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1.
Front Public Health ; 10: 878907, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757620

RESUMO

Coffee production workers can be exposed to inhalational hazards including alpha-diketones such as diacetyl and 2,3-pentanedione. Exposure to diacetyl is associated with the development of occupational lung disease, including obliterative bronchiolitis, a rare and irreversible lung disease. We aimed to identify determinants contributing to task-based exposures to diacetyl and 2,3-pentanedione at 17 U.S. coffee production facilities. We collected 606 personal short-term task-based samples including roasting (n = 189), grinding (n = 74), packaging (n = 203), quality control (QC, n = 44), flavoring (n = 15), and miscellaneous production/café tasks (n = 81), and analyzed for diacetyl and 2,3-pentanedione in accordance with the modified OSHA Method 1013/1016. We also collected instantaneous activity-based (n = 296) and source (n = 312) samples using evacuated canisters. Information on sample-level and process-level determinants relating to production scale, sources of alpha-diketones, and engineering controls was collected. Bayesian mixed-effect regression models accounting for censored data were fit for overall data (all tasks) and specific tasks. Notable determinants identified in univariate analyses were used to fit all plausible models in multiple regression analysis which were summarized using a Bayesian model averaging method. Grinding, flavoring, packaging, and production tasks with ground coffee were associated with the highest short-term and instantaneous-activity exposures for both analytes. Highest instantaneous-sources of diacetyl and 2,3-pentanedione included ground coffee, flavored coffee, liquid flavorings, and off-gassing coffee bins or packages. Determinants contributing to higher exposures to both analytes in all task models included sum of all open storage sources and average percent of coffee production as ground coffee. Additionally, flavoring ground coffee and flavoring during survey contributed to notably higher exposures for both analytes in most, but not all task groups. Alternatively, general exhaust ventilation contributed to lower exposures in all but two models. Additionally, among facilities that flavored, local exhaust ventilation during flavoring processes contributed to lower 2,3-pentanedione exposures during grinding and packaging tasks. Coffee production facilities can consider implementing additional exposure controls for processes, sources, and task-based determinants associated with higher exposures to diacetyl and 2,3-pentanedione, such as isolating, enclosing, and directly exhausting grinders, flavoring mixers, and open storage of off-gassing whole bean and ground coffee, to reduce exposures and minimize risks for lung disease among workers.


Assuntos
Café , Diacetil , Pneumopatias , Exposição Ocupacional , Pentanonas , Teorema de Bayes , Diacetil/análise , Aromatizantes/análise , Humanos , Exposição Ocupacional/análise , Pentanonas/análise
2.
Front Public Health ; 10: 750289, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35664098

RESUMO

Exposure to elevated levels of diacetyl in flavoring and microwave popcorn production has been associated with respiratory impairment among workers including from a severe lung disease known as obliterative bronchiolitis. Laboratory studies demonstrate damage to the respiratory tract in rodents exposed to either diacetyl or the related alpha-diketone 2,3-pentanedione. Respiratory tract damage includes the development of obliterative bronchiolitis-like changes in the lungs of rats repeatedly inhaling either diacetyl or 2,3-pentanedione. In one flavored coffee processing facility, current workers who spent time in higher diacetyl and 2,3-pentanedione areas had lower lung function values, while five former flavoring room workers were diagnosed with obliterative bronchiolitis. In that and other coffee roasting and packaging facilities, grinding roasted coffee beans has been identified as contributing to elevated levels of diacetyl and 2,3-pentanedione. To reduce worker exposures, employers can take various actions to control exposures according to the hierarchy of controls. Because elimination or substitution is not applicable to coffee production facilities not using flavorings, use of engineering controls to control exposures at their source is especially important. This work demonstrates the use of temporary ventilated enclosures around grinding equipment in a single coffee roasting and packaging facility to mitigate diacetyl and 2,3-pentanedione emissions from grinding equipment to the main production space. Concentrations of diacetyl and 2,3-pentanedione were measured in various locations throughout the main production space as well as inside and outside of ventilated enclosures to evaluate the effect of the enclosures on exposures. Diacetyl and 2,3-pentanedione concentrations outside one grinder enclosure decreased by 95 and 92%, respectively, despite ground coffee production increasing by 12%, after the enclosure was installed. Outside a second enclosure, diacetyl and 2,3-pentanedione concentrations both decreased 84%, greater than the 33% decrease in ground coffee production after installation. Temporary ventilated enclosures used as engineering control measures in this study effectively reduced emissions of diacetyl and 2,3-pentanedione at the source in this facility. These findings motivated management to explore options with a grinding equipment manufacturer to permanently ventilate their grinders to reduce emissions of diacetyl and 2,3-pentanedione.


Assuntos
Bronquiolite , Exposição Ocupacional , Animais , Café , Diacetil/análise , Aromatizantes/análise , Exposição Ocupacional/análise , Exposição Ocupacional/prevenção & controle , Pentanonas , Ratos
3.
Environ Sci Technol ; 56(13): 9683-9692, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35696645

RESUMO

The regulation of photosynthetic machinery with a nonoxidative approach is a powerful but challenging strategy for the selective inhibition of bloom-forming cyanobacteria. Acetylacetone (AA) was recently found to be a target-selective cyanocide for Microcystis aeruginosa, but the cause and effect in the studied system are still unclear. By recording of the chemical fingerprints of the cells at two treatment intervals (12 and 72 h with 0.1 mM AA) with omics assays, the molecular mechanism of AA in inactivating Microcystis aeruginosa was elucidated. The results clearly reveal the effect of AA on ferredoxin and the consequent effects on the physiological and biochemical processes of Microcystis aeruginosa. In addition to its role as an electron acceptor of photosystem I, ferredoxin plays pivotal roles in the assimilation of nitrogen in cyanobacterial cells. The effect of AA on ferredoxin and on nonheme iron of photosystem II first cut off the photosynthetic electron transfer flow and then interrupted the synthesis of adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), which ultimately might affect carbon fixation and nitrogen assimilation metabolisms. The results here provide missing pieces in the current knowledge on the selective inhibition of cyanobacteria, which should shed light on the better control of harmful blooms.


Assuntos
Cianobactérias , Microcystis , Carbono , Elétrons , Ferredoxinas , Nitrogênio , Pentanonas
4.
Artigo em Inglês | MEDLINE | ID: mdl-35500841

RESUMO

N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans.


Assuntos
Estimulantes do Sistema Nervoso Central , Pentanonas , Agressão , Animais , Masculino , Metilaminas , Camundongos
5.
J Phys Chem B ; 126(19): 3551-3562, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35536173

RESUMO

Acetylacetone (AcAc) has proven to be a fruitful but highly challenging model system for the experimental and computational interrogation of strong intramolecular hydrogen bonds. Key questions remain, however, regarding the identity of the minimum-energy structure of AcAc and the dynamics of intramolecular proton transfer. Here, we investigate the OH/OD stretch and bend regions of the enol tautomer of AcAc and its deuterated isotopologue with transient absorption and 2D IR spectroscopy. The OH bend region reveals a single dominant diagonal transition near 1625 cm-1 with intense cross peaks to lower-frequency modes, demonstrating highly mixed fingerprint transitions that contain OH bend character. The anharmonic coupling of the OH bend results in a highly elongated OH bend excited-state absorption transition that indicates a large manifold of OH bend overtone/combination bands in the OH stretch region that leads to strong bend-stretch Fermi resonance interactions. The OH and OD stretch regions consist of broad ground-state bleach signals, but there is no clear evidence of ω21 excited-state absorptions due to rapid population relaxation arising from strong intramolecular coupling to bending, fingerprint, and low-frequency H-bond modes. Orientational relaxation dynamics persist for timescales longer than the vibrational lifetimes, with polarization anisotropy components decaying within approximately 2 and 10 periods of the O-O oscillation for the OH and OD stretch, respectively. The significant isotopic dependence of the orientational dynamics is discussed in the context of intramolecular mode coupling, diffusional processes, and contributions from proton/deuteron transfer dynamics.


Assuntos
Prótons , Vibração , Ligação de Hidrogênio , Pentanonas , Análise Espectral
6.
Inorg Chem ; 61(18): 6837-6851, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35471858

RESUMO

Cobalt(III) complexes [Co(TPA)(L1)](ClO4)2 (1), [Co(4-COOH-TPA)(L1)](ClO4)2 (2), [Co(TPA)(L2)]Cl2 (3), and [Co(4-COOH-TPA)(L2)]Cl2 (4) having acetylacetonate-linked boron-dipyrromethene ligands (L1, acac-BODIPY; L2, acac-diiodo-BODIPY) were prepared and characterized, and their utility as bioimaging and phototherapeutic agents was evaluated (TPA, tris-(2-pyridylmethyl)amine; 4-COOH-TPA, 2-((bis-(2-pyridylmethyl)amino)methyl)isonicotinic acid). HL1, HL2, and complex 1 were structurally characterized by X-ray crystallography. Complexes 1 and 2 on photoactivation or in a reducing environment (excess GSH, ascorbic acid, and 3-mercaptopropionic acid) released the acac-BODIPY ligand. They exhibited strong absorbance near 501 nm (ε ∼ (5.2-5.8) × 104 M-1 cm-1) and emission bands near 513 nm (ΦF ∼ 0.13, λex = 490 nm) in dimethyl sulfoxide (DMSO). Complexes 3 and 4 with absorption maxima at ∼536 and ∼538 nm (ε ∼ (1.2-1.8) × 104 M-1 cm-1), respectively, afforded high singlet oxygen quantum yield (ΦΔ âˆ¼ 0.79) in DMSO. Complexes 1-4 showed Co(III)-Co(II) redox responses near -0.2 V versus saturated calomel electrode (SCE) in dimethylformamide (DMF)-0.1 M tetrabutylammonium perchlorate (TBAP). The photocleavage of pUC19 DNA by complex 4 revealed the formation of both singlet oxygen and superoxide anion radicals as the reactive oxygen species (ROS). Confocal fluorescence microscopy showed the selective accumulation of complex 1 in the endoplasmic reticulum (ER) in A-549 cells. Complex 4 exhibited a high phototherapeutic index value (PI > 7000) in HeLa cancer cells (IC50 ∼ 0.007 µM in visible light of 400-700 nm, total dose ∼5 J cm-2). The ancillary ligands in the complexes demonstrated a structure-activity relationship and modulated the Co(III)-Co(II) redox potential, the complex solubility, acac-BODIPY ligand release kinetics, and phototherapeutic efficacy.


Assuntos
Antineoplásicos , Fotoquimioterapia , Antineoplásicos/química , Compostos de Boro , Cobalto/farmacologia , Dimetil Sulfóxido , Hidroxibutiratos , Ligantes , Pentanonas , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete
7.
Front Public Health ; 10: 786924, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35400070

RESUMO

Roasted coffee emits hazardous volatile organic compounds including diacetyl and 2,3-pentanedione. Workers in non-flavored coffee roasting and packaging facilities might inhale diacetyl and 2,3-pentanedione from roasted coffee above occupational exposure limits depending on their work activities and proximity to the source of emissions. Objectives of this laboratory study were to: (1) investigate factors affecting specific emission rates (SERs) of diacetyl and 2,3-pentanedione from freshly roasted coffee, (2) explore the effect of time on SERs of coffee stored in sealed bags for 10-days, and (3) predict exposures to workers in hypothetical workplace scenarios. Two roast levels (light and dark) and three physical forms (whole bean, coarse ground, and fine ground) were investigated. Particle size for whole bean and ground coffee were analyzed using geometric mean of Feret diameter. Emitted chemicals were collected on thermal desorption tubes and quantified using mass spectrometry analysis. SERs developed here coupled with information from previous field surveys provided model input to estimate worker exposures during various activities using a probabilistic, near-field/far-field model. For freshly roasted coffee, mean SER of diacetyl and 2,3-pentantedione increased with decreasing particle size of the physical form (whole bean < coarse ground < fine ground) but was not consistent with roast levels. SERs from freshly roasted coffee increased with roast level for diacetyl but did not change for 2,3-pentanedione. Mean SERs were greatest for diacetyl at 3.60 mg kg-1 h-1 for dark, fine ground and for 2,3-pentanedione at 3.88 mg kg-1 h-1 for light, fine ground. For storage, SERs of whole bean remained constant while SERs of dark roast ground coffee decreased and light roast ground coffee increased. Modeling demonstrated that near-field exposures depend on proximity to the source, duration of exposure, and air velocities in the near-field further supporting previously reported chemical air measurements in coffee roasting and packaging facilities. Control of source emissions using local exhaust ventilation especially around grinding activities as well as modification of work practices could be used to reduce exposures in this workforce.


Assuntos
Diacetil , Exposição Ocupacional , Café , Diacetil/análise , Humanos , Exposição Ocupacional/análise , Pentanonas/análise
8.
Chem Phys Lipids ; 245: 105194, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35288126

RESUMO

The study presents the synthesis of original cholesterol-terminated copolymers comprising acetylacetone-based (AcacI) and N-isopropylacrylamide (NIPAAm) units with a varied arrangement (block and random copolymers). The nanoprecipitation method was used to form empty and doxorubicin-loaded polymeric nanoparticles (PNPs) from these copolymers, which were further studied in terms of their physicochemical and biological properties. Unexpectedly, it was revealed that even empty PNPs are effective against breast cancer cells, specifically towards estrogen-dependent MCF-7 cell line. The anti-cancer efficacy was further improved when a low dose of doxorubicin was introduced to the tested systems. It was shown that the proposed carriers modulate doxorubicin (DOX) compatibility with representatives of normal cells, including immune cells, cardiomyocyte cells, and fibroblasts, and reduce side effects associated with standard chemotherapy. The use of these carriers might be a strategy leading to enhancement of DOX activity in cancer cells which develop resistance through decreased drug penetration or drug efflux.


Assuntos
Neoplasias da Mama , Nanopartículas , Neoplasias da Mama/tratamento farmacológico , Colesterol , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Estrogênios , Feminino , Humanos , Nanopartículas/química , Pentanonas , Polímeros/química
9.
Environ Sci Pollut Res Int ; 29(29): 44282-44296, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35128610

RESUMO

Organic solvents like 2-pentanone and 2-hexanone which are widely used in industrial production make up a large proportion of the source of chemical pollution. What is worrisome is that the cellular and molecular toxicity of 2-pentanone and 2-hexanone has not been reported yet. Based on this, earthworms and catalase (CAT) were chosen as target receptors for the toxicity studies. The cytotoxicity of 2-pentanone and 2-hexanone was revealed by measuring the multiple intracellular indicators of oxidative stress. At the molecular level, changes in the structure and function of CAT were characterized in vitro by the spectroscopy and molecular docking. The results show that 2-pentanone and 2-hexanone that induced the accumulation of reactive oxygen species can eventually reduce coelomocytes viability, accompanying by the regular changes of antioxidant activity and lipid peroxidation level. In addition, the exposure of 2-pentanone and 2-hexanone can shrink the backbone structure of CAT, quench the fluorescence, and misfold the secondary structure. The decrease in enzyme activity should be attributed to the structural changes induced by surface binding. This study discussed the toxicological effects and mechanisms of conventional solvents at the cellular and molecular level, which creatively proposed a joint research method.


Assuntos
Oligoquetos , Poluentes do Solo , Animais , Catalase/metabolismo , Metil n-Butil Cetona/metabolismo , Metil n-Butil Cetona/farmacologia , Simulação de Acoplamento Molecular , Estresse Oxidativo , Pentanonas , Poluentes do Solo/metabolismo , Solventes/farmacologia
10.
ACS Appl Mater Interfaces ; 14(9): 11078-11091, 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35196008

RESUMO

Nanomedicines, while having been approved for cancer therapy, present many challenges such as low stability, rapid clearance, and nonspecificity leading to off-target toxicity. Cubosomes are porous lyotropic liquid crystalline nanoparticles that have shown great premise as drug delivery vehicles; however, their behavior in vivo is largely underexplored, hindering clinical translation. Here, we have engineered cubosomes based on the space group Im3m that are loaded with copper acetylacetonate as a model drug, and their surfaces are functionalized for the first time with Affimer proteins via copper-free click chemistry to actively target overexpressed carcinoembryonic antigens on LS174T colorectal cancer cells. Unlike nontargeted cubosomes, Affimer tagged cubosomes showed preferential accumulation in cancer cells compared to normal cells not only in vitro (2D monolayer cell culture and 3D spheroid models) but also in vivo in colorectal cancer mouse xenografts, while exhibiting low nonspecific absorption and toxicity in other vital organs. Cancerous spheroids had maximum cell death compared to noncancerous cells upon targeted delivery. Xenografts subjected to targeted drug-loaded cubosomes showed a 5-7-fold higher drug accumulation in the tumor tissue compared to the liver, kidneys, and other vital organs, a significant decrease in tumor growth, and an increased survival rate compared to the nontargeted group. This work encompasses the first thorough preclinical investigation of Affimer targeted cubosomes as a cancer therapeutic.


Assuntos
Antígeno Carcinoembrionário/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Animais , Linhagem Celular , Química Click , Liberação Controlada de Fármacos , Humanos , Hidroxibutiratos/farmacologia , Hidroxibutiratos/uso terapêutico , Hidroxibutiratos/toxicidade , Cristais Líquidos/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Pentanonas/farmacologia , Pentanonas/uso terapêutico , Pentanonas/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Mol Sci ; 23(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216339

RESUMO

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.


Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Halogênios/efeitos adversos , Drogas Ilícitas/efeitos adversos , Pentanonas/efeitos adversos , Pirrolidinas/efeitos adversos , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Linhagem Celular , Cocaína/efeitos adversos , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Células HEK293 , Humanos , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular/métodos , Recompensa , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
12.
J Anal Toxicol ; 46(3): e101-e104, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35020879

RESUMO

A 30 year old non-hispanic white male was found unresponsive at his workplace and admitted to the hospital in cardiac arrest. He was pronounced deceased shortly after arrival. At autopsy the pathologist noted a 176 pound, well-nourished, atraumatic, adult male with significant bilateral frothy pulmonary edema (right lung 930 g and left lung 1,130 g), cardiomegaly (430 g), dilated ventricles and slight cerebral edema. Upon completion of the systematic toxicological analysis scope for the Franklin County Coroner's Office Toxicology Laboratory, no known drugs were found. Further review of the gas chromatography--mass spectrometry (GC--MS) full-scan library summary reports showed an unknown peak in both the blood and urine solid phase extracts. An analogue of α-pyrrolidinovalerophenone (α-PVP) was identified, and a GC--MS selected ion monitoring method was developed to identify and quantitate the presence of 4-fluoro-3-methyl-α-PVP. This method quantified the drug at 26 ng/mL in gray top femoral blood, 30 ng/mL in purple top heart blood and 20 ng/mL in red top vitreous humor. Qualitative presence was also observed in the urine but was not detected in the liver. The decedent's cause of death was determined to be due to fluoro-methyl-PVP toxicity and the manner was ruled to be accidental. Investigational follow-up interviews corroborated drug use by the deceased with a preference of research chemicals and synthetic cannabinoids via the internet. No published literature is available currently, and to the author's knowledge this is the first incident of a fatal death solely attributed to this substituted cathinone.


Assuntos
Alcaloides , Pirrolidinas , Adulto , Alcaloides/análise , Humanos , Masculino , Pentanonas , Pirrolidinas/análise
13.
Chirality ; 34(1): 77-85, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34747045

RESUMO

Chiral amine-squaramide is a kind of effective hydrogen bond donor bifunctional catalyst to promote many asymmetric transformations. In this paper, novel chiral tertiary amine-squaramide derived from the natural product of the stevioside was developed and applied into the asymmetric Michael addition of acetylacetone to nitroolefins. This asymmetric reaction performed well, and a series of enantiomerically enriched compounds were obtained in high yields (up to 96%) with excellent enantioselectivities (up to 99% ee).


Assuntos
Alcenos , Diterpenos do Tipo Caurano , Pentanonas , Quinina/análogos & derivados , Estereoisomerismo
14.
Behav Brain Res ; 421: 113713, 2022 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-34906607

RESUMO

Naphyrone, also known as NRG-1, is a novel psychoactive substance (NPS), a cathinone with stimulatory properties available on the grey/illicit drug market for almost a decade. It is structurally related to infamously known powerful stimulants with the pyrovalerone structure, such as alpha-pyrrolidinovalerophenone (α-PVP) or methylenedioxypyrovalerone (MDPV) that are labeled as a cheap replacement for cocaine and other stimulants. Despite the known addictive potential of α-PVP and MDPV, there are no studies directly evaluating naphyrone's addictive potential e.g., in conditioned place preference (CPP) test or using self-administration. Therefore, our study was designed to evaluate the addictive potential in a CPP test in male Wistar rats and compare its effect to another powerful stimulant with a high addictive potential - methamphetamine. Naphyrone increased time spent in the drug-paired compartment with 5 and 20 mg/kg s.c. being significant and 10 mg/kg s.c. reaching the threshold (p = 0.07); the effect was comparable to that of methamphetamine 1.5 mg/kg s.c. The lowest dose, naphyrone 1 mg/kg s.c., had no effect on CPP. Interestingly, no dose response effect was detected. Based on these data, we are able to conclude that naphyrone has an addictive potential and may possess a significant risk to users.


Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Metanfetamina/farmacologia , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Transtornos Relacionados ao Uso de Substâncias , Alcaloides/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Metanfetamina/administração & dosagem , Pentanonas/administração & dosagem , Pirrolidinas/administração & dosagem , Ratos , Ratos Wistar
15.
Toxicol In Vitro ; 79: 105295, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34896600

RESUMO

Aluminum (Al) is highly abundant in the biosphere and can occur in different physico-chemical states. It is present in human food and undergoes transitions between dissolved and particulate species during the passage of the gastrointestinal tract. Moreover, in a complex matrix such as food different inorganic and organic counterions can affect the chemical behavior of Al following oral uptake. In this work, the effects of different counterions, namely chloride, citrate, sulfate, lactate and acetylacetonate, on Al uptake and toxicity in the human intestine are studied. The respective Al salts showed different dissolution behavior in biological media and formed nanoscaled particles correlating in reverse with the amount of their dissolved fraction. The passage through the intestinal barrier was studied using a Caco-2 Transwell® system, showing counterion-dependent variance in cellular uptake and transport. In addition, Al toxicity was investigated using Al species (Al3+, metallic Al0 and oxidic γAl2O3 nanoparticles) and counterions individually or in mixtures on Caco-2 and HepG2 cells. The strongest toxicity was observed using a combination of Al species, depending on solubility, and the lipophilic counterion acetylacetonate. Notably, only the combination of both led to toxicity, while both substances individually did not show toxic effects. A toxification of previously non-toxic Al-species by the presence of acetylacetonate is shown here for the first time. The dependency on the concentration of free Al ions was demonstrated using sodium hydrogen phosphate, which was able to counteract the toxic effects by complexing free Al ions. These findings, using Al salts as an example for a common food contaminant, underline the importance of a consideration of the chemical properties of human nutrition, especially dissolution and hydrophobicity, which can significantly influence the cellular uptake and effects of xenobiotic substances.


Assuntos
Compostos de Alumínio/toxicidade , Alumínio/toxicidade , Nanopartículas Metálicas/toxicidade , Alumínio/química , Alumínio/metabolismo , Compostos de Alumínio/química , Compostos de Alumínio/metabolismo , Disponibilidade Biológica , Células CACO-2 , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Hidroxibutiratos/toxicidade , Intestinos/efeitos dos fármacos , Nanopartículas/toxicidade , Pentanonas/toxicidade
16.
Chemosphere ; 286(Pt 2): 131707, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34365170

RESUMO

2-Pentanone is an excellent organic solvent and extractant, which is widely used in industrial production. 2-Pentanone is harmful to soil organisms when it enters the soil. However, current studies have not clarified the response of the antioxidant enzyme superoxide dismutase (SOD) to 2-Pentanone and its mechanism. In this study, the response of earthworm antioxidant enzyme SOD to 2-Pentanone and its molecular mechanism was investigated at organism molecular levels. The results showed that the SOD activity of earthworms under 2-Pentanone stress was significantly inhibited, and the inability of superoxide anion radicals (·O2-) to be scavenged in time might be one of the reasons for the increase of lipid peroxidation. Under 2-Pentanone exposure conditions, catalase (CAT), an antioxidant enzyme closely related to SOD, and the total antioxidant capacity (T-AOC) of earthworms were activated to resist oxidative damage. On the other hand, the observation of earthworm microstructure provided evidence of a direct risk of 2-Pentanone on earthworm body wall tissues. Molecular-level assays have shown that 2-pentanone altered the secondary structure of SOD, which further led to the loosening of the SOD backbone structure and the extension of the polypeptide chain. On the other hand, 2-pentanone quenched the endogenous fluorescence of SOD in the form of static quenching and formed the 2-pentanone/SOD complex. Molecular simulation results suggested that 2-pentanone tended to bind on the surface of SOD rather than close to the active site, and it is speculated that the alteration of SOD structure is the key reason for the change in its activity. This study enriches the toxicological data of 2-Pentanone on soil organisms, thus responding to the current concerns about its ecological risk.


Assuntos
Oligoquetos , Poluentes do Solo , Animais , Catalase/metabolismo , Malondialdeído , Oligoquetos/metabolismo , Estresse Oxidativo , Pentanonas , Poluentes do Solo/toxicidade , Superóxido Dismutase/metabolismo
17.
J Am Chem Soc ; 143(42): 17452-17464, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34643382

RESUMO

Ketone enolization by sodium hexamethyldisilazide (NaHMDS) shows a marked solvent and substrate dependence. Enolization of 2-methyl-3-pentanone reveals E-Z selectivities in Et3N/toluene (20:1), methyl-t-butyl ether (MTBE, 10:1), N,N,N',N″,N″-pentamethyldiethylenetriamine (PMDTA)/toluene (8:1), TMEDA/toluene (4:1), diglyme (1:1), DME (1:22), and tetrahydrofuran (THF) (1:90). Control experiments show slow or nonexistent stereochemical equilibration in all solvents except THF. Enolate trapping with Me3SiCl/Et3N requires warming to -40 °C whereas Me3SiOTf reacts within seconds. In situ enolate trapping at -78 °C using preformed NaHMDS/Me3SiCl mixtures is effective in Et3N/toluene yet fails in THF by forming (Me3Si)3N. Rate studies show enolization via mono- and disolvated dimers in Et3N/toluene, disolvated dimers in TMEDA, trisolvated monomers in THF/toluene, and free ions with PMDTA. Density functional theory computations explore the selectivities via the E- and Z-based transition structures. Failures of theory-experiment correlations of ionic fragments were considerable even when isodesmic comparisons could have canceled electron correlation errors. Swapping 2-methyl-3-pentanone with a close isostere, 2-methylcyclohexanone, causes a fundamental change in the mechanism to a trisolvated-monomer-based enolization in THF.


Assuntos
Compostos de Organossilício/química , Pentanonas/química , Solventes/química , Deutério/química , Cinética , Modelos Químicos , Estereoisomerismo
18.
Pharmacol Biochem Behav ; 211: 173286, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34634300

RESUMO

RATIONALE: Exposure to a drug can subsequently impact its own reactivity as well as that of other drugs. Given that users of synthetic cathinones, i.e., "bath salts", typically have extensive and varied drug histories, an understanding of the effects of drug history on the behavioral and physiological consequences of synthetic cathiones may be important to their abuse liability. OBJECTIVES: The goal of the current work was to assess the effects of an ethanol pre-exposure on the rewarding and aversive effects of α-PVP. METHODS: Adult male Sprague Dawley rats were exposed to ethanol prior to combined conditioned taste avoidance/conditioned place preference training in which rats were injected with 1.5, 3 or 5 mg/kg of racemic α-PVP or vehicle. Following a 7-day washout period, rats were then tested for thermoregulatory effects of α-PVP using subcutaneous probes to measure body temperature changes over the course of 8 h. This was followed 10 days later by assessments for α-PVP-induced locomotor activity and stereotypies over a 1-h session. RESULTS: α-PVP induced significant dose- and trial-dependent taste avoidance that was significantly attenuated by ethanol history and dose- and time-dependent increases in locomotor activity that were significantly increased by ethanol. α-PVP also induced place preferences and dose- and time-dependent increases in body temperature, but these measures were unaffected by ethanol history. CONCLUSIONS: α-PVP's aversive effects (as measured by taste avoidance) were attenuated, while its rewarding effects (as indexed by place preference conditioning) were unaffected, by ethanol pre-exposure. Such a pattern may indicate increased α-PVP abuse liability, as changes in the balance of aversion and reward may impact overall drug effects and likelihood of drug intake. Future self-administration studies will be necessary to explore this possibility.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Etanol/farmacologia , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Recompensa , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Alcaloides/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração , Paladar/efeitos dos fármacos
20.
J Nat Prod ; 84(9): 2411-2419, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34519213

RESUMO

The soil bacterium Streptomyces pactum ATCC 27456 produces a number of polyketide natural products. Among them is NFAT-133, an inhibitor of the nuclear factor of activated T cells (NFAT) that suppresses interleukin-2 (IL-2) expression and T cell proliferation. Biosynthetic gene inactivation in the ATCC 27456 strain revealed the ability of this strain to produce other polyketide compounds including analogues of NFAT-133. Consequently, seven new derivatives of NFAT-133, TM-129-TM-135, together with a known compound, panowamycin A, were isolated from the culture broth of S. pactum ATCC 27456 ΔptmTDQ. Their chemical structures were elucidated on the basis of their HRESIMS, 1D and 2D NMR spectroscopy, and ECD calculation and spectral data. NFAT-133, TM-132, TM-135, and panowamycin A showed no antibacterial activity or cytotoxicity, but weakly reduced the production of LPS-induced nitric oxide in RAW264.7 cells in a dose-dependent manner. A revised chemical structure of panowamycin A and proposed modes of formation of the new NFAT-133 analogues are also presented.


Assuntos
Pentanóis/farmacologia , Pentanonas/farmacologia , Policetídeos/farmacologia , Streptomyces/química , Animais , Produtos Biológicos , Camundongos , Estrutura Molecular , Células RAW 264.7
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