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1.
Cochrane Database Syst Rev ; 1: CD006282, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-32006461

RESUMO

BACKGROUND: Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. OBJECTIVES: To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. SELECTION CRITERIA: We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing. AUTHORS' CONCLUSIONS: Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.


Assuntos
Fármacos Neuroprotetores/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Adolescente , Aminas/uso terapêutico , Criança , Pré-Escolar , Creatina/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Humanos , Hidroxiureia/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Hormônio Liberador de Tireotropina/uso terapêutico , Ácido gama-Aminobutírico/uso terapêutico
2.
Sci Total Environ ; 711: 134822, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31818591

RESUMO

Phthalates are anti-androgenic chemicals and may cause long-lasting adverse effects on growing fetuses. Understanding their exposure profile during pregnancy, therefore, is of public health importance. Because both behavioral and physiological changes of pregnant women are expected to be substantial, the amount of phthalate exposure is expected to vary significantly over the course of pregnancy. Temporal trend of phthalate exposure during pregnancy, however, is largely unknown, especially in Asian women. The purpose of this study is to investigate the urinary concentrations of metabolites for major phthalates and alternative plasticizers over the course of pregnancy among Korean (n = 81) and Thai women (n = 102). Twenty-four metabolites from 15 plasticizers, such as dimethyl phthalate (DMP), diethyl phthalate (DEP), di-isobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), benzyl butyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP), dioctyl phthalate (DnOP), diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP), di(2-ethylhexyl) terephthalate (DEHTP), and di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH), were measured in urine samples collected in each trimester from pregnant women. While the levels of several phthalate metabolites were significantly different by trimester among Korean women, those of Thai women were relatively consistent. Urinary metabolites of DEP and DnOP were higher in Thai pregnant women compared to Korean pregnant women. The detection frequencies of the DINCH metabolite were 67.4% and 44.9% among Korean and Thai pregnant women, respectively. However, the ratio of DINCH to DEHP metabolites was significantly higher in Thai women. According to risk assessment, 11.9% of Korean and 5.3% of Thai women were considered at risk due to phthalate exposure, and DEHP, DnBP and DiBP were identified as major risk drivers. Considering the vulnerability of growing fetuses, further studies are warranted to identify major sources of exposure to these plasticizers during pregnancy.


Assuntos
Ácidos Cicloexanocarboxílicos/urina , Ácidos Dicarboxílicos/urina , Ácidos Ftálicos/urina , Exposição Ambiental , Poluentes Ambientais , Feminino , Humanos , Gravidez , República da Coreia , Tailândia
4.
Environ Res ; 179(Pt A): 108773, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31605871

RESUMO

Plasticizers are compounds added to plastics to modify their physical proprieties. The most well-known class of plasticizers, the phthalates, has been shown to possess antiandrogenic and tumor promoting activities. 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH) was approved for use in food contact containers in 2006 and has been used as a replacement for phthalates in toys and children products. However, we reported previously that the DINCH metabolite MINCH acts on primary rat adipocytes through the peroxisome proliferator activated receptor (PPAR)-α pathway in a manner similar to phthalates. Evidence from our studies, as well as from the current bibliography on DINCH, suggests that the liver might be one of its target organs. In the present study, we collected tissues from dams exposed subacutely and progeny at postnatal day (PND) 3 and 60 exposed in utero to DINCH (1, 10 and 100 mg/kg bw/day). Exposure to DINCH drastically affected liver gene expression in all 3 age groups tested and in particular at the dose of 1 mg/kg bw/day. The PPAR-α pathway along with other metabolic and DNA replication pathways were affected by DINCH. Modifications in PPAR-α and superoxide dismutase (SOD)-1 protein levels were observed in dams at PND21, as well as male progeny at PND3 and 60. No sign of fibrosis or direct liver toxicity was observed after 8 days of stimulus with low doses of DINCH. This study provides evidence that DINCH is not a biologically inert molecule in the rat, and in the liver its actions are mediated, at least in part, by PPAR-α.


Assuntos
Substâncias Perigosas/toxicidade , Fígado/efeitos dos fármacos , PPAR alfa/metabolismo , Plastificantes/toxicidade , Animais , Criança , Ácidos Cicloexanocarboxílicos/toxicidade , Ácidos Dicarboxílicos , Ésteres , Humanos , Masculino , Ratos , Testes de Toxicidade
5.
Sr Care Pharm ; 34(8): 490-498, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462352

RESUMO

In the midst of a national opioid crisis, Americans have a heightened awareness of the potential for prescription drugs that can be abused. One drug-gabapentin-is frequently prescribed in long-term care facilities for seizures and postherpetic neuralgia, and its use is a growing concern globally. Approved for two uses, but used off-label for many others, gabapentin can induce euphoria at high doses. In older adults, clinicians prescribe it for seizures, pain, migraine, and aggression associated with dementia, among other things. Gabapentin's rapid onset of action, side effect profile, limited drug-drug interactions, and extensive pharmacokinetic data in renal impairment have made prescribers comfortable using it in older adults. This gabapentinoid-a cousin to the Schedule V drug pregabalin-has seen widespread recreational abuse and has led to its reclassification in the United Kingdom and in several U.S. states. Consultant pharmacists need to be aware that the evidence behind off-label use is scant; withdrawal is likely after as few as three weeks of treatment; and drug diversion is possible, even likely. In addition, it is the tenth-most prescribed medication in the United States.


Assuntos
Gabapentina/efeitos adversos , Aminas , Ácidos Cicloexanocarboxílicos , Humanos , Reino Unido , Estados Unidos , Ácido gama-Aminobutírico
6.
J Investig Clin Dent ; 10(4): e12448, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31402607

RESUMO

The aim of this systematic review was to determine the efficacy of gabapentin (GBP) in the treatment of pain of  idiopathic trigeminal neuralgia (TN). A comprehensive literature search was conducted using the Cumulative Index of Nursing and Allied Health Literature (EBSCO Industries), Emcare (Ovid), Medline (Ovid), Medline (PubMed), Scopus (Elsevier) and Web of Science (Clarivate Analytics). The inclusion criteria comprised randomized controlled trials of GBP as a monotherapy in the treatment of idiopathic TN in adult participants and publications in English. All other study methodologies were excluded. The search yielded 1472 articles, and after exclusion, 11 full-text articles were eligible for full-text analysis. Only two studies met the inclusion criteria. There is insufficient evidence either to support or refute the efficacy of GBP in the management of idiopathic TN. Therefore, further well-designed placebo-controlled trials are required to confirm the efficacy of GBP in managing TN pain as a single therapy.


Assuntos
Ácidos Cicloexanocarboxílicos , Neuralgia , Neuralgia do Trigêmeo , Adulto , Aminas , Analgésicos , Gabapentina , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido gama-Aminobutírico
7.
Int J Hyg Environ Health ; 222(8): 1084-1092, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31378638

RESUMO

DINCH (cyclohexane-1,2-dicarboxylic acid-diisononyl ester) is a phthalate plasticizer substitute introduced into the market in 2002. It is increasingly used especially in the production of toys, food contact materials and medical devices. In this measurement campaign on 24-h urine samples of young adults (20-29 years) from the German Environmental Specimen Bank (ESB) collected in 2010, 2011, 2013, 2015 and 2017 (in total 300 samples, 60 samples/year) we analyzed three specific, oxidized DINCH metabolites (OH-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester; cx-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(carboxy-isooctyl) ester, oxo-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester). We merged these data with earlier data of the ESB from the years 1999-2012 and are now able to report levels and time trends of internal DINCH exposure from 1999 to 2017. After first detections of the major oxidized DINCH metabolite OH-MINCH in 2006 (6.7%) detection rates rapidly increased to 43.3% in 2009, 80% in 2010 and 98.3% in 2011 and 2012. From the year 2013 on we could detect OH-MINCH in every urine sample analyzed. The median concentrations of OH-MINCH rapidly increased from 0.15 µg/L in 2010 to twice the concentration in 2011 (0.31 µg/L) with further increases in 2013 (0.37 µg/L), 2015 (0.59 µg/L) and 2017 (0.70 µg/L). Similar increases, albeit at lower detection rates and concentration levels, could be observed for cx-MINCH and oxo-MINCH. All metabolites strongly correlate with each other. For the ESB study population, DINCH exposures are still far below health based guidance values such as the German Human Biomonitoring Value (HBM-I; 4,500 µg/L for the sum of OH-MINCH and cx-MINCH) or the tolerable daily intake (TDI) of EFSA (1 mg/kg bw/d). The median daily DINCH intake (DI) calculated for 2017 was 0.23 µg/kg bw/d, thus 4,310-times lower than the TDI. The maximum DI calculated for one individual in 2012 (42.60 µg/kg bw/d) was a factor of more than 20 below the TDI. The ongoing increase in DINCH exposure needs to be closely monitored in the future, including populations with potentially higher exposures such as children. This close monitoring will enable timely exposure and risk reduction measures if exposures reached critical levels, or if new toxicological data lead to lower health based guidance values. DINCH belongs to the European Human Biomonitoring Initiative (HBM4EU) priority substances for which policy relevant questions still have to be answered.


Assuntos
Ácidos Cicloexanocarboxílicos/urina , Ácidos Dicarboxílicos/urina , Exposição Ambiental/análise , Plastificantes/análise , Adulto , Monitoramento Biológico/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Feminino , Alemanha , Humanos , Masculino , Ácidos Ftálicos , Adulto Jovem
8.
Toxicol Lett ; 314: 82-88, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306742

RESUMO

For decades, phthalates have been widely used as plasticizers in a large number of consumer products, leading to a complex exposure to humans via ingestion, inhalation or dermal uptake. Children may have a higher unintended dust intake per day compared to adults. Therefore, dust intake of children could pose a relevant exposure and subsequently a potential health risk. The aim of this study was to determine the relative bioavailability of certain phthalates, such as di(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and the non-phthalate plasticizer diisononyl 1,2-cyclohexanedicarboxylic acid (DINCH®, Hexamoll®), after ingestion of dust. Seven 5-week-old male piglets were fed five different dust samples collected from daycare centers. Overall, 0.43 g to 0.83 g of dust sieved to 63 µm were administered orally. The piglets' urine was collected over a period of 38 h. The excreted metabolites were quantified using an LC-MS/MS method. The mean uptake rates of the applied doses for DEHP, DINP, and DINCH® were 43% ± 11%, 47% ± 26%, and 9% ± 3.5%, respectively. The metabolites of DEHP and DINP showed maximum concentrations in urine after three to five hours, whereas the metabolites of DINCH®, reached maximum concentrations 24 h post-dose. The oral bioavailability of the investigated plasticizers was higher compared to the bioaccessibility reported from in vitro digestion tests. Furthermore, the bioavailability of DEHP did not vary substantially between the dust samples, whereas a dose-dependent saturation process for DINP was observed. In addition to other intake pathways, dust could be a source of plasticizers in children using the recent intake rates for dust ingestion.


Assuntos
Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Dicarboxílicos/administração & dosagem , Poeira , Ácidos Ftálicos/administração & dosagem , Plastificantes/administração & dosagem , Administração Oral , Fatores Etários , Animais , Animais Recém-Nascidos , Disponibilidade Biológica , Cromatografia Líquida , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/toxicidade , Ácidos Cicloexanocarboxílicos/urina , Ácidos Dicarboxílicos/farmacocinética , Ácidos Dicarboxílicos/toxicidade , Ácidos Dicarboxílicos/urina , Masculino , Ácidos Ftálicos/farmacocinética , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/urina , Plastificantes/farmacocinética , Plastificantes/toxicidade , Medição de Risco , Sus scrofa , Espectrometria de Massas em Tandem , Toxicocinética , Urinálise
9.
J Psychiatr Pract ; 25(4): 308-312, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31291213

RESUMO

Gabapentin is an anticonvulsant medication with an indication from the US Food and Drug Administration for use in partial onset seizures and postherpetic neuralgia in the United States. Currently, gabapentin is only classified as a controlled substance subject to stricter prescribing and distributing regulations in certain states, as opposed to pregabalin, an anticonvulsant with a similar mechanism of action which is a considered a Schedule V medication under federal law. Gabapentin shares a structural similarity to pregabalin, and several case reports have suggested that gabapentin has a similar propensity for abuse. The mechanisms of the gabapentin reward pathway, addiction, and withdrawal, however, are not well known. This case report describes a patient with long-term polysubstance abuse and new onset gabapentin dependence and demonstrates the need for increased surveillance of gabapentin prescribing.


Assuntos
Ácidos Cicloexanocarboxílicos , Gabapentina , Aminas , Humanos , Pregabalina , Ácido gama-Aminobutírico
10.
Amino Acids ; 51(9): 1247-1257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31350614

RESUMO

Somatostatin (SST) is an endogenous cyclic tetradecapeptide hormone that exerts multiple biological activities via a family of five receptors. BIM-23052 (DC-23-99) D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 is a linear SST analog with established in vitro GH-inhibitory activity and high affinity to sstr5, sstr3 and sstr2. The different SSTR subtypes are expressed in different tissues and in some tumor cells. Based on this finding, a series of new analogs of BIM-23052 with expected antitumor activity have been synthesized. The Thr at position 6 in BIM-23052 was replaced by the conformationally hindered Tle, Aib, Ac5c and Ac6c of the new analogs. The peptides were synthesized by standard solid-phase peptide chemistry methods, Fmoc strategy. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29, MDA-MB-23, Hep-G2, HeLa and the normal human diploid cell line Lep-3. All five somatostatin receptor subtypes were modeled and docking was performed to determine the binding affinity of the analogs. The new peptides exhibited different concentration-dependent antiproliferative effect on the tumor cell lines after 24 h of treatment. The compound 3B (Aib6) demonstrated the most pronounced antiproliferative effects on HepG-2 cells with the IC50 = 0.01349 nM. Docking confirmed that all compounds bind well to SST receptors with preference to sstr3 and sstr5, which is most probably the reason for the observed biological effects.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Somatostatina/análogos & derivados , Aminoácidos Cíclicos/química , Ácidos Aminoisobutíricos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ácidos Cicloexanocarboxílicos/química , Cicloleucina/química , Células HT29 , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Receptores de Somatostatina/química , Somatostatina/química , Somatostatina/farmacologia , Relação Estrutura-Atividade
11.
Environ Res ; 173: 342-348, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30953948

RESUMO

To assess human exposure to hazardous diesters of phthalic acid and their substitute di-iso-nonyl cyclohexane-1,2-dicarboxylate (DINCH), concentrations of their metabolites in urine should be determined. For the purpose of this biomonitoring study, a quick and easy sample preparation procedure for the simultaneous determination of eight phthalate and four DINCH metabolites in urine has been implemented and validated. Following the enzymatic hydrolysis and dilution with methanol, the sample is ready for the analysis by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The limits of quantification of this method ranged from 0.15 to 0.4 ng/mL urine with recoveries of 60-126% and repeatability in the range of 1-11%. The validated method was subsequently used for the analysis of urine samples collected from mothers and their newborn children living in two localities of the Czech Republic (Karvina and Ceske Budejovice, 2013-2014). Median concentrations of all measured metabolites (∑metabolites) were slightly lower in the urine samples collected from children (77.7 ng/mL urine) compared to their mothers (115.3 ng/mL urine), but no correlation was found between the concentrations of target compounds in children's and mothers' urine samples. The analyte with the highest concentration was monobutyl phthalate (MBP), with the median concentration of 32.1 ng/mL urine in the urine samples collected from mothers and 17.2 ng/mL urine in the samples collected from their children. This compound was also found in almost all of the measured samples. On the other hand, mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) was not found in any urine sample. The most contaminated samples were collected from children living in the Karvina locality (median ∑metabolites 103.2 ng/mL urine), where the mono (2-ethyl-5-carboxypentyl) phthalate (cx-MEHP) compound contributed 43% to the total content of phthalate metabolites in newborns' urine. The results from our study are comparable with concentrations of the target compounds from Norway and Germany and lower compared to the results concluded in Sweden.


Assuntos
Ácidos Cicloexanocarboxílicos/urina , Ácidos Dicarboxílicos/urina , Exposição Ambiental/estatística & dados numéricos , Ácidos Ftálicos/urina , Adulto , Biomarcadores , Cicloexanos , República Tcheca , Monitoramento Ambiental , Feminino , Humanos , Recém-Nascido , Mães , Espectrometria de Massas em Tandem
12.
Acta Biomater ; 90: 350-361, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30951898

RESUMO

Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids show anti-inflammatory activity for treating inflamed skin diseases, but their efficacy remains low. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis model. OA played dual roles in the nanocarriers as both the active ingredient and lipid matrix in the nanoparticulate core. OA nanoparticles but not free OA could restrain calcium mobilization in activated neutrophils. The inhibition level of superoxide anion and elastase by cilomilast-loaded OA nanocarriers approximated that of free forms. In the mouse model, the intradermal nanosystems reduced imiquimod-induced epidermal thickening from 230.4 to 63.1 µm. Transepidermal water loss was decreased from 30.2 to 11.3 g/m2/h by integrated nanocarriers. The nanosystems mitigated neutrophil infiltration and hyperproliferation in the psoriasiform lesion via decreased expression of cytokines and chemokines. STATEMENT OF SIGNIFICANCE: The long-term therapy for psoriasis is unsatisfactory due to the possible adverse effects and inefficiency after prolonged use. Both phosphodiesterase (PDE4) inhibitors and omega-9 fatty acids such as oleic acid (OA) show anti-inflammatory activity for treating inflamed skin diseases. Combinatorial agents are anticipated to offer an advanced strategy for efficient therapy. OA is also ideal for incorporation into nanoparticles to enhance particulate emulsification, drug entrapment, and biocompatibility. We prepared cilomilast-loaded oleic acid (OA) nanocarriers to test the inhibitory capability against human neutrophil stimulation and a murine psoriasis lesion. OA nanocarriers are indigenous to prevent neutrophil activation and the deterioration of psoriatic lesion. Cilomilast incorporation in OA nanocarriers could further mitigate the clinical score and suppressing proinflammatory mediators.


Assuntos
Ácidos Cicloexanocarboxílicos , Portadores de Fármacos , Nanopartículas , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/metabolismo , Nitrilos , Ácido Oleico , Inibidores da Fosfodiesterase 4 , Psoríase , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Neutrófilos/patologia , Nitrilos/química , Nitrilos/farmacocinética , Nitrilos/farmacologia , Ácido Oleico/química , Ácido Oleico/farmacocinética , Ácido Oleico/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/farmacologia , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Psoríase/patologia
13.
Int J Hyg Environ Health ; 222(3): 583-589, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30898526

RESUMO

BACKGROUND: Phthalic acid esters are widely used to improve the plasticity of PVC in medical devices (MD). The most famous plasticizer is DEHP, whose use in medical devices has been contested by the European authorities since 2008. Several alternative plasticizers are being considered to replace DEHP, such as DEHT, TOTM, DINP or DINCH, but they are also released from the PVC throughout their life cycle and are metabolized in the same way as DEHP. OBJECTIVES: Our study focuses on the in vitro cytotoxicity of two alternative plasticizers (DINCH and DINP) contained in certain medical devices. They are likely to migrate and be transformed in vivo into the primary and secondary metabolites by a metabolism similar to that of DEHP. This preliminary study is the first to assess the in vitro cytotoxicity of oxidized metabolites of DINCH and DINP based on the EN ISO 10-993-5 standards documents. METHODS: We have studied the complete multi-step organic synthesis of secondary metabolites of DINP and DINCH and have performed cytotoxicity tests on L929 murine cells according to the EN ISO 10993-5 standard design for the biocompatibility of a MD. The tested concentrations of obtained metabolites (0.01, 0.05 and 0.1 mg/mL) covered the range likely to be found for DEHP (total metabolism) in biological fluids coming into direct contact with the MD. The concentrations tested in our study were chosen based on a complete transformation of the plasticizers released after direct contact between a MD and the patient's blood. RESULTS: Only 7-oxo-MMeOCH is cytotoxic at the highest concentration (0.1 mg/mL) after 7 days of exposure, just like 5-oxo-MEHP for the same concentration. By contrast, 7-OH-MMeOP, 7-cx-MMeOP, 7-oxo-MMeOP, 7-OH-MMeOCH and 7-cx-MMeOCH were not found to be cytotoxic. CONCLUSION: The known concentrations of these secondary metabolites in urinary samples are in the µg/L range, i.e. about 100-1000 times lower than the concentrations tested in this study. Cytotoxicity is known to be dose-dependent but it is not always the case for endocrine perturbations and the secondary metabolites could induce endocrine perturbations at very low doses.


Assuntos
Ácidos Cicloexanocarboxílicos/toxicidade , Ácidos Dicarboxílicos/toxicidade , Dietilexilftalato/toxicidade , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/metabolismo , Ácidos Dicarboxílicos/metabolismo , Dietilexilftalato/metabolismo , Equipamentos e Provisões , Camundongos , Ácidos Ftálicos/metabolismo , Plastificantes/metabolismo
14.
Talanta ; 198: 230-236, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30876555

RESUMO

Alternative plasticizers (APs) have been increasingly used in the last decade to replace conventional phthalate esters, in particular di(2-ethylhexyl) phthalate (DEHP), due to the toxicity of the latter. However, there is currently very little data about the toxicity of and exposure to APs. No method exists so far for the analysis of multiple exposure biomarkers. The objective of this work consisted in developing a simple bioanalytical procedure for the analysis of multiple exposure biomarkers of APs in human urine and serum. Focus was set on metabolites of di(2-propylheptyl) phthalate (DPrHpP), di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP) and di-2-ethylhexyl adipate (DEHA). A sample preparation protocol was developed and optimized using Oasis HLB solid-phase extraction (SPE) cartridges. Subsequently, an instrumental method based on liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS) was optimized. Following established guidelines, the sample preparation and instrumental methods were validated in terms of recovery, matrix effects, carry-over, linearity, limits of quantification, within- and between-run precision and trueness. Obtained results were satisfactory for all compounds except for one of the metabolites of DEHA (i.e., mono(2-ethylhexyl) adipate (MEHA)). A pilot biomonitoring study was carried out to assess the method's ability to detect and quantify target analytes in human urine and serum. In urine, most analytes could be detected with frequencies ranging from 8% for mono(2-ethyl-5-hydroxyhexyl) adipate (OH-MEHA) and cyclohexane-1,2-dicarboxylic mono hydroxyisononyl ester (OH-MINCH) to 92% for mono(2-ethyl-5-oxohexyl) adipate (oxo-MEHA), whilst most compounds could not be detected in serum, except for mono(2-ethylhexyl) terephthalate (MEHTP) and mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPrHpP) which were detected in all samples. The obtained results show that the developed method can be used to simultaneously analyse multiple exposure biomarkers to APs in human urine and serum.


Assuntos
Plastificantes/química , Adipatos/sangue , Adipatos/metabolismo , Adipatos/urina , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Cromatografia Líquida , Ácidos Cicloexanocarboxílicos/sangue , Ácidos Cicloexanocarboxílicos/metabolismo , Ácidos Cicloexanocarboxílicos/urina , Ácidos Dicarboxílicos/sangue , Ácidos Dicarboxílicos/metabolismo , Ácidos Dicarboxílicos/urina , Humanos , Ácidos Ftálicos/sangue , Ácidos Ftálicos/metabolismo , Ácidos Ftálicos/urina , Espectrometria de Massas em Tandem
15.
Environ Microbiol ; 21(5): 1833-1846, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30895699

RESUMO

Syntrophy is essential for the efficient conversion of organic carbon to methane in natural and constructed environments, but little is known about the enzymes involved in syntrophic carbon and electron flow. Syntrophus aciditrophicus strain SB syntrophically degrades benzoate and cyclohexane-1-carboxylate and catalyses the novel synthesis of benzoate and cyclohexane-1-carboxylate from crotonate. We used proteomic, biochemical and metabolomic approaches to determine what enzymes are used for fatty, aromatic and alicyclic acid degradation versus for benzoate and cyclohexane-1-carboxylate synthesis. Enzymes involved in the metabolism of cyclohex-1,5-diene carboxyl-CoA to acetyl-CoA were in high abundance in S. aciditrophicus cells grown in pure culture on crotonate and in coculture with Methanospirillum hungatei on crotonate, benzoate or cyclohexane-1-carboxylate. Incorporation of 13 C-atoms from 1-[13 C]-acetate into crotonate, benzoate and cyclohexane-1-carboxylate during growth on these different substrates showed that the pathways are reversible. A protein conduit for syntrophic reverse electron transfer from acyl-CoA intermediates to formate was detected. Ligases and membrane-bound pyrophosphatases make pyrophosphate needed for the synthesis of ATP by an acetyl-CoA synthetase. Syntrophus aciditrophicus, thus, uses a core set of enzymes that operates close to thermodynamic equilibrium to conserve energy in a novel and highly efficient manner.


Assuntos
Ácidos/metabolismo , Proteínas de Bactérias/metabolismo , Deltaproteobacteria/metabolismo , Acetatos/metabolismo , Acetilcoenzima A/metabolismo , Ácidos/química , Acil Coenzima A/metabolismo , Proteínas de Bactérias/genética , Benzoatos/metabolismo , Ácidos Cicloexanocarboxílicos/metabolismo , Deltaproteobacteria/enzimologia , Deltaproteobacteria/genética , Transporte de Elétrons , Metano/metabolismo , Methanospirillum/metabolismo , Proteômica
16.
FEBS J ; 286(11): 2118-2134, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30771275

RESUMO

Alternative routes for the post-chorismate branch of the biosynthetic pathway leading to tyrosine exist, the 4-hydroxyphenylpyruvate or the arogenate route. The arogenate route involves the transamination of prephenate into arogenate. In a previous study, we found that, depending on the microorganisms possessing the arogenate route, three different aminotransferases evolved to perform prephenate transamination, that is, 1ß aspartate aminotransferase (1ß AAT), N-succinyl-l,l-diaminopimelate aminotransferase, and branched-chain aminotransferase. The present work aimed at identifying molecular determinant(s) of 1ß AAT prephenate aminotransferase (PAT) activity. To that purpose, we conducted X-ray crystal structure analysis of two PAT competent 1ß AAT from Arabidopsis thaliana and Rhizobium meliloti and one PAT incompetent 1ß AAT from R. meliloti. This structural analysis supported by site-directed mutagenesis, modeling, and molecular dynamics simulations allowed us to identify a molecular determinant of PAT activity in the flexible N-terminal loop of 1ß AAT. Our data reveal that a Lys/Arg/Gln residue in position 12 in the sequence (numbering according to Thermus thermophilus 1ß AAT), present only in PAT competent enzymes, could interact with the 4-hydroxyl group of the prephenate substrate, and thus may have a central role in the acquisition of PAT activity by 1ß AAT.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimologia , Aspartato Aminotransferases/metabolismo , Ácidos Cicloexanocarboxílicos/metabolismo , Cicloexenos/metabolismo , Sinorhizobium meliloti/enzimologia , Transaminases/metabolismo , Tirosina/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Aminoácidos Dicarboxílicos/biossíntese , Proteínas de Arabidopsis/química , Aspartato Aminotransferases/química , Cloroplastos/enzimologia , Sequência Conservada , Cristalografia por Raios X , Modelos Moleculares , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Especificidade por Substrato , Thermus thermophilus/enzimologia , Transaminases/química , Tirosina/análogos & derivados , Tirosina/biossíntese
17.
J Struct Biol ; 205(3): 44-52, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30742895

RESUMO

The 2-carboxy-6-hydroxyoctahydroindole (Choi) moiety is a hallmark of aeruginosins, a class of cyanobacterial derived bioactive linear tetrapeptides that possess antithrombotic activity. The biosynthetic pathway of Choi has yet to be resolved. AerE is a cupin superfamily enzyme that was shown to be involved in the biosynthesis of Choi, but its exact role remains unclear. This study reports the functional characterization and structural analyses of AerE. Enzymatic observation reveals that AerE can dramatically accelerate 1,3-allylic isomerization of the non-aromatic decarboxylation product of prephenate, dihydro-4-hydroxyphenylpyruvate (H2HPP). This olefin isomerization reaction can occur non-enzymatically and is the second step of the biosynthetic pathway from prephenate to Choi. The results of comparative structural analysis and substrate analogue binding geometry analysis combined with the results of mutational studies suggest that AerE employs an induced fit strategy to bind and stabilize the substrate in a particular conformation that is possibly favorable for 1,3-allylic isomerization of H2HPP through coordinate bonds, hydrogen bonds, π-π conjugation interaction and hydrophobic interactions. All of these interactions are critical for the catalytic efficiency.


Assuntos
Proteínas de Bactérias/química , Indóis/química , Isomerases/química , Microcystis/química , Oligopeptídeos/química , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Clonagem Molecular , Cristalografia por Raios X , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/metabolismo , Cicloexenos/química , Cicloexenos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Fibrinolíticos/química , Fibrinolíticos/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Indóis/metabolismo , Isomerases/genética , Isomerases/metabolismo , Cinética , Microcystis/enzimologia , Modelos Moleculares , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Ácidos Fenilpirúvicos/química , Ácidos Fenilpirúvicos/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade por Substrato
20.
Artigo em Inglês | MEDLINE | ID: mdl-30661601

RESUMO

Identification of the characterization of cysteinyl leukotrienes receptor (CysLTRs) could facilitate our understanding of these receptors' role in asthma. We aimed to investigate the localization and interactions of CysLTRs using a mouse model of asthma. BALB/c mice were administered ovalbumin (OVA) to induce allergic asthma. Some mice were administered the antagonists of CysLTR1, CysLTR2, and purinergic receptor P2Y12 (P2Y12R) (montelukast, HAMI 3379 and clopidogrel, respectively). The expression levels of CysLTR1, CysLTR2, and P2Y12R on lung tissues and inflammatory cells were evaluated by western blot, flow cytometry, and immunochemistry. CysLTR1 and P2Y12R were significantly up-regulated in lung tissues (P < 0.05 for each) from mouse after being sensitized and challenged with OVA (OVA/OVA). The ratio of CysLTR1: CysLTR2: P2Y12R in lungs of negative control (NC) mice was shifted from 1:0.43:0.35 to 1:0.65:1.34 in OVA/OVA mice. Montelukast significantly diminished the up-regulation of CysLTR1, CysLTR2, and P2Y12R (P < 0.05 for each), while the effects of HAMI 3379 and clopidogrel were predominant on the expression of CysLTR2 and P2Y12R, respectively. Montelukast predominantly diminished the cell count, while clopidogrel potently inhibited the release of interleukin (IL)-4, IL-5, and IL-13. Our study demonstrated the interactions between CysLTRs, thereby highlighting the potential synergistic effects of CysLTR antagonists in asthma treatment.


Assuntos
Asma/metabolismo , Receptores de Leucotrienos/metabolismo , Acetatos/farmacologia , Acetatos/uso terapêutico , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Clopidogrel/farmacologia , Clopidogrel/uso terapêutico , Ácidos Cicloexanocarboxílicos/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Eosinófilos/efeitos dos fármacos , Feminino , Inflamação/tratamento farmacológico , Interleucinas/metabolismo , Antagonistas de Leucotrienos/farmacologia , Antagonistas de Leucotrienos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/farmacologia , Ácidos Ftálicos/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Receptores Purinérgicos P2Y12/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
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