RESUMEN
Alkaptonuria is an inborn error of metabolism inherited as an autosomal recessive disorder due to a mutation in the homogentisic acid dioxygenase gene. It occurs rarely (global prevalence of alkaptonuria is 1 in 100,000 to 250,000), and mainly affects the joints and connective tissue of the body due to deposition of homogentisic acid giving affected areas a blue-black discoloration (ochronosis).In this case report, we present a male patient, aged 47 years, with joint and scleral involvement. He had been diagnosed many years ago with the disease by gas chromatography. His symptoms kept progressively worsening since he was recently prescribed physiotherapy and vitamin C for his disease, which has not been shown to be an effective treatment. A main reason for his disease deterioration was also the lack of nitisinone availability in his home country, as well as in the subcontinent region generally. We also presen a summary of some previously reported cases and treatment regimens to compare our case and present the comparison as a learning source for future physicians.
Asunto(s)
Alcaptonuria , Humanos , Alcaptonuria/tratamiento farmacológico , Alcaptonuria/diagnóstico , Masculino , Persona de Mediana Edad , Ácido Ascórbico/uso terapéutico , Nitrobenzoatos/uso terapéutico , Ocronosis , Ciclohexanonas/uso terapéutico , Ácido Homogentísico , Modalidades de FisioterapiaRESUMEN
During the investigation of firearm-related incidents, gunshot residues (GSR) can be collected on the scene and individuals (e.g., shooters or bystanders). Their analysis can give valuable information for the reconstruction of the events. Since GSR collection on persons of interest generally occurs a few minutes to hours after discharge, knowledge is needed to understand how organic (O), and inorganic (I) residues are transferred and persist. In this research, the quantities of OGSR and IGSR were assessed on the right and left hands, forearms, face, and nostrils of four shooters. Specimens were collected immediately before the discharge (shooter's blank specimens) and shortly after (30 min) using carbon adhesive stubs. Organic compounds were first extracted from the collection device and analysed using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Subsequently, IGSR particles were detected on the same stub using scanning electron microscopy coupled with energy-dispersive X-ray spectrometry (SEM/EDS). Shooter's blank specimen analysis revealed background contamination of both O and IGSR in the shooter's environment, predominantly attributed to the presence of an indoor shooting range. However, the background quantities generally remained below the associated 30-minute specimen. Thirty minutes after a discharge, higher quantities were generally detected on the shooter's right and left hands than on other collection regions for both GSR types. Forearms and face emerged as interesting collection alternatives, especially in cases where a person of interest may have washed their hands in the interval between the discharge and collection. In contrast, very low amounts of GSR were detected in the nostrils. Furthermore, the results indicated that OGSR and IGSR have different transfer and persistence mechanisms.
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Armas de Fuego , Balística Forense , Mano , Humanos , Balística Forense/métodos , Cara/anatomía & histología , Microscopía Electrónica de Rastreo , Espectrometría por Rayos X , Nariz , Antimonio/análisis , Antebrazo , Espectrometría de Masas en Tándem , Bario/análisis , Heridas por Arma de Fuego , Cromatografía Líquida de Alta Presión , CiclohexanonasRESUMEN
INTRODUCTION: Protein nutrition disorder in alkaptonuria (AKU), resulting in increased homogentisic acid (HGA) before nitisinone therapy and increased tyrosine (TYR) during nitisinone therapy, may benefit from dietetic intervention. The aim of this study was to characterise the diet and their effects prospectively in those who received formal dietetic intervention in the nitisinone-receiving National Alkaptonuria Centre (NAC) patients with those who did not in no-nitisinone Suitability of Nitisinone in Alkaptonuria 2 (SN2 N-) and nitisinone-treated SN2 (SN2 N+) randomised study groups. PATIENTS AND METHODS: A total of 63, 69, and 69 AKU patients from the NAC, SN2 N-, and SN2 N+ were studied for anthropometric (weight, BMI), body composition (including muscle mass, %body fat, hand grip strength), chemical characteristics (serum TYR, serum phenylalanine, urine urea or uUREA, and urine creatinine or uCREAT), and corneal keratopathy. Nitisinone 2 mg and 10 mg were employed in the NAC and SN2 N+ groups, respectively. Dieticians managed protein intake in the NAC, while the SN2 N- and SN2 N+ groups only received advice on self-directed protein restriction during four years of study duration. RESULTS: uUREA decreased in the NAC, SN2 N-, and SN2 N+ groups, showing that protein restriction was achieved in these groups. Body weight and BMI increased in the NAC and SN2 N+ groups. uCREAT decreased significantly in SN2 N- and SN2 N+ compared with the NAC over four years of study. Corneal keratopathy was less frequent in the NAC than in the SN2 N+ group. Active dietetic intervention in NAC stabilised lean body mass (muscle mass, hand grip strength) despite a decrease in uUREA and uCREAT, as well as sTYR. CONCLUSION: Ongoing dietetic intervention prevented loss of lean body mass despite protein restriction and moderated serum tyrosine increase, leading to less prevalent corneal keratopathy. Protein restriction risks fat mass gain.
Asunto(s)
Alcaptonuria , Composición Corporal , Ciclohexanonas , Nitrobenzoatos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Composición Corporal/efectos de los fármacos , Anciano , Tirosina/sangre , Tirosina/análogos & derivados , Adulto , Estudios Prospectivos , Índice de Masa Corporal , Estado Nutricional , Fenilalanina/sangre , Antropometría , Ácido Homogentísico/orina , Fuerza de la ManoRESUMEN
Harmful algal bloom (HAB) is an unresolved existing problem worldwide. Here, we reported a novel algicidal bacterium, Pseudomonas fragi YB2, capable of lysing multiple algal species. To Chlorella vulgaris, YB2 exhibited a maximum algicidal rate of 95.02 % at 120 h. The uniqueness of YB2 lies in its ability to self-produce three algicidal compounds: 2-methyl-1, 3-cyclohexanedione (2-MECHD), N-phenyl-2-naphthylamine, and cyclo (Pro-Leu). The algicidal properties of 2-MECHD have not been previously reported. YB2 significantly affected the chloroplast and mitochondrion, thus decreasing in chlorophyll a by 4.74 times for 120 h and succinate dehydrogenase activity by 103 times for 36 h. These physiological damages disrupted reactive oxygen species and Ca2+ homeostasis at the cellular level, increasing cytosolic superoxide dismutase (23 %), catalase (35 %), and Ca2+ influx. Additionally, the disruption of Ca2+ homeostasis rarely reported in algicidal bacteria-algae interaction was observed using the non-invasive micro-test technology. We proposed a putative algicidal mechanism based on the algicidal outcomes and physiological algicidal effects and explored the potential of YB2 through an algicidal simulation test. Overall, this study is the first to report the algicidal bacterium P. fragi and identify a novel algicidal compound, 2-MECHD, providing new insights and a potent microbial resource for the biocontrol of HAB.
Asunto(s)
Chlorella vulgaris , Pseudomonas , Pseudomonas/metabolismo , Pseudomonas/efectos de los fármacos , Chlorella vulgaris/efectos de los fármacos , Chlorella vulgaris/metabolismo , Ciclohexanonas/toxicidad , Ciclohexanonas/química , Especies Reactivas de Oxígeno/metabolismo , Calcio/metabolismo , Clorofila A/metabolismoRESUMEN
BACKGROUND: The large-scale biocatalytic application of oxidoreductases requires systems for a cost-effective and efficient regeneration of redox cofactors. These represent the major bottleneck for industrial bioproduction and an important cost factor. In this work, co-expression of the genes of invertase and a Baeyer-Villiger monooxygenase from Burkholderia xenovorans to E. coli W ΔcscR and E. coli BL21 (DE3) enabled efficient biotransformation of cyclohexanone to the polymer precursor, ε-caprolactone using sucrose as electron source for regeneration of redox cofactors, at rates comparable to glucose. E. coli W ΔcscR has a native csc regulon enabling sucrose utilization and is deregulated via deletion of the repressor gene (cscR), thus enabling sucrose uptake even at concentrations below 6 mM (2 g L-1). On the other hand, E. coli BL21 (DE3), which is widely used as an expression host does not contain a csc regulon. RESULTS: Herein, we show a proof of concept where the co-expression of invertase for both E. coli hosts was sufficient for efficient sucrose utilization to sustain cofactor regeneration in the Baeyer-Villiger oxidation of cyclohexanone. Using E. coli W ΔcscR, a specific activity of 37 U gDCW-1 was obtained, demonstrating the suitability of the strain for recombinant gene co-expression and subsequent whole-cell biotransformation. In addition, the same co-expression cassette was transferred and investigated with E. coli BL21 (DE3), which showed a specific activity of 17 U gDCW- 1. Finally, biotransformation using photosynthetically-derived sucrose from Synechocystis S02 with E. coli W ΔcscR expressing BVMO showed complete conversion of cyclohexanone after 3 h, especially with the strain expressing the invertase gene in the periplasm. CONCLUSIONS: Results show that sucrose can be an alternative electron source to drive whole-cell biotransformations in recombinant E. coli strains opening novel strategies for sustainable chemical production.
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Escherichia coli , Sacarosa , beta-Fructofuranosidasa , Escherichia coli/genética , Escherichia coli/metabolismo , beta-Fructofuranosidasa/metabolismo , beta-Fructofuranosidasa/genética , Sacarosa/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxigenasas de Función Mixta/genética , Ciclohexanonas/metabolismo , Oxidación-Reducción , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/genética , Electrones , Biotransformación , Caproatos , LactonasRESUMEN
Electrocatalytic coupled biofilter (EBF) technology organically integrates the characteristics of electrochemistry and microbial redox, providing ideas for effectively improving biological treatment performance. In this study, an EBF system was developed for enhanced degradation of cyclohexanone in contaminated water. Experimental results show that the system can effectively remove cyclohexanone in contaminated water. Under the optimal parameters, the removal rates of cyclohexanone, TP, NH4+-N and TN were 97.61 ± 1.31%, 76.31 ± 1.67%, 94.14 ± 2.13% and 95.87 ± 1.01% respectively. Degradation kinetics studies found that electrolysis, adsorption, and biodegradation pathways play a major role in the degradation of cyclohexanone. Microbial community analysis indicates that voltage can affect the structure of the microbial community, with the dominant genera shifting from Acidovorax (0 V) to Brevundimonas (0.7 V). Additionally, Acidovorax, Cupriavidus, Ralstonia, and Hydrogenophaga have high abundance in the biofilm and can effectively metabolize cyclohexanone and its intermediates, facilitating the removal of cyclohexanone. In summary, this research can guide the development and construction of highly stable EBF systems and is expected to be used for advanced treatment of industrial wastewater containing cyclohexanone.
Asunto(s)
Biodegradación Ambiental , Ciclohexanonas , Filtración , Eliminación de Residuos Líquidos , Aguas Residuales , Contaminantes Químicos del Agua , Ciclohexanonas/química , Ciclohexanonas/metabolismo , Aguas Residuales/química , Eliminación de Residuos Líquidos/métodos , Filtración/métodos , Contaminantes Químicos del Agua/metabolismoRESUMEN
Bone metastasis in metastatic breast cancer commonly results in osteolytic lesions due to osteoclast activity, promoting bone destruction and tumor progression. The bioactive fungal isolates, 4-acetyl-antroquinonol B (4-AAQB) and erinacine A, have diverse pharmacological and biological activities. However, their effects on breast cancer bone metastasis treatment remain unclear. Our study aimed to examine the impact of 4-AAQB or erinacine A on breast cancer metastases in bone. The effects of 4-AAQB and erinacine A on breast cancer-induced osteoclastogenesis, breast cancer migration, production of prometastatic cytokine (TGF-ß) and marker (MMP-9), as well as potential MAPK signaling transductions were assessed. The results revealed that 4-AAQB and erinacine A effectively suppressed breast cancer-induced osteoclastogenesis and migration, and reduced TGF-ß and MMP-9 production via Erk or JNK signaling transductions, specifically in breast cancer cells or in breast cancer cells-induced osteoclasts. Based on these findings, either 4-AAQB or erinacine A showed promise in preventing breast cancer metastases in bone.
Asunto(s)
Neoplasias de la Mama , Metaloproteinasa 9 de la Matriz , Osteoclastos , Osteogénesis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Femenino , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Animales , Factor de Crecimiento Transformador beta/metabolismo , Neoplasias Óseas/secundario , Neoplasias Óseas/tratamiento farmacológico , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ciclohexanonas , 4-Butirolactona/análogos & derivadosRESUMEN
The interaction between Nitisinone (NTBC) and bovine serum albumin (BSA) as the transport protein in a circulating system was investigated for the first time utilizing various analytical (UV-Vis spectrophotometry, fluorescence spectroscopy, dynamic light scattering, and differential scanning calorimetry) and computational (molecular docking and molecular dynamics simulations) methods. The BSA fluorescence intensity was quenched upon interaction with NTBC, and the quenching mechanism was observed as static. The interaction between NTBC and BSA was examined at 288 K, 298 K, and 308 K where the binding constants were found to be 1.44 × 105 ± 0.22 M-1, 5.18 × 104 ± 0.20 M-1, and 3.02 × 104 ± 0.22 M-1 respectively, suggesting an intermediate binding affinity between NTBC and BSA. Changes in the microenvironment surrounding tryptophan and tyrosine residues of BSA were elucidated using 3-D fluorescence spectroscopy. Thermodynamic studies revealed the calculated values of ΔH = - 54.34 ± 5 kJ/mol and ΔS = - 0.0908 ± 0.24 kJ/mol K-1, indicating the involvement of van der Waals forces and hydrogen bonds in the interaction between NTBC and BSA. Moreover, the interaction's spontaneous nature was evidenced by negative ΔG values across all temperatures. Using dynamic light scattering, it was observed that higher NTBC concentrations led to a gradual rise in hydrodynamic diameter and notable aggregation of the NTBC-BSA complex. Moreover, changing signal values and shifted peaks of BSA, NTBC, and complex in differential scanning calorimetry curves, meant there were molecular interactions between the NTBC and BSA. In silico approaches also elucidated how NTBC binds to active sites on BSA, further supporting other findings. Moreover, molecular docking studies offer a more profound insight into the changing dynamics of hydrophobic, hydrogen, and halogen bonding involved in stabilizing the NTBC-BSA complex.
Asunto(s)
Ciclohexanonas , Simulación del Acoplamiento Molecular , Nitrobenzoatos , Unión Proteica , Albúmina Sérica Bovina , Espectrometría de Fluorescencia , Termodinámica , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Animales , Bovinos , Nitrobenzoatos/química , Nitrobenzoatos/metabolismo , Ciclohexanonas/química , Ciclohexanonas/metabolismo , Simulación de Dinámica Molecular , Espectrofotometría Ultravioleta , Sitios de Unión , Rastreo Diferencial de CalorimetríaRESUMEN
The physiological parameters such as growth, Chl a content, and photosynthetic performance of the experimental cyanobacterium Anabaenopsis circularis HKAR-22 were estimated to evaluate the cumulative effects of photosynthetically active radiation (PAR) and ultraviolet (UV) radiation. Maximum induction of UV-screening molecules, MAAs, was observed under the treatment condition of PAR + UV-A + UV-B (PAB) radiations. UV/VIS absorption spectroscopy and HPLC-PDA detection primarily confirmed the presence of MAA-shinorine (SN) having absorption maxima (λmax) at 332.3 nm and retention time (RT) of 1.47 min. For further validation of the presence of SN, HRMS, FTIR and NMR were utilized. UV-stress elevated the in vivo ROS scavenging and in vitro enzymatic antioxidant capabilities. SN exhibited substantial and concentration-dependent antioxidant capabilities which was determined utilizing 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate (ABTS), ferric reducing power (FRAP) and superoxide radical scavenging assay (SRSA). The density functional theory (DFT) method using B3LYP energy model and 6-311G++(d,p) basis set was implied to perform the quantum chemical calculation to systematically investigate the antioxidant nature of SN. The principal pathways involved in the antioxidant reactions along with the basic molecular descriptors affecting the antioxidant potentials of a compound were also studied. The results favor the potential of SN as an active ingredient to be used in cosmeceutical formulations.
Asunto(s)
Antioxidantes , Cianobacterias , Teoría Funcional de la Densidad , Rayos Ultravioleta , Antioxidantes/química , Cianobacterias/química , Cianobacterias/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Ciclohexanonas/química , Fotosíntesis , Especies Reactivas de Oxígeno/metabolismo , Clorofila A/química , Clorofila A/metabolismo , Compuestos de Bifenilo/química , Picratos/antagonistas & inhibidores , Picratos/química , Depuradores de Radicales Libres/química , Ciclohexilaminas , Glicina/análogos & derivados , Ácidos Sulfónicos , BenzotiazolesRESUMEN
Chimeric mouse models with a humanized liver (Hu-HEP mice) provide a unique tool to study human hepatotropic virus diseases, including viral infection, viral pathogenesis, and anti-viral therapy. Here, we describe a detailed protocol for studying hepatitis B infection in NRG-derived fumarylacetoacetate hydrolase (FAH) knockout mice repopulated with human hepatocytes (FRG-Hu HEP mice). The procedures include (1) maintenance and genotyping of the FRG mice, (2) intrasplenic injection of primary human hepatocytes (PHH), (3) 2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) drug reduction cycling to improve human hepatocyte repopulation, (4) human albumin detection, and (5) HBV infection and detection. The method is simple and allows for highly reproducible generation of FRG-Hu HEP mice for HBV infection and therapy investigations.
Asunto(s)
Modelos Animales de Enfermedad , Virus de la Hepatitis B , Hepatitis B , Hepatocitos , Hidrolasas , Hígado , Ratones Noqueados , Animales , Humanos , Ratones , Hidrolasas/genética , Hidrolasas/metabolismo , Hidrolasas/deficiencia , Hepatitis B/virología , Virus de la Hepatitis B/genética , Hígado/virología , Hígado/patología , Hepatocitos/virología , Hepatocitos/trasplante , Ratones Endogámicos NOD , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Quimera , Ciclohexanonas , NitrobenzoatosRESUMEN
BACKGROUND: The formation of amyloid-ß (Aß) plaques is one of the key neuropathological hallmarks of Alzheimer's disease (AD). Near-infrared (NIR) probes show great potential for imaging of Aß plaques in vivo and in vitro. Dicyanoisophorone (DCIP) based Aß probes have attracted considerable attention due to their exceptional properties. However, DCIP probes still has some drawbacks, such as short emission wavelength (<650 nm) and low fluorescence intensity after binding to Aß. It is clear that further modification is needed to improve their luminescence efficiency and sensitivity. RESULTS: We designed and synthesize four novel pyrrolidine-alkylamino-substituted DCIP derivatives (6a-d) as imaging agents for ß-amyloid (Aß) aggregates. Compound 6c responds better to Aß aggregates than the other three compounds (6a, 6b and 6d) and its precursor DCIP. The calculated detection limit is to be as low as 0.23 µM. Compound 6c shows no cytotoxicity in the tested concentration for SH-SY5Y and HL-7702 cells. Additionally, compound 6c is successfully applied to monitor Aß aggregates in live SH-SY5Y cells and APP/PS1 transgenic mice. The retention time in the transgenic mice brain is much longer than that of age-matched wild-type mice. SIGNIFICANCE: The results indicates that compound 6c had an excellent ability to penetrate the blood-brain barrier and it could effectively distinguish APP/PS1 transgenic mice and wide-type mice. This represents its promising applications for Aß detection in basic and biomedical research.
Asunto(s)
Ciclohexanonas , Humanos , Línea Celular , Precursor de Proteína beta-Amiloide/análisis , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Pirrolidinas/química , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Ciclohexanonas/farmacología , Espectroscopía Infrarroja Corta , Estructura Molecular , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Espectrometría de Fluorescencia , Modelos Moleculares , Estructura Terciaria de Proteína , Simulación del Acoplamiento Molecular , Supervivencia Celular/efectos de los fármacos , Animales , Ratones , Masculino , Ratones Endogámicos C57BL , Encéfalo/metabolismo , Aminación , AlquilaciónRESUMEN
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.
Asunto(s)
Productos Biológicos , Catálisis , Productos Biológicos/síntesis química , Productos Biológicos/química , Estereoisomerismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Alcaloides de Cinchona/química , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Fenómenos Químicos Orgánicos , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Aminas/química , Aminas/síntesis química , Tiourea/química , Tiourea/síntesis química , Resorcinoles/síntesis química , Resorcinoles/química , Indanos/síntesis química , Indanos/químicaRESUMEN
INTRODUCTION: Tyrosinaemia type I is a rare hereditary metabolic disease caused by deficiency of the enzyme involved in the breakdown of tyrosine. Since the use of nitisinone in addition to diet in 1992, survival rates have increased significantly, but more and more socio-emotional problems have become apparent. The aim of the study was the assessment the relationship between variations in serum tyrosine and phenylalanine levels and measurements of socio-emotional functioning and determination of patients' IQs. THE AIM OF THE STUDY: was the assessment the relationship between variations in serum tyrosine and phenylalanine levels and measurements of socio-emotional functioning and determination of patients' IQs. MATERIAL AND METHODS: Twelve children were studied, from a single centre, born between 1994 and 2012, treated with nitisinone and a low-phenylalanine and -tyrosine diet. The psychological evaluation was conducted using the parent form of the Child Behaviour Checklist (CBCL)/4-18. Additionally, the patients' IQs were measured using the Stanford-Binet 5 (SB5) Intelligence Scale. Statistical analyses were performed using PAWS software suite version 26. We found that phenylalanine variability over time correlated with measures of emotional and behavioural functioning. This relationship holds true for externalising behaviour, associated with the experience of maladjustment and aggression. Total score intellectual and cognitive function was within the norm for all patients. CONCLUSIONS: To maintain better quality of life for patients and their families in terms of emotional and behavioural functioning, it may be important to avoid spikes (significant fluctuations) in phenylalanine levels. Regular, detailed psychological evaluations are recommended to detect potential problems and implement interventions aimed at achieving the best possible individual development and realise the intellectual and behavioural potential, thereby improving the patient's and her family's quality of life.
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Fenilalanina , Tirosinemias , Humanos , Tirosinemias/sangre , Tirosinemias/psicología , Niño , Masculino , Femenino , Fenilalanina/sangre , Preescolar , Adolescente , Tirosina/sangre , Ciclohexanonas/uso terapéutico , Emociones , Calidad de Vida , Nitrobenzoatos/uso terapéutico , Conducta Infantil/psicologíaRESUMEN
Mesotrione is a herbicide used in agricultural production; however, its stability and long-term residues pose ecological risks to soil health and subsequent crops. In this research, the strain Amycolatopsis nivea La24 was identified as capable of completely degrading 50 mgâL-1 mesotrione within 48 h. It exhibited a broad adaptability to various environment and could degrade three sulfonylurea herbicides (nicosulfuron, chlorimuron-methyl, and cinosulfuron). Non-target metabonomic and mass spectrometry demonstrated that La24 strain broke down the mesotrione parent molecule by targeting the ß-diketone bond and nitro group, resulting in the production of five possible degradation products. The differentially expressed genes were significantly enriched in fatty acid degradation, amino acid metabolism, and other pathways, and the differentially metabolites in glutathione metabolism, arginine/proline metabolism, cysteine/methionine metabolism, and other pathways. Additionally, it was confirmed by heterologous expression that nitroreductase was directly involved in the mesotrione degradation, and NDMA-dependent methanol dehydrogenase would increase the resistance to mesotrione. Finally, the intracellular response of La24 during mesotrione degradation was proposed. This work provides insight for a comprehensive understanding of the mesotrione biodegradation mechanism, significantly expands the resources for pollutant degradation, and offers the potential for a more sustainable solution to address herbicide pollution in soil.
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Amycolatopsis , Biodegradación Ambiental , Ciclohexanonas , Herbicidas , Herbicidas/metabolismo , Herbicidas/química , Ciclohexanonas/metabolismo , Amycolatopsis/metabolismo , Amycolatopsis/genética , Metabolómica , Compuestos de Sulfonilurea/metabolismo , Contaminantes del Suelo/metabolismo , MultiómicaRESUMEN
Isophorone is a cyclic ketone that has gained significant attention in the field of organic chemistry due to its versatile reactivity and structural attributes. Derivatives of isophorone offer a broad spectrum of applications ranging from pharmaceuticals to polymer chemistry. With the aim of developing novel hybrid structures based on benzylidene by combining with isophorone scaffold, we report 3 derivatives of the benzylidene-isophorone hybrids and its potent anticancer activity. In order to optimize the anticancer activity of hybrids di-substitution of -Cl group in C2 and C6 position of phenyl ring (compound1), -OCH3 group in C2 and C5 position of phenyl ring (compound2), and -OCH3 group in C2 and C3 position of phenyl ring (compound3) of benzylidene (PhCH=) moiety were made. The structure of Compounds1,2 and 3 were elucidated using spectral and XRD methods. Compounds1,2 and 3 exhibit space group P c a 21, P-1, and P 1 21/n 1 respectively. Compounds1,2 and 3 were tested for the potent anticancer activity on MDA MB-231 cell line. All the three compounds exhibit good anticancer activity on the breast cancer cells. The parent hybrid with ortho, ortho directing -Cl (1) exhibits strong antiproliferation effect (IC50 = 0.028 µM) on MDA-MB 231 cell line. However, hybrid structures with ortho, meta directing -OCH3 (2) group showed moderate effect (IC50 = 0.061 µM) and hybrid with ortho, meta directing -OCH3 (3) substitution showed the least potent anticancer activity (IC50 = 0.074 µM). The benzylidene-isophorone hybrids exhibit anticancer effects in the following order: 1 > 2 > 3.
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Antineoplásicos , Compuestos de Bencilideno , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Compuestos de Bencilideno/farmacología , Compuestos de Bencilideno/química , Proliferación Celular/efectos de los fármacos , Modelos Moleculares , Cristalografía por Rayos X , CiclohexanonasRESUMEN
Mesotrione, as a widely used herbicide, is present in the environment in detectable amounts, causing serious damage. Here, we aimed to investigate the effect of mesotrione on Caco-2 cells and the possibility of its toxicity mitigation by cichoric acid. Therefore, we analyzed the cytotoxicity of both these compounds and the selected oxidative stress parameters, apoptosis and interaction of both the tested compounds with the cell membrane and their accumulation within the cells. In cytotoxicity studies, the stimulating activity of mesotrione was observed, and simultaneously, the inhibitory effect of cichoric acid was noticed. This effect was related to the results of oxidative stress analysis and apoptosis measurements. The activity level of key enzymes (glutathione peroxidase, catalase and superoxide dismutase) in Caco-2 cells exposed to cichoric acid was higher as compared to that of the control. The treatment with mesotrione did not induce apoptosis in the Caco-2 cells. The penetration of the studied compounds into the Caco-2 cells was measured by using an HPLC methodology, and the results indicate mesotrione's high penetration capacity. The distribution of charge on the surface of the cell membranes changed under the influence of both compounds. Considering the mutual interactions of beneficial and potentially toxic food ingredients, it should be noted that, despite the observed favorable trend, cichoric acid is not able to overcome the toxic and cancer-stimulating effects of this pesticide.
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Apoptosis , Ácidos Cafeicos , Ciclohexanonas , Estrés Oxidativo , Humanos , Células CACO-2 , Apoptosis/efectos de los fármacos , Ciclohexanonas/farmacología , Estrés Oxidativo/efectos de los fármacos , Ácidos Cafeicos/farmacología , Succinatos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Herbicidas/toxicidad , Superóxido Dismutasa/metabolismo , Supervivencia Celular/efectos de los fármacos , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismoRESUMEN
In the risk assessment of agrochemicals, there has been a historical paucity of using data to refine the default adjustment factors, even though large datasets are available to support this. The current state of the science for addressing uncertainty regarding animal to human extrapolation (AFA) is to develop a "data-derived" adjustment factor (DDEF) to quantify such differences, if data are available. Toxicokinetic (TK) and toxicodynamic (TD) differences between species can be utilized for the DDEF, with human datasets being ideal yet rare. We identified a case for a currently registered herbicide, mesotrione, in which human TK and TD are available. This case study outlines an approach for the development of DDEFs using comparative human and animal data and based on an adverse outcome pathway (AOP) for inhibition of 4-hydroxyphenol pyruvate dioxygenase (HHPD). The calculated DDEF for rat to human extrapolation (AFA) for kinetics (AFAK = 2.5) was multiplied by the AFA for dynamics (AFAD = 0.3) resulting in a composite DDEF of â¼1 (AFA = 0.75). This reflects the AOP and available scientific evidence that humans are less sensitive than rats to the effects of HPPD inhibitors. Further analyses were conducted utilizing in vitro datasets from hepatocytes and liver cytosols and extrapolated to whole animal using in vitro to in vivo extrapolation (IVIVE) to support toxicodynamic extrapolation. The in vitro datasets resulted in the same AFAD as derived for in vivo data (AFAD = 0.3). These analyses demonstrate that a majority of the species differences are related to toxicodynamics. Future work with additional in vitro/in vivo datasets for other HPPD inhibitors and cell types will further support this result. This work demonstrates utilization of all available toxicokinetic and toxicodynamic data to replace default uncertainty factors for agrochemical human health risk assessment.
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4-Hidroxifenilpiruvato Dioxigenasa , Ciclohexanonas , Humanos , Animales , Ratas , Ciclohexanonas/toxicidad , Medición de Riesgo , 4-Hidroxifenilpiruvato Dioxigenasa/antagonistas & inhibidores , Especificidad de la Especie , Herbicidas/toxicidad , Toxicocinética , Rutas de Resultados AdversosRESUMEN
Phytochemical investigation on the fruits of Cydonia oblonga Mill., a traditional Uighur medicine, led to the isolation of seven undescribed and nine known megastigmane glycosides. Their structures including absolute configurations were characterized by an extensive analysis of spectroscopic data including HRESIMS and NMR, combined with ECD calculations. Additionally, compounds 1, 2, 4, and 6-16 exhibited anti-inflammatory activity by inhibiting the secretion of cytokines TNF-α and IL-6 in RAW264.7 cells induced by lipopolysaccharides (LPS) with inhibitory rates of 10.79%-44.58% at 20 µM.
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Ciclohexanonas , Glicósidos , Lipopolisacáridos , Norisoprenoides , Norisoprenoides/química , Norisoprenoides/farmacología , Norisoprenoides/aislamiento & purificación , Ratones , Glicósidos/química , Glicósidos/aislamiento & purificación , Glicósidos/farmacología , Células RAW 264.7 , Animales , Ciclohexanonas/química , Ciclohexanonas/farmacología , Ciclohexanonas/aislamiento & purificación , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Estructura Molecular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , GlucósidosRESUMEN
The presence of undesired agrochemicals residues in soil and water poses risks to both human health and the environment. The behavior of pesticides in soil depends both on the physico-chemical properties of pesticides and soil type. This study examined the adsorption-desorption and leaching behavior of the maize herbicide tembotrione in soils of the upper (UGPZ), trans (TGPZ) and middle Gangetic plain zones of India. Soil samples were extracted using acetone followed by partitioning with dichloromethane, whereas liquid-liquid extraction using dichloromethane was used for aqueous samples. Residues of tembotrione and its metabolite TCMBA, {2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy) methyl] benzoic acid}, were quantified using liquid chromatography-tandem mass spectrometry. The data revealed that tembotrione adsorption decreased with increasing pH and dissolved organic matter but increased with salinity. The maximum adsorption occurred at pH 4, 0.01 m sodium citrate and 4 g/L NaCl, with corresponding Freundlich constants of 1.83, 2.28 and 3.32, respectively. The hysteresis index <1 indicated faster adsorption than desorption. Leaching studies under different flow conditions revealed least mobility in UGPZ soil and high mobility in TGPZ soil, consistent with groundwater ubiquity scores of 4.27 and 4.81, respectively. Soil amendments decreased tembotrione mobility in the order: unamended > wheat straw ash > wheat straw > farm yard manure > compost. The transformation of tembotrione to TCMBA and its mobility in soil columns were also assessed.
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Ciclohexanonas , Contaminantes del Suelo , India , Contaminantes del Suelo/química , Contaminantes del Suelo/análisis , Adsorción , Ciclohexanonas/química , Ciclohexanonas/análisis , Suelo/química , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida/métodos , Herbicidas/química , Herbicidas/análisis , Modelos Lineales , Límite de Detección , Reproducibilidad de los Resultados , SulfonasRESUMEN
The endocannabinoid system (ECS) regulates neurotransmission linked to synaptic plasticity, cognition, and emotion. While it has been demonstrated that dysregulation of the ECS in adulthood is relevant not only to central nervous system (CNS) disorders such as autism spectrum disorder, cognitive dysfunction, and depression but also to brain function, there are few studies on how dysregulation of the ECS in the neonatal period affects the manifestation and pathophysiology of CNS disorders later in life. In this study, DO34, a diacylglycerol lipase alpha (DAGLα) inhibitor affecting endocannabinoid 2-AG production, was injected into C57BL/6N male mice from postnatal day (PND) 7 to PND 10, inducing dysregulation of the ECS in the neonatal period. Subsequently, we examined whether it affects neuronal function in adulthood through electrophysiological and behavioral evaluation. DO34-injected mice showed significantly decreased cognitive functions, attributed to impairment of hippocampal synaptic plasticity. The findings suggest that regulation of ECS activity in the neonatal period may induce enduring effects on adult brain function.