RESUMO
The two-component system GacS/A and the posttranscriptional control system Rsm constitute a genetic regulation pathway in Gammaproteobacteria; in some species of Pseudomonas, this pathway is part of a multikinase network (MKN) that regulates the activity of the Rsm system. In this network, the activity of GacS is controlled by other kinases. One of the most studied MKNs is the MKN-GacS of Pseudomonas aeruginosa, where GacS is controlled by the kinases RetS and LadS; RetS decreases the kinase activity of GacS, whereas LadS stimulates the activity of the central kinase GacS. Outside of the Pseudomonas genus, the network has been studied only in Azotobacter vinelandii. In this work, we report the study of the RetS kinase of A. vinelandii; as expected, the phenotypes affected in gacS mutants, such as production of alginates, polyhydroxybutyrate, and alkylresorcinols and swimming motility, were also affected in retS mutants. Interestingly, our data indicated that RetS in A. vinelandii acts as a positive regulator of GacA activity. Consistent with this finding, mutation in retS also negatively affected the expression of small regulatory RNAs belonging to the Rsm family. We also confirmed the interaction of RetS with GacS, as well as with the phosphotransfer protein HptB.
Assuntos
Alginatos , Azotobacter vinelandii , Proteínas de Bactérias , Regulação Bacteriana da Expressão Gênica , Azotobacter vinelandii/genética , Azotobacter vinelandii/enzimologia , Azotobacter vinelandii/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Alginatos/metabolismo , Resorcinóis/metabolismo , Histidina Quinase/genética , Histidina Quinase/metabolismo , Poliésteres/metabolismo , Hidroxibutiratos/metabolismoRESUMO
Foods contaminants pose a challenge for food producers and consumers. Due to its spontaneous formation during heating and storage, hydroxymethylfurfural (HMF) is a prevalent contaminant in foods rich in carbohydrates and proteins. Colorimetric assays, such as the Seliwanoff test, offer a rapid and cost-effective method for HMF quantification but require careful optimization to ensure accuracy. We addressed potential interference in the Seliwanoff assay by systematically evaluating parameters like incubation time, temperature, and resorcinol or hydrochloric acid concentration, as well as the presence of interfering carbohydrates. Samples were analyzed using a UV-Vis spectrophotometer in scan mode, and data obtained were validated using HPLC, which also enabled quantification of unreacted HMF for assessing the protocol's accuracy. Incubation time and hydrochloric acid percentage positively influenced the colorimetric assay, while the opposite effect was observed with the increase in resorcinol concentration. Interference from carbohydrates was eliminated by reducing the acid content in the working reagent. HPLC analyses corroborated the spectrophotometer data and confirmed the efficacy of the proposed method. The average HMF content in balsamic vinegar samples was 1.97 ± 0.94 mg/mL. Spectrophotometric approaches demonstrated to efficiently determine HMF in complex food matrices. The HMF levels detected in balsamic vinegars significantly exceeded the maximum limits established for honey. This finding underscores the urgent need for regulations that restrict contaminant levels in various food products.
Assuntos
Furaldeído , Espectrofotometria , Furaldeído/análogos & derivados , Furaldeído/análise , Espectrofotometria/métodos , Cromatografia Líquida de Alta Pressão/métodos , Resorcinóis/análise , Resorcinóis/química , Contaminação de Alimentos/análise , Análise de Alimentos/métodos , Ácido Acético/análise , Ácido Acético/químicaRESUMO
The interaction of active substances with molecular structures in stratum corneum (SC) is crucial for the efficacy and safety of cosmetic formulations and topical drugs. However, the molecular architecture of SC is highly complex and methods to unambiguously localize exogenous molecules within SC are lacking. Consequently, little is known about the distribution of actives within SC, and proposed penetration mechanisms through SC are typically limited to simple diffusion via a tortuous (lipid only) or transverse (across corneocytes and lipid matrix) pathway. In this work, 3D mass spectrometry imaging is used to determine the spatial distributions of four active substances at subcellular resolution in SC, including partitioning between the corneocytes and the intercellular lipid matrix. The results indicate that caffeine, 2-methyl resorcinol and oxybenzone are homogeneously distributed in the corneocytes but largely absent in the lipid matrix, despite considerable differences in lipophilicity. In contrast, the distribution- of jasmonic acid derivative is more inhomogeneous and indicates considerable localization to both the lipid phase and the corneocytes.
Assuntos
Epiderme , Epiderme/metabolismo , Lipídeos/química , Lipídeos/análise , Humanos , Cafeína/metabolismo , Animais , Benzofenonas/metabolismo , Resorcinóis/metabolismo , Resorcinóis/farmacologia , Espectrometria de MassasRESUMO
This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.
Assuntos
Produtos Biológicos , Catálise , Produtos Biológicos/síntese química , Produtos Biológicos/química , Estereoisomerismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Alcaloides de Cinchona/química , Cicloexanonas/síntese química , Cicloexanonas/química , Fenômenos de Química Orgânica , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Aminas/química , Aminas/síntese química , Tioureia/química , Tioureia/síntese química , Resorcinóis/síntese química , Resorcinóis/química , Indanos/síntese química , Indanos/químicaRESUMO
Hypoxia is known as a specific signal of various diseases, such as liver fibrosis. We designed a hypoxia-sensitive fluorometric approach that cleaved the azo bond (NâN) in the presence of hypoxia-controlled agents (sodium dithionite and azoreductase). 4-(2-Pyridylazo) resorcinol (Py-NâN-RC) bears a desirable hypoxia-responsive linker (NâN), and its azo bond breakup can only occur in the presence of sodium dithionite and azoreductase and leads to the release of 2,4-dihydroxyaniline, which can react with 3-[2-(2-aminoethylamino)ethylamino]propyltrimethoxysilane to generate yellow fluorescent silicon nanoparticles. This approach exhibited high selectivity and sensitivity toward both sodium dithionite and azoreductase over other potential interferences. The mouse liver microsome, which is known to contain azoreductase, was applied and confirmed the feasibility of the designed platform. Py-NâN-RC is expected to be a practical substrate for hypoxia-related biological analyses. Furthermore, silicon nanoparticles were successfully applied for Hela cell imaging owing to their negligible cytotoxicity and superb biocompatibility.
Assuntos
Compostos Azo , Nanopartículas , Silício , Silício/química , Humanos , Nanopartículas/química , Células HeLa , Compostos Azo/química , Animais , Camundongos , Resorcinóis/química , Hipóxia/metabolismo , Hipóxia Celular , Estrutura Molecular , Nitrorredutases/metabolismoRESUMO
Taking advantage of the competitive binding affinity towards Ti(IV) between 4-(2-pyridylazo) resorcinol (PAR) and phthalate, a simple indicator displacement (ID)-based colorimetric assay was designed for indirect determination of a well-known phthalic acid ester, dibutyl phthalate (DBP). The indicator PAR and Ti(IV) formed a purplish-red-colored Ti(IV)-PAR complex (λmax = 540â¯nm) at a 1:1 ratio. In the presence of pre-hydrolyzed DBP, colorless complex formation of phthalate ion (emerging from alkaline hydrolysis of DBP) with Ti(IV) resulted in a hypsochromic shift in absorbance maximum, accompanying a color change from purplish-red to yellowish-orange (λmax = 390â¯nm) by the release of PAR from Ti(IV)-PAR system. Based on this mechanism, the linear response range of the system for DBP was found to lie between 0.16 and 0.37â¯mmolâ¯L-1 with an experimental detection limit of 11.6 µmol L-1. The recommended Ti(IV)-PAR system was successfully applied to DBP-containing pharmaceutical products (as real sample) after a simple clean-up process for removing possible water-soluble interferents. The analytical results obtained from the recommended method (by applying the standard addition approach) and the reference liquid chromatography-tandem mass spectrometric (LC-MS/MS) method were statistically compared using DBP-extract of the drug samples. Consequently, a simple and selective colorimetric ID strategy was proposed for the analysis of DBP in pharmaceuticals for the first time.
Assuntos
Colorimetria , Dibutilftalato , Limite de Detecção , Resorcinóis , Titânio , Colorimetria/métodos , Resorcinóis/química , Resorcinóis/análise , Titânio/química , Dibutilftalato/análise , Dibutilftalato/química , Espectrometria de Massas em Tandem/métodos , Hidrólise , Cromatografia Líquida de Alta Pressão/métodosRESUMO
A moment analysis method was developed for the study of solute permeation at the interface of spherical molecular aggregates. At first, new moment equations were developed for determining the partition equilibrium constant (Kp) and permeation rate constants (kin and kout) of solutes from the first absolute (µ1A) and second central (µ2C) moments of elution peaks measured by using high-performance liquid chromatography (HPLC). Then, the method was applied to the analysis of mass transfer phenomena of three solutes, i.e., hydroquinone, resorcinol, and catechol, at the interface of sodium dodecylsulfate (SDS) micelles. HPLC data were measured by using an ODS column and an aqueous phosphate buffer solution (pH = 7.0) as the mobile phase solvent. Pulse response experiments were conducted while changing SDS concentration (5 - 20 mmol dm-3) in the mobile phase under the conditions that the surface of ODS stationary phase was dynamically coated by SDS monomers. In order to demonstrate the effectiveness of the moment analysis method using HPLC, the values of Kp, kin, and kout were determined for the three solutes as 35 - 69, 2.4 × 10-8 - 1.4 × 10-6 m s-1, and 7.0 × 10-10 - 2.1 × 10-8 m s-1, respectively. Their values increase with an increase in the hydrophobicity of the solutes. The method has some advantages for the study of interfacial solute permeation of molecular aggregates. For example, neither immobilization nor chemical modification of both solute molecules and molecular aggregates is required when elution peaks are measured by using HPLC. Interfacial solute permeation takes place in the mobile phase without any chemical reaction or physical action on molecular aggregates. The values of Kp, kin, and kout were analytically determined from those of µ1A and µ2C by using the moment equations. The results of this study must contribute to the dissemination of an opportunity for studying the interfacial solute permeation of molecular aggregates to many researchers because of extremely high versatility of HPLC.
Assuntos
Resorcinóis , Dodecilsulfato de Sódio , Cromatografia Líquida de Alta Pressão/métodos , Dodecilsulfato de Sódio/química , Resorcinóis/química , Micelas , Hidroquinonas/química , Catecóis/química , Cinética , PermeabilidadeRESUMO
PANoptosis is manifested with simultaneous activation of biomarkers for both pyroptotic, apoptotic and necroptotic signaling via the molecular platform PANoptosome and it is involved in pathologies of various inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). Scutellarin is a flavonoid isolated from herbal Erigeron breviscapus (Vant.) Hand.-Mazz. and has been shown to possess multiple pharmacological effects, but it is unknown whether scutellarin has any effects on PANoptosis and related inflammatory diseases. In this study, we found that scutellarin inhibited cell death in bone marrow-derived macrophages (BMDMs) and J774A.1 cells treated with TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (OXO) plus lipopolysaccharide (LPS), which has been commonly used to induce PANoptosis. Western blotting showed that scutellarin dose-dependently inhibited the activation biomarkers for pyroptotic (Caspase-1p10 and GSDMD-NT), apoptotic (cleaved Casp3/8/9 and GSDME-NT), and necroptotic (phosphorylated MLKL) signaling. The inhibitory effect of scutellarin was unaffected by NLRP3 or Caspase-1 deletion. Interestingly, scutellarin blocked the assembly of PANoptosome that encompasses ASC, RIPK3, Caspase-8 and ZBP1, suggesting its action on upstream signaling. Consistent with this, scutellarin inhibited mitochondrial damage and mitochondrial reactive oxygen species (mtROS) generation in cells treated with OXO+LPS. Further, mito-TEMPO that can scavenge mtROS significantly inhibited OXO+LPS-induced PANoptotic cell death. In line with the in vitro results, scutellarin markedly alleviated systemic inflammation, multiple organ injury, and activation of PANoptotic biomarkers in mice with HLH. Collectively, our data suggest that scutellarin can inhibit PANoptosis by suppressing mitochondrial damage and mtROS generation and thereby mitigating multiple organ injury in mice with inflammatory disorders.
Assuntos
Apigenina , Glucuronatos , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Mitocôndrias , Espécies Reativas de Oxigênio , Apigenina/farmacologia , Apigenina/uso terapêutico , Glucuronatos/farmacologia , Glucuronatos/uso terapêutico , Animais , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Linhagem Celular , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Necroptose/efeitos dos fármacos , Masculino , MAP Quinase Quinase Quinases/metabolismo , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Zearalenona/administração & dosagem , Lactonas , ResorcinóisRESUMO
Aims: Epidemiological studies that use dietary biomarkers to investigate the association between whole grain intake and the risk of obesity are sparse. We assessed the association between urinary alkylresorcinol metabolites including 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA) and 3,5-dihydroxybenzoic acid (DHBA), biomarkers of whole grain wheat and rye intake, and body fat measures. Methods: We measured urinary excretion of DHPPA and DHBA, body weight, height, and circumferences of the waist and hip at the baseline and again after 1-year in a representative sample of 306 community-dwelling adults in Huoshan, China. We also measured liver fat accumulation [indicated by the controlled attenuation parameter (CAP)] and other body composition after 1 year. Multivariate-adjusted linear models and linear mixed-effects models were used to analyze single measurement and repeated measurements, respectively. Results: Each 1 µg g-1 creatinine increase in urinary DHPPA levels was associated with 0.21%, 0.23%, 3.64%, and 4.80% decrease in body weight, body mass index (BMI), body fat mass (BFM) and visceral fat level (VFL), respectively (all P < 0.05). Higher DHBA levels were inversely associated with CAP (percentage difference per 1 µg g-1 creatinine increment: -1.98%, P < 0.05). Higher total urinary alkylresorcinol metabolite (DHPPA + DHBA) levels were associated with lower body weight, BMI, BFM, VFL, and CAP, with the percentage differences per 1 µg g-1 creatinine increment of -0.27%, -0.27%, -3.79%, -5.12%, and -2.24%, respectively (all P < 0.05). Conclusions: Our findings suggest that the intake of whole grain wheat and rye, reflected by urinary DHPPA and DHBA, is favorably associated with liver fat and other fat measures.
Assuntos
Biomarcadores , Fígado , Resorcinóis , Secale , Triticum , Grãos Integrais , Humanos , Secale/metabolismo , Triticum/metabolismo , Masculino , Feminino , Biomarcadores/urina , Pessoa de Meia-Idade , Resorcinóis/urina , Resorcinóis/metabolismo , Adulto , Fígado/metabolismo , Índice de Massa Corporal , China , Tecido Adiposo/metabolismo , Hidroxibenzoatos/urina , Hidroxibenzoatos/metabolismo , Propionatos/urina , Propionatos/metabolismo , Obesidade/metabolismo , Obesidade/urina , FenilpropionatosRESUMO
Imbalanced nutrition, such as a high-fat/high-carbohydrate diet, is associated with negative effects on human health. The composition and metabolic activity of the human gut microbiota are closely related to the type of diet and have been shown to change significantly in response to changes in food content and food supplement administration. Alkylresorcinols (ARs) are lipophilic molecules that have been found to improve lipid metabolism and glycemic control and decrease systemic inflammation. Furthermore, alkylresorcinol intake is associated with changes in intestinal microbiota metabolic activity. However, the exact mechanism through which alkylresorcinols modulate microbiota activity and host metabolism has not been determined. In this study, alterations in the small intestinal microbiota (SIM) and the large intestinal microbiota (LIM) were investigated in mice fed a high-fat diet with or without pentadecylresorcinol (C15) supplementation. High-throughput sequencing was applied for jejunal and colonic microbiota analysis. The results revealed that C15 supplementation in combination with a high-fat diet could decrease blood glucose levels. High-throughput sequencing analysis indicated that C15 intake significantly increased (p < 0.0001) the abundance of the probiotic bacteria Akkermansia muciniphila and Bifidobacterium pseudolongum in both the small and large intestines and increased the alpha diversity of LIM (p < 0.05), but not SIM. The preliminary results suggested that one of the mechanisms of the protective effects of alkylresorcinol on a high-fat diet is the modulation of the content of SIM and LIM and metabolic activity to increase the probiotic bacteria that alleviate unhealthy metabolic changes in the host.
Assuntos
Akkermansia , Dieta Hiperlipídica , Suplementos Nutricionais , Microbioma Gastrointestinal , Resorcinóis , Animais , Dieta Hiperlipídica/efeitos adversos , Resorcinóis/farmacologia , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Akkermansia/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/microbiologia , Intestino Delgado/metabolismoRESUMO
Introduction: Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-ß-activated kinase 1 (TAK1) plays a pivotal role in regulating oxidative stress and inflammation across various diseases. 5Z-7-Oxozeaenol (OZ), a specific inhibitor of TAK1, has exhibited therapeutic effects in various conditions. However, the impact of OZ following ICH and its underlying molecular mechanisms remain elusive. This study aimed to explore the possible role of OZ in ICH and its underlying mechanisms by inhibiting oxidative stress-mediated pyroptosis. Methods: Adult male Sprague-Dawley rats were subjected to an ICH model, followed by treatment with OZ. Neurobehavioral function, blood-brain barrier integrity, neuronal pyroptosis, and oxidative stress markers were assessed using various techniques including behavioral tests, immunofluorescence staining, western blotting, transmission electron microscopy, and biochemical assays. Results: Our study revealed that OZ administration significantly inhibited phosphorylated TAK1 expression post-ICH. Furthermore, TAK1 blockade by OZ attenuated blood-brain barrier (BBB) disruption, neuroinflammation, and oxidative damage while enhancing neurobehavioral function. Mechanistically, OZ administration markedly reduced ROS production and oxidative stress by facilitating nuclear factor-erythroid 2-related factor 2 (NRF2) nuclear translocation. This was accompanied by a subsequent suppression of the NOD-like receptor protein 3 (NLRP3) activation-mediated inflammatory cascade and neuronal pyroptosis. Discussion: Our findings highlight that OZ alleviates brain injury and oxidative stress-mediated pyroptosis via the NRF2 pathway. Inhibition of TAK1 emerges as a promising approach for managing ICH.
Assuntos
Hemorragia Cerebral , MAP Quinase Quinase Quinases , Fator 2 Relacionado a NF-E2 , Neurônios , Estresse Oxidativo , Piroptose , Transdução de Sinais , Animais , Masculino , Ratos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Modelos Animais de Doenças , Lactonas , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Resorcinóis , Transdução de Sinais/efeitos dos fármacos , Zearalenona/administração & dosagemRESUMO
Alkylresorcinols are important biomarkers for evaluating whole wheat foods. However, their structures encompass a broad spectrum of homologs, making isolating and analyzing individual alkylresorcinol notably challenging. Herein, we synthesized highly selective molecularly imprinted polymers (MIPs) utilizing a facile and cost-effective precipitation polymerization method and 5-heneicosylresorcinol (ARC21:0) as the template molecule. Various crucial preparation parameters were systematically optimized, such as different porogens, functional monomers, imprinting ratios, and polymerization time. The polymers were characterized through scanning electron microscopy and Fourier transform infrared spectroscopy, and their adsorption performances were thoroughly evaluated. MIPs exhibited a notably enhanced adsorption capacity compared with that of non-imprinted polymers, reaching an optimal adsorption amount of 71.75 mg·mL-1 and imprinting factor of 2.02. Altogether, the synthesized MIPs showed superior affinity and selectivity for ARC21:0, as confirmed by their selective extraction, suggesting their potential applications in the analysis, separation, and monitoring of ARC21:0 in whole wheat foods.
Assuntos
Farinha , Polímeros Molecularmente Impressos , Resorcinóis , Triticum , Triticum/química , Adsorção , Resorcinóis/química , Farinha/análise , Polímeros Molecularmente Impressos/química , Extração em Fase Sólida/métodos , Impressão Molecular , Polimerização , Polímeros/química , Polímeros/síntese químicaRESUMO
RATIONALE: Alkylresorcinols (AR) are cereal-specific biomarkers and have recently been found in archaeological pots. However, their low concentrations and high susceptibility to degradation make them difficult to detect using conventional gas chromatography mass spectrometry (GC/MS). Here we describe the development of a more sensitive liquid chromatography mass spectrometry (LC/MS) method to detect these compounds. METHOD: A method based on the use of ultra-high-performance liquid chromatography (UHPLC) coupled to an Orbitrap mass analyser was established and validated for the detection of low-concentration ARs in pottery. During the preliminary experiments, UHPLC-Q/Orbitrap MS (ultra-high-performance liquid chromatography-quadrupole/Orbitrap mass spectrometry) was demonstrated to be more sensitive, and a wide range of AR homologues in cereal extracts were detected, unlike UHPLC-QTOFMS (ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry) and GC/MS. The developed method was utilised to profile AR homologue distribution in modern cereal samples and reanalyse AR-containing pots from the archaeological site of Must Farm. RESULTS: A highly sensitive LC/MS method with a limit of detection (LOD) of 0.02 µg/g and a limit of quantification (LOQ) of 0.06 µg/g was used to profile ARs in five modern cereal grains. The obtained LOD is 250 times lower than that obtained using the conventional GC/MS approach. AR 21:0 was the most abundant homologue in all four Triticum spp.-einkorn, emmer, Khorasan wheat and common wheat. Meanwhile, AR 25:0 was the predominant homologue in barley, potentially enabling differentiation between wheat and barley. The developed LC/MS-based method was successfully used to analyse ARs extracted from Must Farm potsherds and identified the cereal species most likely processed in the pots-emmer wheat. CONCLUSION: The described method offers an alternative and more sensitive approach for detecting and identifying ARs in ancient pottery. It has been successfully utilised to detect AR homologues in archaeological samples and discriminate which cereal species-wheat and barley-were processed in the pots.
Assuntos
Arqueologia , Grão Comestível , Espectrometria de Massas , Resorcinóis , Cromatografia Líquida de Alta Pressão/métodos , Arqueologia/métodos , Resorcinóis/análise , Resorcinóis/química , Grão Comestível/química , Espectrometria de Massas/métodos , Reprodutibilidade dos Testes , Limite de DetecçãoRESUMO
Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor ß-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.
Assuntos
Proteínas Reguladoras de Apoptose , Modelos Animais de Doenças , Lipopolissacarídeos , MAP Quinase Quinase Quinases , Macrófagos , Sepse , Animais , Sepse/imunologia , Sepse/tratamento farmacológico , Sepse/metabolismo , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Camundongos Endogâmicos C57BL , Fosforilação , Humanos , Ubiquitinação , Zearalenona/análogos & derivados , Zearalenona/farmacologia , Zearalenona/administração & dosagem , Fator 6 Associado a Receptor de TNF/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Inflamação/metabolismo , Inflamação/patologia , Monoéster Fosfórico Hidrolases/metabolismo , Camundongos Knockout , Lactonas , ResorcinóisRESUMO
Lignocellulosic biomass is a highly sustainable and largely carbon dioxide neutral feedstock for the production of biofuels and advanced biomaterials. Although thermochemical pretreatment is typically used to increase the efficiency of cell wall deconstruction, genetic engineering of the major plant cell wall polymers, especially lignin, has shown promise as an alternative approach to reduce biomass recalcitrance. Poplar trees with reduced lignin content and altered composition were previously developed by overexpressing bacterial 3-dehydroshikimate dehydratase (QsuB) enzyme to divert carbon flux from the shikimate pathway. In this work, three transgenic poplar lines with increasing QsuB expression levels and different lignin contents were studied using small-angle neutron scattering (SANS) and wide-angle X-ray scattering (WAXS). SANS showed that although the cellulose microfibril cross-sectional dimension remained unchanged, the ordered organization of the microfibrils progressively decreased with increased QsuB expression. This was correlated with decreasing total lignin content in the QsuB lines. WAXS showed that the crystallite dimensions of cellulose microfibrils transverse to the growth direction were not affected by the QsuB expression, but the crystallite dimensions parallel to the growth direction were decreased by â¼20%. Cellulose crystallinity was also decreased with increased QsuB expression, which could be related to high levels of 3,4-dihydroxybenzoate, the product of QsuB expression, disrupting microfibril crystallization. In addition, the cellulose microfibril orientation angle showed a bimodal distribution at higher QsuB expression levels. Overall, this study provides new structural insights into the impact of ectopic synthesis of small-molecule metabolites on cellulose organization and structure that can be used for future efforts aimed at reducing biomass recalcitrance.
Assuntos
Celulose , Populus , Celulose/química , Populus/genética , Populus/metabolismo , Populus/química , Hidroxibenzoatos/química , Hidroxibenzoatos/metabolismo , Lignina/química , Plantas Geneticamente Modificadas , Hidroliases/metabolismo , Hidroliases/genética , Biomassa , Parede Celular/metabolismo , Parede Celular/química , ResorcinóisRESUMO
Human Hsp90 chaperones are implicated in various aspects of cancer. Due to this, Hsp90 has been explored as potential target in cancer treatment. Initial attempts to use Hsp90 inhibitors in drug trials failed due to toxicity and inefficacy. The next generation of drugs were less toxic but still insufficiently effective in a clinical setting. Recently, a lot of effort is being put into understanding the consequences of Hsp90 isoform selective inhibition, expecting that this might hold the key in targeting Hsp90 for disease treatment. Here we investigate a series of compounds containing the aryl-resorcinol scaffold with a 5-membered ring as a promising class of new human Hsp90 inhibitors, reaching nanomolar affinity. We compare how the replacement of 5-membered ring, from thiadiazole to imidazole, as well as a variety of their substituents, influences the potency of these inhibitors for Hsp90 alpha and beta isoforms. To further elucidate the dissimilarity in ligand selectivity between the isoforms, a mutant protein was constructed and tested against the ligand library. In addition, we performed a series of molecular dynamics (MD) and docking simulations to further explain our experimental findings as well as evaluated key compounds in cell assays. Our results deepen the understanding of Hsp90 isoform ligand selectivity and serve as an informative base for further Hsp90 inhibitor optimization.
Assuntos
Desenho de Fármacos , Proteínas de Choque Térmico HSP90 , Imidazóis , Resorcinóis , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Resorcinóis/química , Resorcinóis/farmacologia , Resorcinóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese químicaRESUMO
Organophosphate esters (OPEs) have been demonstrated to induce various forms of toxicity in aquatic organisms. However, a scarcity of evidence impedes the conclusive determination of whether OPEs manifest sex-dependent toxic effects. Here, we investigated the effects of tris (1-chloro-2-propyl) phosphate (TCPP) and resorcinol bis (diphenyl phosphate) (RDP) on the intestines of both female and male zebrafish. The results indicated that, in comparison to TCPP, RDP induced more pronounced intestinal microstructural damage and oxidative stress, particularly in male zebrafish. 16S rRNA sequencing and metabolomics revealed significant alterations in the species richness and oxidative stress-related metabolites in the intestinal microbiota of zebrafish under exposure to both TCPP and RDP, manifesting gender-specific effects. Based on differential species analysis, we defined invasive species and applied invasion theory to analyze the reasons for changes in the male fish intestinal community. Correlation analysis demonstrated that alien species may have potential effects on metabolism. Overall, this study reveals a pronounced gender-dependent impact on both the intestinal microbiota and metabolic disruptions of zebrafish due to OPEs exposure and offers a novel perspective on the influence of pollutants on intestinal microbial communities and metabolism.
Assuntos
Microbioma Gastrointestinal , Resorcinóis , Poluentes Químicos da Água , Peixe-Zebra , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Resorcinóis/toxicidade , Feminino , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo/efeitos dos fármacos , RNA Ribossômico 16SRESUMO
Oxomollugin is a degraded product of mollugin and was found to be an active compound that inhibits LPS-induced NF-κB activation. In this study, we investigated the inhibitory activity of oxomollugin, focusing on TLR4 signaling pathway, resulting in NF-κB activation. Oxomollugin inhibited the LPS-induced association of essential factors for initial activation of TLR4 signaling, MyD88, IRAK4 and TRAF6. Furthermore, oxomollugin showed suppressive effects on LPS-induced modification of IRAK1, IRAK2 and TRAF6, LPS-induced association of TRAF6-TAK1/TAB2, and followed by IKKα/ß phosphorylation, which critical in signal transduction leading to LPS-induced NF-κB activation. The consistent results suggested that oxomollugin inhibits LPS-induced NF-κB activation via the suppression against signal transduction in TLR4 signaling pathway.The activities of oxomollugin reported in this study provides a deeper understanding on biological activity of mollugin derivatives as anti-inflammatory compounds.
Assuntos
Lipopolissacarídeos , NF-kappa B , Transdução de Sinais , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Camundongos , Humanos , Células RAW 264.7 , Fosforilação/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , Lactonas , Resorcinóis , Zearalenona/administração & dosagemRESUMO
PURPOSE OF REVIEW: Topical therapies are a mainstay of treatment for mild psoriasis and may be a useful adjunct in treatment of moderate-to-severe psoriasis. This review summarizes recent advances in topical therapies for psoriasis and currently available treatments. RECENT FINDINGS: Topical aryl hydrocarbon receptor modulators (tapinarof) and topical phosphodiesterase-4 inhibitors (roflumilast) have been proven effective in randomized controlled trials for psoriasis. Although topical JAK inhibitors have also been studied, none are currently licensed for treatment of psoriasis. Topical corticosteroids and vitamin D analogues remain the most commonly used and widely available topical treatments for psoriasis. Cost may limit use of novel topical agents. SUMMARY: Although the novel topical agents tapinarof and roflumilast are licensed for treatment of psoriasis by the FDA in the United States, they have not yet been licensed in Europe, and it remains to be seen whether they will be limited by cost.
Assuntos
Aminopiridinas , Ciclopropanos , Inibidores da Fosfodiesterase 4 , Psoríase , Humanos , Psoríase/tratamento farmacológico , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/uso terapêutico , Ciclopropanos/administração & dosagem , Ciclopropanos/uso terapêutico , Aminopiridinas/uso terapêutico , Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Vitamina D/administração & dosagem , Vitamina D/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Niacinamida/análogos & derivados , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Resorcinóis , EstilbenosRESUMO
Authenticating whole wheat foods poses a significant challenge for both the grain industry and consumers. Alkylresorcinols (ARs), serving as biomarkers of whole wheat, play a crucial role in assessing the authenticity of whole wheat foods. Herein, we introduce a novel molecularly imprinted electrochemical sensor with modifications involving a molecularly imprinted polymer (MIP) and MXene nanosheets, enabling highly sensitive and selective detection of ARs. Notably, we specifically chose 5-heneicosylresorcinol (AR21), the predominant homologue in whole wheat, as the template molecule. α-Cyclodextrin and acrylamide served as dual functional monomers, establishing a robust multiple interaction between the MIP and AR21. As a result, the sensor exhibited a wide linear range of 0.005 to 100 µg·mL-1 and a low detection limit of 2.52 ng·mL-1, demonstrating exceptional selectivity and stability. When applied to commercial whole wheat foods, the assay achieved satisfactory recoveries and accuracy, strongly validating the practicality and effectiveness of this analytical technique.