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1.
BMC Microbiol ; 22(1): 227, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36171563

RESUMO

BACKGROUND: Environmental contamination from synthetic plastics and their additives is a widespread problem. Phthalate esters are a class of refractory synthetic organic compounds which are widely used in plastics, coatings, and for several industrial applications such as packaging, pharmaceuticals, and/or paints. They are released into the environment during production, use and disposal, and some of them are potential mutagens and carcinogens. Isophthalate (1,3-benzenedicarboxylic acid) is a synthetic chemical that is globally produced at a million-ton scale for industrial applications and is considered a priority pollutant. Here we describe the biochemical characterization of an enzyme involved in anaerobic degradation of isophthalate by the syntrophically fermenting bacterium Syntrophorhabdus aromaticivorans strain UI that activate isophthalate to isophthalyl-CoA followed by its decarboxylation to benzoyl-CoA. RESULTS: Isophthalate:Coenzyme A ligase (IPCL, AMP-forming) that activates isophthalate to isophthalyl-CoA was heterologously expressed in E. coli (49.6 kDa) for biochemical characterization. IPCL is homologous to phenylacetate-CoA ligase that belongs to the family of ligases that form carbon-sulfur bonds. In the presence of coenzyme A, Mg2+ and ATP, IPCL converts isophthalate to isophthalyl-CoA, AMP and pyrophosphate (PPi). The enzyme was specifically induced after anaerobic growth of S. aromaticivorans in a medium containing isophthalate as the sole carbon source. Therefore, IPCL exhibited high substrate specificity and affinity towards isophthalate. Only substrates that are structurally related to isophthalate, such as glutarate and 3-hydroxybenzoate, could be partially converted to the respective coenzyme A esters. Notably, no activity could be measured with substrates such as phthalate, terephthalate and benzoate. Acetyl-CoA or succinyl-CoA did not serve as CoA donors. The enzyme has a theoretical pI of 6.8 and exhibited optimal activity between pH 7.0 to 7.5. The optimal temperature was between 25 °C and 37 °C. Denaturation temperature (Tm) of IPCL was found to be at about 63 °C. The apparent KM values for isophthalate, CoA, and ATP were 409 µM, 642 µM, and 3580 µM, respectively. Although S. aromaticivorans is a strictly anaerobic bacterium, the enzyme was found to be oxygen-insensitive and catalysed isophthalyl-CoA formation under both anoxic and oxic conditions. CONCLUSION: We have successfully cloned the ipcl gene, expressed and characterized the corresponding IPCL enzyme, which plays a key role in isophthalate activation that initiates its activation and further degradation by S. aromaticivorans. Its biochemical characterization represents an important step in the elucidation of the complete degradation pathway of isophthalate.


Assuntos
Difosfatos , Poluentes Ambientais , Acetilcoenzima A/metabolismo , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Anaerobiose , Composição de Bases , Benzoatos/metabolismo , Carbono , Carcinógenos , Coenzima A/metabolismo , Coenzima A Ligases , Escherichia coli/metabolismo , Glutaratos , Hidroxibenzoatos , Mutagênicos , Oxigênio , Fenilacetatos/metabolismo , Ácidos Ftálicos , Filogenia , Plásticos , RNA Ribossômico 16S , Análise de Sequência de DNA , Enxofre , Xenobióticos
2.
Sheng Wu Gong Cheng Xue Bao ; 38(9): 3466-3477, 2022 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-36151814

RESUMO

The 4-hydroxyphenylacetate 3-hydroxylase (4HPA3H), originated from Escherichia coli, converts p-coumaric acid to caffeic acid. In order to improve the efficiency of caffeic acid biosynthesis, we engineered E. coli for overexpression of 4HPA3H. The high-density fermentation of the engineered E. coli was conducted in a 5 L bioreactor. Subsequently, the conditions for whole-cell biocatalysis were optimized. The dry cell weight of the 4HPA3H-expressed strain reached 34.80 g/L. After incubated in the bioreactor for 6 h, 18.74 g/L (0.85 g/(L·OD600)) of caffeic acid was obtained, with a conversion rate of 78.81% achieved. To the best of our knowledge, the titer of caffeic acid is the highest reported to date. The high-density fermentation of E. coli for overexpression of 4HPA3H and the efficient biosynthesis of caffeic acid may facilitate future large-scale production of caffeic acid.


Assuntos
Escherichia coli , Oxigenases de Função Mista , Ácidos Cafeicos , Escherichia coli/genética , Escherichia coli/metabolismo , Fermentação , Engenharia Metabólica , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Fenilacetatos
3.
Mol Biol Rep ; 49(9): 8273-8280, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35960408

RESUMO

BACKGROUNDS: Malignant melanoma is an aggressive skin tumor with a rapidly increasing incidence and there is not yet a successful treatment strategy. Vulpinic acid (VA) is derived from secondary metabolites from lichen species. In the current study, we, for the first time, investigated the anti-cancer effects of VA and the underlying mechanism VA induced programmed cell death in melanoma. METHODS: The anti-cancer effects of VA on melanoma cells were evaluated by the xCELLigence system, flow cytometry, caspase-3 activity and RT-PCR analysis. RESULTS: Our results showed that VA had a strong anti-proliferative effect on A-375 melanoma cells without damaging human epidermal melanocyte cells. Additionally, VA promoted apoptotic cell death through G2/M arrest and the activation of both intrinsic and extrinsic apoptosis pathways according to the analysis of 88 genes associated with apoptosis by qRT-PCR. CONCLUSIONS: Our findings suggest that VA could become an alternative topical and transdermal treatment strategy in the treatment of maligned melanoma cancer. However, further investigations are needed to assess the underlying molecular mechanism of VA mediated apoptotic cell death in the treatment of melanoma.


Assuntos
Apoptose , Melanoma , Linhagem Celular Tumoral , Furanos , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Fenilacetatos
5.
Eur J Pharm Sci ; 177: 106264, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35868434

RESUMO

AIMS: Vicagrel is a novel antiplatelet drug used to mitigate clopidogrel resistance due to CYP2C19 polymorphism. This study aimed to develop a semi-mechanistic population pharmacokinetic (PopPK) model to characterize the pharmacokinetic (PK) profile of M15-2, the active metabolite of vicagrel and clopidogrel, and to evaluate the influence of CYP2C19 polymorphisms and other covariates in healthy subjects and patients with acute coronary syndrome (ACS) after oral administration. METHODS: The analysis utilized data from 213 subjects, including 178 healthy subjects and 35 patients, from five clinical trials. PopPK modeling and simulation were used to estimate PopPK parameters and evaluate the impact of covariates. RESULTS: The M15-2 PK profiles were well characterized by a model incorporating transit compartments, two-compartment parent models and two-compartment M15-2 models for both vicagrel and clopidogrel. The parameter estimates indicated the dose fraction of vicagrel that formed M15-2 was approximately 20-fold that of clopidogrel. Covariate analysis identified a significant effect of CYP2C19 on M15-2 apparent clearance (CL/F) and apparent volume of distribution (V3/F) for clopidogrel but only CL/F for vicagrel. The analysis suggested that the nonlinear PK of M15-2 for clopidogrel was due the first-step bioactivation of clopidogrel to 2-oxoclopidogrel. CONCLUSION: The model illustrated the bioactivation of vicagrel is more efficient and less dependent on CYP2C19 than that of clopidogrel. M15-2 is formed in a linear process from vicagrel, versus a nonlinear and less predictable process from clopidogrel. Advantages in both PK and pharmacogenetics suggest that vicagrel may reduce the complexity of currently recommended CYP2C19-based dosage adjustment for clopidogrel.


Assuntos
Inibidores da Agregação Plaquetária , Ticlopidina , Clopidogrel , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Galanina/análogos & derivados , Humanos , Fenilacetatos , Inibidores da Agregação Plaquetária/uso terapêutico , Substância P/análogos & derivados , Tiofenos
6.
Molecules ; 27(12)2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35744950

RESUMO

EGFR and Wnt/ß-catenin signaling pathways play a prominent role in tumor progression in various human cancers including non-small-cell lung carcinoma (NSCLC). Transactivation and crosstalk between the EGFR and Wnt/ß-catenin pathways may contribute to the aggressiveness of cancers. Targeting these oncogenic pathways with small molecules is an attractive approach to counteract various types of cancers. In this study, we demonstrate the effect of euphorbiasteroid (EPBS) on the EGFR and Wnt/ß-catenin pathways in NSCLC cells. EPBS induced preferential cytotoxicity toward A549 (wildtype EGFR-expressing) cells over PC-9 (mutant EGFR-expressing) cells. EPBS suppressed the expression of EGFR, Wnt3a, ß-catenin, and FZD-1, and the reduction in ß-catenin levels was found to be mediated through the activation of GSK-3ß. EPBS reduced the phosphorylation of GSK-3ßS9 with a parallel increase in ß-TrCP and phosphorylation of GSK-3ßY216. Lithium chloride treatment increased the phosphorylation of GSK-3ßS9 and nuclear localization of ß-catenin, whereas EPBS reverted these effects. Forced expression or depletion of EGFR in NSCLC cells increased or decreased the levels of Wnt3a, ß-catenin, and FZD-1, respectively. Overall, EPBS abrogates EGFR and Wnt/ß-catenin pathways to impart its anticancer activity in NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diterpenos , Receptores ErbB/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Fenilacetatos , Via de Sinalização Wnt , beta Catenina/metabolismo
9.
mBio ; 13(3): e0186321, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35467424

RESUMO

The opportunistic pathogen Acinetobacter baumannii is responsible for a wide range of infections that are becoming increasingly difficult to treat due to extremely high rates of multidrug resistance. Acinetobacter's pathogenic potential is thought to rely on a "persist and resist" strategy that facilitates its remarkable ability to survive under a variety of harsh conditions. The paa operon is involved in the catabolism of phenylacetic acid (PAA), an intermediate in phenylalanine degradation, and is the most differentially regulated pathway under many environmental conditions. We found that, under subinhibitory concentrations of antibiotics, A. baumannii upregulates expression of the paa operon while simultaneously repressing chaperone-usher Csu pilus expression and biofilm formation. These phenotypes are reverted either by exogenous addition of PAA and its nonmetabolizable derivative 4-fluoro-PAA or by a mutation that blocks PAA degradation. Interference with PAA degradation increases susceptibility to antibiotics and hydrogen peroxide treatment. Transcriptomic and proteomic analyses identified a subset of genes and proteins whose expression is affected by addition of PAA or disruption of the paa pathway. Finally, we demonstrated that blocking PAA catabolism results in attenuated virulence in a murine catheter-associated urinary tract infection (CAUTI) model. We conclude that the paa operon is part of a regulatory network that responds to antibiotic and oxidative stress and is important for virulence. PAA has known regulatory functions in plants, and our experiments suggest that PAA is a cross-kingdom signaling molecule. Interference with this pathway may lead, in the future, to novel therapeutic strategies against A. baumannii infections. IMPORTANCE Acinetobacter baumannii causes a wide range of infections that are difficult to treat due to increasing rates of multidrug resistance; however, the mechanisms that this pathogen uses to respond to stress are poorly understood. Here, we describe a new mechanism of stress signaling in Acinetobacter that is mediated by the metabolite phenylacetic acid (PAA). We found that disrupting PAA catabolism interfered with A. baumannii's ability to adapt to stress, leading to decreased antibiotic tolerance and hydrogen peroxide resistance. We propose that investigating this stress response could lead to the development of novel therapeutics. In fact, PAA derivatives constitute a group of FDA-approved nonsteroidal anti-inflammatory drugs that could potentially be repurposed as antivirulence therapies to target multidrug-resistant Acinetobacter infections.


Assuntos
Acinetobacter baumannii , Antibacterianos , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Biofilmes , Farmacorresistência Bacteriana Múltipla , Peróxido de Hidrogênio/metabolismo , Camundongos , Estresse Oxidativo , Fenilacetatos , Proteômica
10.
J Vet Pharmacol Ther ; 45(4): 325-351, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35460083

RESUMO

Robenacoxib is a veterinary-approved non-steroidal anti-inflammatory drug (NSAID) of the coxib group. It possesses anti-hyperalgesic, anti-inflammatory and anti-pyretic properties. Robenacoxib inhibits the cyclooxygenase (COX)-2 isoform of COX selectively (in vitro IC50 ratios COX-1:COX-2, 129:1 in dogs, 32:1 in cats). At registered dosages (2 mg/kg subcutaneously in dogs and cats, 1-4 mg/kg orally in dogs and 1-2.4 mg/kg orally in cats), robenacoxib produces significant inhibition of COX-2 whilst sparing COX-1. The pharmacokinetic (PK) profile of robenacoxib is characterized by a high degree of binding to plasma proteins (>98%) and moderate volume of distribution (at steady state, 240 ml/kg in dogs and 190 ml/kg in cats). In consequence, the terminal half-life in blood (<2 h) is short, despite moderate body clearance (0.81 L/kg/h) in dogs and low clearance (0.44 L/kg/h) in cats. Excretion is principally in the bile (65% in dogs and 72% in cats). Robenacoxib concentrates in inflamed tissues, and clinical efficacy is achieved with once-daily dosing, despite the short blood terminal half-life. In dogs, no relevant breed differences in robenacoxib PK have been detected. Robenacoxib has a wide safety margin; in healthy laboratory animals daily oral doses 20-fold (dog, 1 month), eight-fold (cat, 6 weeks) and five-fold (dog, 6 months) higher than recommended clinical doses were well tolerated. Clinical efficacy and safety have been demonstrated in orthopaedic and soft tissue surgery, and in musculoskeletal disorders in dogs and cats.


Assuntos
Doenças do Gato , Doenças do Cão , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças do Gato/induzido quimicamente , Doenças do Gato/tratamento farmacológico , Gatos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Difenilamina/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Fenilacetatos/farmacologia , Fenilacetatos/uso terapêutico
11.
Food Chem Toxicol ; 163 Suppl 1: 113055, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35460830

RESUMO

Therefore, the phenethyl formate MOE for the fertility endpoint can be calculated by dividing the phenethyl alcohol NOAEL in mg/kg/day by the total systemic exposure to phenethyl formate, 1000/0.00062 or 1612903.


Assuntos
Odorantes , Perfumes , Qualidade de Produtos para o Consumidor , Formiatos , Perfumes/toxicidade , Fenilacetatos , Sistema de Registros , Medição de Risco , Testes de Toxicidade
13.
Clin Transl Sci ; 15(6): 1449-1459, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35238476

RESUMO

Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours' standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child-Turcotte-Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose-dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%-60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.


Assuntos
Encefalopatia Hepática , Adulto , Amônia/metabolismo , Amônia/uso terapêutico , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/metabolismo , Humanos , Ornitina/análogos & derivados , Fenilacetatos
14.
J Am Chem Soc ; 144(12): 5629-5642, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35293728

RESUMO

Human ornithine aminotransferase (hOAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacological inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT inactivators (CPP-115 and OV329). Inspired by the inactivation mechanistic difference between these two aminotransferases, a series of analogues were designed and synthesized, leading to the discovery of analogue 10b as a highly selective and potent hOAT inhibitor. Intact protein mass spectrometry, protein crystallography, and dialysis experiments indicated that 10b was converted to an irreversible tight-binding adduct (34) in the active site of hOAT, as was the unsaturated analogue (11). The comparison of kinetic studies between 10b and 11 suggested that the active intermediate (17b) was only generated in hOAT and not in GABA-AT. Molecular docking studies and pKa computational calculations highlighted the importance of chirality and the endocyclic double bond for inhibitory activity. The turnover mechanism of 10b was supported by mass spectrometric analysis of dissociable products and fluoride ion release experiments. Notably, the stopped-flow experiments were highly consistent with the proposed mechanism, suggesting a relatively slow hydrolysis rate for hOAT. The novel second-deprotonation mechanism of 10b contributes to its high potency and significantly enhanced selectivity for hOAT inhibition.


Assuntos
4-Aminobutirato Transaminase , Neoplasias Hepáticas , Ácidos Carboxílicos , Inibidores Enzimáticos/química , Humanos , Cinética , Simulação de Acoplamento Molecular , Ornitina-Oxo-Ácido Transaminase , Fenilacetatos , Fosfato de Piridoxal/química , Ácido gama-Aminobutírico
15.
Chem Commun (Camb) ; 58(32): 4993-4996, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35357385

RESUMO

The use of a native directing group to promote C-H activation is highly desirable. Herein, we report a method of native carboxyl-assisted, Pd(II)-catalyzed ortho-C-H acetoxylation of both hydrocinnamic and phenylacetic acids that can be found in many biologically active molecules as the key moieties. Based on the broad scope and the application potential showcased with drug molecules, it is anticipated that this C-H acetoxylation reaction will find attractive applicability in future synthetic endeavors.


Assuntos
Paládio , Fenilacetatos , Catálise
16.
J Oleo Sci ; 71(2): 247-255, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35110467

RESUMO

Disorganization and breakdown of extracellular matrix proteins like fibronectin, collagen, and elastin are key characteristics of skin aging due to the increased activation of important proteolytic enzymes like elastases and collagenase enzymes. Also, inhibition of their enzymatic activities by natural molecules might be a promising factor to prevent extrinsic skin aging. All chemicals were obtained from Sigma-Aldrich unless otherwise stated. The assay employed was based on spectrophotometric methods reported in the literature. The collagenase and elastase inhibition assays of some phenolic compounds were performed according to the previous studies. These compounds showed excellent to good inhibitory activities of vulpinic acid against studied these enzymes with IC50 values of 195.36 µM for collagenase and 25.24 µM for elastase. The molecular docking calculations were conducted to investigate the chemical and biological activity of vulpinic acid and usnic acid against collagenase and elastase. The results indicated that these two compounds can interact with the essential residues of the enzymes and affect their activities. The calculations of binding free energies were also performed to obtain more details about the characteristics and free energies of the ligand-enzyme complexes. Additionally, both compounds exhibited the most potent inhibition in the three lung cancer cells, with an IC50 value of 21-68 µM, indicating that vulpinic acid is more potent than Doxorubicin, which exhibited an IC50 value of 21-29 µM.


Assuntos
Antineoplásicos , Benzofuranos/farmacologia , Colagenases/metabolismo , Furanos/farmacologia , Neoplasias Pulmonares/patologia , Elastase Pancreática/metabolismo , Fenilacetatos/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Proteínas da Matriz Extracelular/metabolismo , Humanos , Modelos Moleculares , Envelhecimento da Pele/fisiologia
17.
Indian J Ophthalmol ; 70(3): 807-812, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35225519

RESUMO

PURPOSE: To compare the efficacy of a once-daily dose of 0.3% nepafenac and three times daily dose of 0.1% nepafenac in controlling pain and inflammation following phacoemulsification. METHODS: In this prospective randomized control single-blind study. patients who underwent uneventful phacoemulsification were divided into two groups. Group A received 0.1% nepafenac eye drops three times/day for 4 weeks and group B received 0.3% nepafenac eye drops once daily for 4 weeks following phacoemulsification. All the patients received moxifloxacin 0.5% eye drops four times/day for 2 weeks. None of the patients in any group received any form of corticosteroids. RESULTS: The mean age of the patients in group A was 63.55 ± 8.5 years, while in group B, it was 60.05 ± 7.76 years. There was no significant result in the preoperative baseline demographics and intraoperative parameters between both the groups. The results were statistically insignificant in terms of inflammatory markers between both groups on day 1. But, on day 7, group B showed better results in terms of lid edema, conjunctival congestion, and anterior chamber cells. The patients in group B also perceived significantly less pain on day 1 (P = 0.02) and day 7 (P < 0.001). The central macular thickness was also significantly lower in group B at day 30. (: P < .001) and day 90 (P < .001), respectively. CONCLUSION: Once-daily dose of higher concentrated nepafenac (0.3%) is equally effective and shows better results than 0.1% nepafenac for pain and inflammation control.


Assuntos
Benzenoacetamidas , Facoemulsificação , Idoso , Anti-Inflamatórios não Esteroides , Método Duplo-Cego , Humanos , Inflamação , Pessoa de Meia-Idade , Soluções Oftálmicas , Dor , Fenilacetatos , Estudos Prospectivos , Método Simples-Cego
19.
Int J Mol Sci ; 23(3)2022 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-35163684

RESUMO

Aldehyde dehydrogenases (ALDHs) are the major enzyme superfamily for the aldehyde metabolism. Since the ALDH polymorphism leads to the accumulation of acetaldehyde, we considered that the enhancement of the liver ALDH activity by certain food ingredients could help prevent alcohol-induced chronic diseases. Here, we evaluated the modulating effects of 3-hydroxyphenylacetic acid (OPAC), the major metabolite of quercetin glycosides, on the ALDH activity and acetaldehyde-induced cytotoxicity in the cultured cell models. OPAC significantly enhanced the total ALDH activity not only in mouse hepatoma Hepa1c1c7 cells, but also in human hepatoma HepG2 cells. OPAC significantly increased not only the nuclear level of aryl hydrocarbon receptor (AhR), but also the AhR-dependent reporter gene expression, though not the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent one. The pretreatment of OPAC at the concentration required for the ALDH upregulation completely inhibited the acetaldehyde-induced cytotoxicity. Silencing AhR impaired the resistant effect of OPAC against acetaldehyde. These results strongly suggested that OPAC protects the cells from the acetaldehyde-induced cytotoxicity, mainly through the AhR-dependent and Nrf2-independent enhancement of the total ALDH activity. Our findings suggest that OPAC has a protective potential in hepatocyte models and could offer a new preventive possibility of quercetin glycosides for targeting alcohol-induced chronic diseases.


Assuntos
Aldeído Desidrogenase/metabolismo , Glicosídeos/metabolismo , Hepatócitos/patologia , Intestinos/metabolismo , Fenilacetatos/farmacologia , Substâncias Protetoras/farmacologia , Quercetina/metabolismo , Acetaldeído , Aldeído Desidrogenase/genética , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoproteção/efeitos dos fármacos , Glicosídeos/química , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Fenilacetatos/química , Quercetina/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo
20.
Ophthalmol Glaucoma ; 5(5): 516-524, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35196591

RESUMO

PURPOSE: To assess the safety and efficacy of 0.1% nepafenac versus 0.09% bromfenac eye drops in controlling inflammation after neodymium yttrium-aluminum-garnet (YAG) laser peripheral iridotomy (LPI). DESIGN: Single-masked, single-center, randomized controlled trial. PARTICIPANTS: One hundred and sixty eyes of patients with primary angle-closure suspect (PACS) and primary angle closure (PAC) undergoing bilateral LPI. METHODS: Patients were randomized in a 1:1 ratio to receive 0.1% nepafenac thrice daily or 0.09% bromfenac eye drops twice daily for 2 weeks after neodymium YAG LPI. Assessment was performed by masked investigators at 2 weeks after LPI. A Glaucoma Symptom Scale (GSS) questionnaire was administered both at baseline and 2 weeks after LPI. Subjective comfort scores to the study medications were assessed on the basis of a Likert scale at 2 weeks after LPI. In patients with bilateral PACS or PAC, the right eye was analyzed, and in asymmetrical disease (i.e., when one eye had PACS and the other eye had PAC), the eye with PAC was analyzed. MAIN OUTCOME MEASURES: The primary outcome (end point) was uncontrolled inflammation, defined as symptomatic inflammation within 1 week after LPI, the presence of anterior chamber cells at 2 weeks, or rebound inflammation after medication discontinuation. The secondary outcome was patient-reported comfort levels with study medications based on the GSS and Likert scale. RESULTS: At 2 weeks after LPI, 7 patients (6 with PACS and 1 with PAC) in the nepafenac group and 2 patients with PACS in the bromfenac group achieved the primary end point, without a difference between the medication groups (P = 0.09). Post-LPI burning, smarting, and stinging was more common in the bromfenac group (P = 0.01), which also had a higher comfort score on the Likert scale (P = 0.004). The need for repeat LPI was comparable (10.0% in the nepafenac group vs. 15.4% in the bromfenac group; P = 0.22). A multivariate analysis revealed that a greater number of laser shots was associated with the need for repeat LPI (odds ratio, 1.05; 95% confidence interval, 1.00-1.10; P = 0.04). CONCLUSIONS: Topical 0.09% bromfenac is noninferior to 0.1% nepafenac in controlling inflammation after LPI in eyes with PACS and PAC. Nepafenac may be associated with higher patient-reported comfort.


Assuntos
Glaucoma de Ângulo Fechado , Iridectomia , Benzenoacetamidas , Benzofenonas , Bromobenzenos , Glaucoma de Ângulo Fechado/diagnóstico , Glaucoma de Ângulo Fechado/cirurgia , Humanos , Inflamação/diagnóstico , Inflamação/etiologia , Iridectomia/métodos , Iris , Neodímio , Soluções Oftálmicas , Fenilacetatos
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