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1.
Medicine (Baltimore) ; 99(32): e21634, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769929

RESUMO

INTRODUCTION: Arginineemia, also known as arginase deficiency, is a rare autosomal recessive metabolic disease. The diagnosis sometimes may be delayed due to atypical clinical manifestations. Confirmation of arginineemia depends on genetic testing. PATIENT CONCERNS: We reported a Chinese male child presenting with hyperargininemia and progressive spastic diplegia, who has a novel compound heterozygous mutation in the arginase-1 (ARG1) gene (c.263-266delAGAA, p.K88Rfs45;c.674T>C,p.L216P), respectively, coming from his mother and father. DIAGNOSIS: The patient was diagnosed with argininemia with a novel compound homozygous mutation of the ARG1 gene at the age of 12 years. INTERVENTIONS: The patient had a low-protein diet (0.8 g/kg/day). Baclofen, eperisone hydrochloride, botulinum toxin, and rehabilitation training were used to improve his spastic diplegia symptoms for 3 months. OUTCOMES: The patient's blood arginine was still high after 3 months' low-protein diet. His spastic diplegia symptoms had not aggravated after 3 months' treatment. CONCLUSIONS: Argininemia should be considered in a patient with slowly progressive neurologic manifestations, especially spastic diplegia. This case also suggests that tandem mass spectrometry should be used as an effective tool in the validity of neonatal screening for early diagnosis.


Assuntos
Arginase/genética , Hiperargininemia/complicações , Arginase/sangue , Arginase/urina , Baclofeno/uso terapêutico , Toxinas Botulínicas/uso terapêutico , Paralisia Cerebral/complicações , Paralisia Cerebral/tratamento farmacológico , Criança , China , Dieta com Restrição de Proteínas/métodos , Humanos , Hiperargininemia/genética , Hiperargininemia/fisiopatologia , Masculino , Propiofenonas/uso terapêutico
2.
Life Sci ; 254: 117807, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32422304

RESUMO

AIMS: Xanthohumol (XN), a natural prenylated flavonoid isolated from Humulus lupulus L. (hops), possess the therapeutic effects in glioblastoma multiforme (GBM), which is a grade IV aggressive glioma in adults. However, low bioavailability and extractive yield limit the clinical applications of XN. To comprehensively investigate XN-mediated gene networks in inducing cell death is helpful for drug development and cancer research. Therefore, we aim to identify the detailed molecular mechanisms of XN's effects on exhibiting cytotoxicity for GBM therapy. METHODS AND KEY FINDINGS: XN significantly induced GBM cell death and enhanced temozolomide (TMZ) cytotoxicity, a first-line therapeutic drug of GBM. XN-mediated transcriptome profiles and canonical pathways were identified. DNA repair signaling, a well-established mechanism against TMZ cytotoxicity, was significantly correlated with XN-downregulated genes. Replication factor C subunit 2 (RFC2), a DNA repair-related gene, was obviously downregulated in XN-treated cells. Higher RFC2 levels which occupied poor patient survival were also observed in high grade GBM patients and tumors. Inhibition of RFC2 reduced cell viability, induced cell apoptosis, and enhanced both XN and TMZ cytotoxicity. By intersecting array data, bioinformatic prediction, and in vitro experiments, microRNA (miR)-4749-5p, a XN-upregulated microRNA, was identified to target to RFC2 3'UTR and inhibited RFC2 expression. A negative correlation existed between miR-4749-5p and RFC2 in GBM patients. Overexpression of miR-4749-5p significantly promoted XN- and TMZ-mediated cytotoxicity, and reduced RFC2 levels. SIGNIFICANCE: Consequently, we suggest that miR-4749-5p targeting RFC2 signaling participates in XN-enhanced TMZ cytotoxicity of GBM. Our findings provide new potential therapeutic directions for future GBM therapy.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Flavonoides/farmacologia , Glioblastoma/fisiopatologia , MicroRNAs/fisiologia , Propiofenonas/farmacologia , Proteína de Replicação C/biossíntese , Temozolomida/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína de Replicação C/antagonistas & inibidores , Transdução de Sinais
3.
Phytomedicine ; 71: 153233, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32454348

RESUMO

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability. PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers. CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Propiofenonas/química , Propiofenonas/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Feminino , Flavonoides/farmacocinética , Adjuvante de Freund/efeitos adversos , Interleucina-6/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Micelas , Estresse Oxidativo/efeitos dos fármacos , Propiofenonas/farmacocinética , Ratos Wistar , Solubilidade , Fator de Necrose Tumoral alfa/metabolismo
4.
Environ Int ; 137: 105495, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32120142

RESUMO

The increased use of sunscreens and other cosmetics containing UV filters causes human and environmental burden. Avobenzone is a widely used UV filter. In its pure form it is known to undergo several transformations including photo-isomerisation, photodegradation, and halogenation. Over 60 disinfection by-products were identified as transformation products of avobenzone in different disinfection reactions of chlorination and bromination in fresh and seawater. Two occasional samples of swimming pool water demonstrated the presence of some of these by-products at noticeable levels as judged by GC-MS peak areas. Although the toxicity of the majority of these products remain unknown, chlorinated phenols and acetophenones are known to be rather toxic. Aquatic bromination of avobenzone resulted in the identification of 33 disinfection by-products (DBPs). Many of them contain bromine in the molecular structure. Addition of copper salt slightly decreases conversion rate simultaneously increasing the levels of major brominated products. Photostability of 3 commercial sunscreen products (solar protection factor 30) containing avobenzone was studied under different experimental conditions including UVA/UVB, UVC photostimulation and chlorination. The commercial sunscreen products have completely different enhancing and inhibitory effect on avobenzone degradation under UVC light. The complex composition of commercial products caused also a protective shield in case of chlorinated solutions of commercial formulations exposed to chlorine and UVA/UVB light at the same time.


Assuntos
Desinfetantes , Propiofenonas , Piscinas , Poluentes Químicos da Água , Purificação da Água , Cloro , Desinfecção , Halogenação , Humanos , Propiofenonas/química
5.
Sci Total Environ ; 714: 136879, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32018996

RESUMO

Oxybenzone (OBZ), avobenzone (AVB), octocrylene (OCR) and octinoxate (OMC) are ultraviolet (UV) filters commonly added to chemical sunscreens. These UV filters are known to widely contaminate the environment through a variety of anthropogenic sources, including sewage discharge. However, systematic studies of the damage caused by these four UV filters and their toxicopathological differences in a variety of plant species are lacking. In this study, we demonstrated that irrigation with water containing these four UV filters could significantly inhibit the aboveground growth of cucumber plant. All of the UV filters decreased photosynthesis through nonstomatal factors but via different inhibitory mechanisms. Only OBZ inhibited photosynthesis by directly inhibiting photosynthetic electron transport, while the other three (AVB, OCR, and OMC) inhibited photosynthesis by inhibiting the Calvin-Benson cycle. Additionally, these four UV filters also decreased plant respiration under long-term treatment. Photosynthesis and respiration inhibition led to the over production of reactive oxygen species (ROS) and the formation of lipid peroxidation damage products, which further damaged the structure and function of plant cells, causing secondary pathologies and potentially leading to reduced crop yields. The study also demonstrated that these four UV filters caused different degrees of phototoxic damage to cucumber plants. On the basis of comprehensive evaluation, we speculated that the order of the four UV filters in terms of plant damage was OBZ > AVB > OMC > OCR. Because of the severe damaging effects of these UV filters on plant growth, the application of contaminated biosolids/reclaimed water in agriculture reduces agricultural production and may damage ecosystems. The results of this study can advance recognition of the hazards associated with environmental and agricultural pollution via UV filters and encourage consumers and the industry to limit or reduce the application of cosmetics and over-the-counter drugs containing these substances.


Assuntos
Cucumis sativus , Acrilatos , Benzofenonas , Cinamatos , Ecossistema , Propiofenonas , Protetores Solares , Raios Ultravioleta
6.
Sci Adv ; 6(2): eaaw8702, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31934620

RESUMO

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aß(1-42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.


Assuntos
Sistema Nervoso Central/citologia , Ensaios de Triagem em Larga Escala , Mitocôndrias/metabolismo , Neurônios/citologia , Trifosfato de Adenosina/biossíntese , Animais , Células Cultivadas , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenótipo , Propiofenonas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
7.
JAMA ; 323(3): 256-267, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961417

RESUMO

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.


Assuntos
Propiofenonas/sangue , Absorção Cutânea , Protetores Solares/farmacocinética , Acrilatos/sangue , Acrilatos/farmacocinética , Adulto , Benzofenonas/sangue , Benzofenonas/farmacocinética , Cinamatos/sangue , Cinamatos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propiofenonas/farmacocinética , Salicilatos/sangue , Salicilatos/farmacocinética , Protetores Solares/efeitos adversos
8.
PLoS One ; 15(1): e0227774, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978078

RESUMO

The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a ß-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.


Assuntos
Drogas Desenhadas/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Metanfetamina/análogos & derivados , Metanfetamina/efeitos adversos , Propiofenonas/efeitos adversos , Psicotrópicos/efeitos adversos , Animais , DNA Bacteriano/isolamento & purificação , Drogas Desenhadas/administração & dosagem , Feminino , Microbioma Gastrointestinal/genética , Metanfetamina/administração & dosagem , Camundongos , Modelos Animais , Propiofenonas/administração & dosagem , Psicotrópicos/administração & dosagem , RNA Ribossômico 16S/genética
9.
Toxicol Lett ; 320: 113-123, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634548

RESUMO

3,4-Dimethylmethcathinone (3,4-DMMC) is a new psychoactive substance whose recreational use and trade have recently increased. Given the absence of information on the toxicokinetics of 3,4-DMMC, the present work aimed at validating a GC-MS methodology for the drug quantification in biological matrices, and further characterizing its biodistribution in Wistar rats. The method was validated based on the evaluation of the drug stability, limit of detection and quantification, linearity, selectivity, precision, accuracy and recovery. To characterize biodistribution, Wistar rats were administered with 20 or 40 mg/Kg of 3,4-DMMC i.p.. After 1 h or 24 h, rats were anaesthetized, euthanized and blood, brain, liver, heart, kidneys, lungs, spleen, urine (only at 24 h), and a portion of gut, muscle and adipose tissue were collected for analysis. After 1 h, 3,4-DMMC was present in all analysed matrices, and the presence of two metabolites was further detected in all of them. The drug accumulation was higher in kidneys, lungs, spleen and brain. After 24 h, 3,4-DMMC was only present in urine, along with five metabolites. All metabolites were tentatively identified. Through elucidation of the most appropriate analytical matrices and the metabolites that may have the largest detection windows, these data are expected to assist in future clinical and forensic investigations.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas , Drogas Ilícitas/farmacocinética , Propiofenonas/farmacocinética , Psicotrópicos/farmacocinética , Animais , Biotransformação , Estabilidade de Medicamentos , Feminino , Injeções Intraperitoneais , Limite de Detecção , Propiofenonas/administração & dosagem , Psicotrópicos/administração & dosagem , Ratos Wistar , Reprodutibilidade dos Testes , Distribuição Tecidual
10.
Environ Toxicol ; 35(2): 136-144, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31714664

RESUMO

Colorectal cancer (CRC) is a major health problem and third most common deaths in western world. Dietary interventions together with modified dietary style can prevent the CRC in humans. Xanthohumol (XHA), a polyphenol isolated from Humulus lupulus L. contains many beneficial effects. The aim of the study is to analyze the effect of XHA on Azoxymethane (AOM)-induced experimental CRC in rats. Levels of MDA were increased and enzymic antioxidants levels were decreased in AOM-induced rats. However, these levels were reversed upon XHA treatment. Further, the mRNA expressions of iNOS and COX-2 were also downregulated in XHA treated rats compared to AOM-induced rats. Further, we found that administration of XHA suppressed the wnt/ß-catenin signaling together with modulation of apoptotic proteins Bax, Bcl-2, and caspase 3. We conclude that XHA can able to quench the free radicals, inhibits cell proliferation and induces apoptosis, thus it can be a chemopreventive/therapeutic agent against CRC.


Assuntos
Focos de Criptas Aberrantes/prevenção & controle , Antioxidantes/farmacologia , Azoximetano/toxicidade , Neoplasias Colorretais/prevenção & controle , Flavonoides/farmacologia , Propiofenonas/farmacologia , Focos de Criptas Aberrantes/induzido quimicamente , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/induzido quimicamente , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
11.
J Chromatogr A ; 1613: 460673, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-31708220

RESUMO

The uptake, translocation and transformation of three UV-blockers commonly employed in sunscreens, namely avobenzone, octocrylene and octisalate from water by Lemna gibba and Cyperus alternifolius was investigated. Reversed phase high performance liquid chromatography coupled to drift-tube ion-mobility quadrupole time-of-flight mass spectrometry was used for analyzing the extracts from the selected plants after incubation with the UV-blockers for one week. For avobenzone several transformation products resulting from hydroxylation, demethylation and oxidation of the parent molecule could be identified by measuring accurate mass, performing MS/MS experiments and by determining their drift-tube collision cross sections employing nitrogen as drift gas. In addition, the plants were subjected to two commercially available sunscreens, providing similar results to those obtained for the standard solutions of the UV-blockers. Finally, a kinetic study on the uptake and transformation of avobenzone, octocrylene and octisalate was conducted over a period of 216 h, revealing that the UV-filters were mostly present in their parent form and only to a smaller part converted into transformation products.


Assuntos
Araceae/metabolismo , Cromatografia Líquida de Alta Pressão , Cyperus/metabolismo , Protetores Solares/farmacocinética , Espectrometria de Massas em Tandem , Acrilatos/farmacocinética , Biotransformação , Espectrometria de Mobilidade Iônica , Propiofenonas/farmacocinética , Salicilatos/farmacocinética
13.
Toxicol In Vitro ; 62: 104667, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629901

RESUMO

Serum is an important component in cell culture medium. It also possesses potent antioxidant properties. Therefore, the conventional protocols for detecting reactive oxygen species (ROS) in cultured cells with fluorescent probes include washing and suspending cells with serum-free buffers, such as PBS. This transient serum deprivation is essential for the ROS detecting. Unfortunately, it may also cause unexpected results, which push us to choose more optimal experiment conditions. In the present study, we found an acute lytic cell death induced by xanthohumol (XN), which obstructed ROS detecting in human leukemia cell line HL-60 cells. XN induced ROS burst, caused cell swelling, membrane permeability increase, LDH release, and ultimately an acute lytic cell death and cell rupture. These effects could be alleviated by the antioxidant N-Acetyl-L-cysteine (NAC). Apoptosis, pyroptosis or necroptosis were not observed in this process. Results also indicated that 2% serum addition had already completely scavenged ROS induced by 10 µM XN. Taken together, it is strongly suggested to detecting ROS in a serum-free medium when studying where and how ROS generated in cells. The concentration at the ROS maximum point (10 µM XN in this study) can be selected as the optimal concentration.


Assuntos
Flavonoides/toxicidade , Propiofenonas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Células HL-60 , Humanos , Interleucina-1beta/metabolismo , L-Lactato Desidrogenase/metabolismo , Soro
14.
Anal Chim Acta ; 1093: 160-167, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31735210

RESUMO

In this study, poly(butyl methacrylate-co-ethyleneglycol dimethacrylate) polymeric monoliths were in situ developed within 0.75 mm i.d. poly(ethylene-co-tetrafluoroethylene) (ETFE) tubing by UV polymerization via three different free-radical initiators (α,α'-azobisisobutyronitrile (AIBN), 2,2-dimethoxy-2-phenylacetophenone (DMPA) and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMPP). The influence of the nature of each photo-initiator and irradiation time on the morphological features of the polymer was investigated by scanning electron microscopy, and the chromatographic properties of the resulting microbore columns were evaluated using alkyl benzenes as test substances. The beds photo-initiated with MTMPP gave the best performance (minimum plate heights of 38 µm for alkyl benzenes) and exhibited a satisfactory reproducibility in the chromatographic parameters (RSD < 11%). These monolithic columns were also successfully applied to the separation of phenylurea herbicides, proteins and a tryptic digest of ß-casein.


Assuntos
Acetofenonas/química , Cromatografia Líquida de Alta Pressão/instrumentação , Morfolinas/química , Nitrilos/química , Ácidos Polimetacrílicos/química , Politetrafluoretileno/análogos & derivados , Propiofenonas/química , Acetofenonas/efeitos da radiação , Caseínas/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Herbicidas/isolamento & purificação , Metacrilatos/química , Morfolinas/efeitos da radiação , Nitrilos/efeitos da radiação , Fragmentos de Peptídeos/isolamento & purificação , Compostos de Fenilureia/isolamento & purificação , Polimerização , Ácidos Polimetacrílicos/síntese química , Politetrafluoretileno/química , Propiofenonas/efeitos da radiação , Raios Ultravioleta
15.
Food Funct ; 10(12): 7865-7874, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31793596

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease. The molecular mechanisms of AD are not yet clear, and no effective treatments are available to cure AD. Because of the huge number of patients and related costs, it is urgent to discover new medicines to prevent or cure AD. In this study, xanthohumol (XN), a natural botanic compound, is found to inhibit tau protein aggregation and disaggregate tau fibrils. XN directly interacts with tau protein at sites sporadically located in all four repeating domains with a Kd value of 52 µM. Binding with XN does not alter the secondary structures of tau protein. Cellular experiments showed that XN exhibits little cytotoxicity and attenuates apoptosis induced by tau oligomers. The results provide preliminary experimental data to develop XN into medicines, food products, or nutritional supplements for AD. The findings also provide data for computational drug design.


Assuntos
Flavonoides/química , Propiofenonas/química , Proteínas tau/química , Animais , Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Cinética , Camundongos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Propiofenonas/farmacologia , Agregados Proteicos , Agregação Patológica de Proteínas , Proteínas tau/genética , Proteínas tau/metabolismo , Proteínas tau/toxicidade
16.
Acta Biochim Pol ; 66(4): 559-565, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31820895

RESUMO

Two biotinylated derivatives of the main hop chalcone xanthohumol (1) were prepared by a one-step synthesis via esterification using biotin and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC×HCl) and 4-dimethylaminopyridine (DMAP) as coupling reagents. The products were characterized spectroscopically and their antiproliferative activity toward MCF-7, MCF-10A, HepG2, MDA-MB-231, 4T1 and Balb/3T3 cell lines was investigated using the SRB assay. For all three tested compounds the best activity was noted in the case of human (MCF-7) and mice (4T1) breast cancer cell lines (IC50 values < 9 µM). Both biotinylated derivatives showed slightly higher anticancer activity than xanthohumol (1) towards all types of tested breast cancer cells. Double biotinylated xanthohumol (3) proved to be the most active in inhibiting cell growth, with IC50 values equal to 5.35 ± 1.5 µM for 4T1 and 8.03 ± 0.53 µM for MCF-7 cell lines. Compound 3 was also more active than 1 and 2 against liver cancer cells HepG2 (IC50 = 17.37 ± 5.1 µM), while the IC50 values for 1 and 2 were equal to 21.5 ± 2.7 and 22.1 ± 3.9 µM, respectively. 4­O­biotinylxanthohumol (2) was the second most active growth inhibitor, particularly with respect to MCF-7 (IC50 = 6.19 ± 1.7 µM) and 4T1 (IC50 = 6.64 ± 0.4 µM) cell lines. Our preliminary study on biotinylated xanthohumol (1) have shown that this type of functionalization is an effective method for the production of active biomolecules and study on this area should be continued thereby extending their applications.


Assuntos
Antineoplásicos/farmacologia , Biotinilação/genética , Neoplasias da Mama/tratamento farmacológico , Flavonoides/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Propiofenonas/farmacologia , Animais , Antineoplásicos/química , Células 3T3 BALB , Neoplasias da Mama/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Flavonoides/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Células MCF-7 , Camundongos , Propiofenonas/química
17.
Molecules ; 24(23)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766540

RESUMO

Four novel xanthohumol (XN) cocrystals with pharmaceutically acceptable coformers, such as nicotinamide (NIC), glutarimide (GA), acetamide (AC), and caffeine (CF) in the 1:1 stoichiometry were obtained by the slow evaporation solution growth technique. The structure of the cocrystals was determined by single crystal X-ray diffraction. The analysis of packing and interactions in the crystal lattice revealed that molecules in the target cocrystals were packed into almost flat layers, formed by the O-HO, O-HN, and N-HO-type contacts between the xanthohumol and coformer molecules. The results provided details about synthons responsible for crystal net stabilization and all hydrogen bonds observed in the crystal lattice. The main synthon was formed via the hydrogen bond between the hydroxyl group in the B ring of XN and coformers. The three-dimensional crystal lattice was stabilized by the hydrogen XN-XN interactions whereas the π-π stacking interactions played an additional role in layer binding, with the exception of low quality cocrystals formed with caffeine. Application of FTIR and Raman spectroscopy confirmed that the crystalline phase of obtained cocrystals was not a simple combination of individual components and completely different crystal phases resulted from the effect of intermolecular interactions. The multivariate analysis showed the changes in the spectra, and this technique can be applied in a combination with vibrational spectroscopy for fast screening of new crystal phases. Additionally, the solubility studies of pure XN and its cocrystals exhibited a 2.6-fold enhancement in XN solubility in aqueous solution for XN-AC and, to a lesser extent, for other cocrystals.


Assuntos
Chalconas/química , Cristalografia por Raios X/métodos , Flavonoides/química , Modelos Moleculares , Prenilação , Propiofenonas/química , Análise Espectral Raman/métodos , Acetamidas/química , Cafeína/química , Varredura Diferencial de Calorimetria , Cristalização , Niacinamida/química , Piperidonas/química , Vibração
18.
Vet Microbiol ; 238: 108431, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31648725

RESUMO

The infection by porcine reproductive and respiratory syndrome virus (PRRSV) has a severe impact on the world swine industry. However, commercially available vaccines provide only incomplete protection against this disease. Thus, novel approaches to control PRRSV infection are essential for the robust and sustainable swine industry. In our previous study, Xanthohumol (Xn), a prenylated flavonoid extracted for hops (Humulus lupulus L), was screened from 386 natural products to inhibit PRRSV proliferation and alleviate oxidative stress induced by PRRSV via the Nrf2-HMOX1 axis in Marc-145 cells. In this study, we furtherly found that Xn could inhibit PRRSV different sub-genotype strains infection with a low IC50 value in porcine primary alveolar macrophages (PAMs). In addition, it caused decreased expression of interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor-α in PAMs infected with PRRSV or treated with lipopolysaccharide. Animal challenge experiments showed that Xn effectively alleviated clinical signs, lung pathology, and inflammatory responses in lung tissues of pigs induced by highly pathogenic PRRSV infection. The results demonstrate that Xn is a promising therapeutic agent to combat PRRSV infections.


Assuntos
Flavonoides/farmacologia , Flavonoides/uso terapêutico , Síndrome Respiratória e Reprodutiva Suína/tratamento farmacológico , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Propiofenonas/farmacologia , Propiofenonas/uso terapêutico , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Produtos Biológicos/farmacologia , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Concentração Inibidora 50 , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/virologia , Suínos
19.
Int J Biol Sci ; 15(11): 2497-2508, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31595166

RESUMO

Deregulation of glycolysis is a common phenomenon in human colorectal cancer (CRC). In the present study, we reported that Hexokinase 2 (HK2) is overexpressed in human CRC tissues and cell lines, knockout of HK2 inhibited cell proliferation, colony formation, and xenograft tumor growth. We demonstrated that the natural compound, xanthohumol, has a profound anti-tumor effect on CRC via down-regulation of HK2 and glycolysis. Xanthohumol suppressed CRC cell growth both in vitro and in vivo. Treatment with xanthohumol promoted the release of cytochrome C and activated the intrinsic apoptosis pathway. Moreover, our results revealed that xanthohumol down-regulated the EGFR-Akt signaling, exogenous overexpression of constitutively activated Akt1 significantly impaired xanthohumol-induced glycolysis suppression and apoptosis induction. Our results suggest that targeting HK2 appears to be a new approach for clinical CRC prevention or treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Hexoquinase/metabolismo , Propiofenonas/farmacologia , Propiofenonas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Citocromos c/metabolismo , Feminino , Glicólise/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Molecules ; 24(19)2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31590450

RESUMO

UV-curable inks, coatings, and adhesives are being increasingly used in food packaging systems. When exposed to UV energy, UV-photoinitiators (PI's) present in the formulations produce free radicals which catalyze polymerization of monomers and pre-polymers into resins. In addition to photopolymerization, other free radical reactions occur in these systems resulting in the formation of chemically varied photolytic decomposition products, many of which are low molecular weight chemical species with high migration potential. This research conducted model experiments in which 24 commonly used PI's were exposed to UV-energy at the typical upper limit of commercial UV-printing press conditions. UV-irradiated PI's were analyzed by gas chromatography-mass spectrometry (GC-MS) and electrospray-mass spectrometry (ESI-MS) in order to identify photolytic decomposition products. Subsequently, migration studies of 258 UV-cure food packaging samples were conducted using GC-MS; PI's and photolytic decomposition products were found in nearly all samples analyzed. One hundred-thirteen photolytic decomposition products were identified. Eighteen intact PI's and 21 photolytic decomposition products were observed as migrants from the 258 samples analyzed, and these were evaluated for frequency of occurrence and migratory concentration range. The most commonly observed PI's were 2-hydroxy-2-methylpropiophenone and benzophenone. The most commonly observed photolytic decomposition products were 2,4,6-trimethylbenzaldehyde and 1-phenyl-2-butanone. This compilation of PI photolytic decomposition data and associated migration data will aid industry in identifying and tracing non-intentionally added substances (NIAS) in food packaging materials.


Assuntos
Benzaldeídos/isolamento & purificação , Butanonas/isolamento & purificação , Contaminação de Alimentos/análise , Embalagem de Alimentos , Benzaldeídos/metabolismo , Benzofenonas/química , Butanonas/química , Cromatografia Gasosa-Espectrometria de Massas , Estrutura Molecular , Fotólise , Propiofenonas/química , Espectrometria de Massas por Ionização por Electrospray , Raios Ultravioleta
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