Polymers; Reproducibility of Results; Stereoisomerism; Tandem Mass Spectrometry
PubMed: 31928773
DOI: 10.1016/j.chroma.2019.460835 -
Frontiers in Behavioral Neuroscience 2019Long-term binge alcohol consumption alters the signaling of numerous neurotransmitters in the brain including noradrenaline (NE) and serotonin (5-HT). Alterations in the...
Long-term binge alcohol consumption alters the signaling of numerous neurotransmitters in the brain including noradrenaline (NE) and serotonin (5-HT). Alterations in the signaling of these neuronal pathways result in dysfunctional emotional states like anxiety and depression which are typically seen during alcohol withdrawal. Interestingly, studies have demonstrated that the development of alcohol-induced negative affective states is linked to disrupted neurogenesis in the dentate gyrus (DG) region of the hippocampus in alcohol-dependent animals. We have previously shown that modulation of NE and 5-HT activity by pharmacological targeting of β-adrenoreceptors (β-ARs) and 5-HT1A/1B receptors with pindolol reduces consumption in long-term alcohol-consuming mice. Since these receptors are also involved in emotional homeostasis and hippocampal neurogenesis, we investigated the effects of pindolol administration on emotional and neurogenic deficits in mice consuming long-term alcohol (18 weeks). We report that acute administration of pindolol (32 mg/kg) reduces anxiety-like behavior in mice at 24 h withdrawal in the marble-burying test (MBT) and the elevated plus-maze (EPM). We also show that chronic (2 weeks) pindolol treatment (32 mg/kg/day) attenuates alcohol-induced impairments in the density of immature neurons (DCX) but not newborn cells (BrdU) in the hippocampal DG. Pindolol treatment also restores the normal proportion of newborn proliferating cells (BrdU/Ki67/DCX), newborn proliferating immature neurons (BrdU/Ki67/DCX) and newborn non-proliferating immature neurons (BrdU/Ki67/DCX) following long-term alcohol intake. These results suggest that pindolol, through its unique pharmacology may rescue some but not all deficits of long-term alcohol abuse on the brain, adding further value to its properties as a strong pharmaceutical option for alcohol use disorders (AUDs).
PubMed: 31849624
DOI: 10.3389/fnbeh.2019.00264 -
Epilepsy & Behavior Reports 2019We report a case of a 52-year-old man with drug-resistant temporal lobe epilepsy, with post-ictal violent aggressive behaviors. Postictal violent outbursts would occur...
We report a case of a 52-year-old man with drug-resistant temporal lobe epilepsy, with post-ictal violent aggressive behaviors. Postictal violent outbursts would occur 3-4 times per year following clusters of seizures or generalized tonic-clonic convulsions. The violent outbursts were traumatizing for his family, and lead to multiple emergency department presentations as well as conflicts with police over the course of nine years. After initiation of pindolol the patient has had no episodes of violent behavior in two years despite experiencing the same frequency and severity of seizures as before pindolol. The abrupt cessation of postictal violent outbursts after introduction of pindolol in this case provides a novel management option for the treatment of postictal violence in patients with drug-resistant epilepsy and supports the importance of the beta adrenergic and potentially serotonergic systems in postictal violent behavior.
PubMed: 31799509
DOI: 10.1016/j.ebr.2019.100346 -
Pharmacological Reports : PR Dec 2019The present study evaluated the antioxidant, antinociceptive and anti-edematogenic effects of Se-[(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] 4-chlorobenzoselenolate...
Se - [(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl] 4-chlorobenzoselenolate reduces the nociceptive and edematogenic response by chemical noxious stimuli in mice: Implications of multi-target actions.
BACKGROUND
The present study evaluated the antioxidant, antinociceptive and anti-edematogenic effects of Se-[(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] 4-chlorobenzoselenolate (Se-DMC).
METHODS
In vitro experiments were carried out to evaluate Se-DMC antioxidant action. Thiobarbituric acid reactive species levels, 2,2'-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-thylbenzthiazoline-6-sulfonic acid) radicals scavenging and glutathione S-transferase-like activity were determined. Male Swiss mice were orally pretreated with Se-DMC (1, 10 and 50 mg/kg), meloxicam (50 mg/kg) or vehicle 30 min prior to acetic acid or glutamate test. To extend our knowledge of the pharmacological properties of this compound, it was tested in an inflammatory model through ear edema induced by croton oil. The contribution of glutamatergic and serotonergic systems was also investigated.
RESULTS
In vitro experiments revealed that Se-DMC exerts antioxidant activity. Nociception induced by glutamate or acetic acid was reduced by Se-DMC or meloxicam. Se-DMC diminished the paw edema formation induced by glutamate, while meloxicam did not show any effect. Se-DMC and meloxicam decreased the ear edema formation and protected against the increase in myeloperoxidase activity in mice ear induced by croton oil. The pretreatment of animals with MK-801 did not alter antinociception caused by Se-DMC in the glutamate test. The antinociceptive effect exerted by Se-DMC in the acetic acid test was reverted by the pretreatment of mice with different serotonergic antagonists (WAY100635, ketanserin and pindolol).
CONCLUSIONS
Data presented here showed that the modulation of serotonergic and glutamatergic systems and the anti-inflammatory and antioxidant actions could contribute to the antinociceptive and anti-edematogenic effects of Se-DMC and it supported the therapeutic potential of this compound.
Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Edema; Glutamic Acid; Male; Mice; Nociception; Pain Measurement; Selenium
PubMed: 31669884
DOI: 10.1016/j.pharep.2019.07.003