RESUMO
OBJECTIVES: Wilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract's copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat WD, there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the efficacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood. METHODS: Ninety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan-Meier analysis. RESULTS: The median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p < 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p < 0.05), but no significant difference was observed between DPA and zinc (p = 0.22). CONCLUSIONS: In pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc are associated with more adverse effects compared to trientine.
Assuntos
Degeneração Hepatolenticular , Penicilamina , Trientina , Zinco , Humanos , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/metabolismo , Penicilamina/uso terapêutico , Penicilamina/efeitos adversos , Trientina/uso terapêutico , Trientina/efeitos adversos , Criança , Masculino , Feminino , Zinco/uso terapêutico , Adolescente , Pré-Escolar , Quelantes/uso terapêutico , Resultado do TratamentoRESUMO
Climate change caused by the greenhouse gases CO2 remains a topic of global concern. To mitigate the excessive levels of anthrophonic CO2 in the atmosphere, CO2 capture methods have been developed and among these, adsorption is an especially promising method. This paper presents a series of amine functionalized biochar obtained from desiccated coconut waste (amine-biochar@DCW) for use as CO2 adsorbent. They are ethylenediamine-functionalized biochar@DCW (EDA-biochar@DCW), diethylenetriamine-functionalized biochar@DCW (DETA-biochar@DCW), triethylenetetramine-functionalized biochar@DCW (TETA-biochar@DCW), tetraethylenepentamine-functionalized biochar@DCW (TEPA-biochar@DCW), and pentaethylenehexamine-functionalized biochar@DCW (PEHA-biochar@DCW). The adsorbents were obtained through amine functionalization of biochar and they are characterized using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) spectroscopy, Brunauer-Emmett-Teller (BET), and thermogravimetric analysis (TGA). The CO2 adsorption study was conducted isothermally and using a thermogravimetric analyzer. From the results of the characterization analyses, a series of amine-biochar@DCW adsorbents had larger specific surface area in the range of 16.2 m2/g-37.1 m2/g as compare to surface area of pristine DCW (1.34 m2/g). Furthermore, the results showed an increase in C and N contents as well as the appearance of NH stretching, NH bending, CN stretching, and CN bending, suggesting the presence of amine on the surface of biochar@DCW. The CO2 adsorption experiment shows that among the amine modified biochar adsorbents, TETA-biochar@DCW has the highest CO2 adsorption capacity (61.78 mg/g) when using a mass ratio (m:m) of biochar@DCW:TETA (1:2). The adsorption kinetics on the TETA-biochar@DCW was best fitted by the pseudo-second model (R2 = 0.9998), suggesting the adsorption process occurs through chemisorption. Additionally, TETA-biochar@DCW was found to have high selectivity toward CO2 gas and good reusability even after five CO2 adsorption-desorption cycles. The results demonstrate the potential of novel CO2 adsorbents based on amine functionalized on desiccated coconut waste biochar.
Assuntos
Dióxido de Carbono , Cocos , Dióxido de Carbono/química , Porosidade , Carvão Vegetal , Espectroscopia de Infravermelho com Transformada de Fourier , Trientina , Adsorção , CinéticaRESUMO
Seven undescribed sesquiterpenes, including three dimeric guaianolide sesquiterpenes artemongolides G-I (1-3) and four sesquiterpene lactones artemanomalide D-G (16-19), along with seventeen known compounds isoabsinthin (4), absinthin (5), 11-eptabsinthin (6), 11, 11'-bis-epiabsinthin (7), 10', 11'- epiabsinthin (8), anabsinthin (9), isoanabsinthin (10), absinthin D (11), anabsin (12), caruifolin D (13), gnapholide (14), caruifolin C (15), 1ß(R),10ß(S)-dihydroxy-3-oxo-11ß (S)H-4,11(13)-guaien-6α(S),12-olide (20), 1α,6α,8α-trihydroxy-5α,7ßH-guaia-3,10(14),11(13)-trien-12-oic acid (21), 1α,6α,8α-trihydroxy-5α,7ßH-guaia-3,9,11(13)-trien-12-oic acid (22), argyinolide J (23), artabsinolide A (24) were isolated from the plant Artemisia mongolica. The structures were determined by interpreting NMR, HRESIMS and ECD data. The X-ray crystal structure of 4, 7 and 8 were reported for the first time. In the anti-vitiligo activity test, compounds 2, 7, 12, 23 and 24 demonstrated activity in promoting melanogenesis at a concentration of 50 µM in B16 cells, with 8-methoxypsoralan (8-MOP) as a positive control. Further research on the mechanism revealed that artemongolides H (2) enhance the expression of MITF and TRPs by upregulating p-Akt and p-GSK-3ß, leading to an increase in ß-catenin content in the cell cytoplasm. Subsequently, ß-catenin translocates into the nucleus, resulting in melanogenesis. The results supported the regulation of melanogenesis by artemongolide H (2) through the Akt/GSK3ß/ß-catenin signaling pathway. The anti-inflammatory results demonstrated that compounds 4, 5, 6, 9 and 14 can inhibit the upregulation of IL-6 mRNA and CCL2 mRNA expression. Compound 12 specifically inhibited the upregulation of IL-6 mRNA expression. These compounds exhibited significant anti-inflammatory activities. The activity results revealed that these sesquiterpene compounds have the potential to become lead compounds for the treatment of vitiligo and inflammatory diseases.
Assuntos
Artemisia , Asteraceae , Sesquiterpenos , Artemisia/química , beta Catenina , Glicogênio Sintase Quinase 3 beta , Interleucina-6 , Proteínas Proto-Oncogênicas c-akt , Trientina , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/química , Anti-Inflamatórios , RNA Mensageiro , Lactonas/farmacologia , Lactonas/química , Asteraceae/química , Estrutura MolecularRESUMO
A novel sulfonated group and triethylenetetramine modified GO/chitosan (GO-CS) adsorbent (T-SGO-CS) was successfully prepared and utilized for the adsorption of heavy metal ions from single-metal, binary-metal, and ternary-metal solutions. In a single system, the adsorption capacity was 312.28 mg/g for Pb2+, 260.52 mg/g for Cd2+, and 84.61 mg/g for Ni2+, whereas, Adsorption of Pb(II), Cd(II), and Ni(II) in binary and ternary systems was systematically studied. In tertiary systems, the effect of competitive adsorption was more pronounced. In addition, T-SGO-CS exhibited a high adsorption capacity and was recyclable for Pb2+, Cd2+, and Ni2+. T-SGO-CS is a novel and highly efficient adsorbent for omnidirectionally enhancing the adsorption of Pb2+, Cd2+, and Ni2+, as demonstrated by these results. Therefore, T-SGO-CS could be investigated as a potential new material for future applications in heavy metal removal.
Assuntos
Quitosana , Grafite , Metais Pesados , Poluentes Químicos da Água , Cádmio , Trientina , Chumbo , Adsorção , Íons , Poluentes Químicos da Água/análise , CinéticaRESUMO
BACKGROUND AND AIMS: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. APPROACH AND RESULTS: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04. CONCLUSIONS: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
Assuntos
Degeneração Hepatolenticular , Penicilamina , Humanos , Penicilamina/farmacologia , Penicilamina/uso terapêutico , Trientina/farmacologia , Trientina/uso terapêutico , Cobre , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de Cobre/uso terapêutico , Degeneração Hepatolenticular/tratamento farmacológico , Tomografia por Emissão de PósitronsRESUMO
Seven steroidal saponins including three new 16,23-cyclocholestanes (1-3) and one new pregane (4) were isolated from the roots of Dracaena cambodiana Pierre ex Gagnep. Their chemical structures were elucidated to be (23R,25R)-26-O-ß-D-glucopyranosyl-16,23-cyclocholesta-5,17(20)-dien-22-one-3ß,16α,26-triol-3-O-α-L-rhamnopyranosyl-(1â2)-[α-L-rhamnopyranosyl-(1â3)]-ß-D-glucopyranoside (1), (23R,25R)-26-O-ß-D-glucopyranosyl-16,23-cyclocholesta-5,17,20(22)-trien-3ß,22,26-triol-3-O-α-L-rhamnopyranosyl-(1â3)-ß-D-glucopyranoside (2), (23R,25R)-16,23-cyclocholesta-5,16,20(22)-trien-3ß,22,26-triol-3-O-α-L-rhamnopyranosyl-(1â3)-ß-D-glucopyranoside (3), 3ß-[(O-α-L-rhamnopyranosyl-(1â3)-[α-L-rhamnopyranosyl-(1â2)]-ß-D-gluco-pyranosyl)oxy]-pregna-5,17(20)-diene-16-one-20-carboxylic acid 4''''-O-ß-D-glucopyranosylisopentyl ester (4), cambodianoside A (5), diosbulbiside C (6), and diosbulbiside D (7), by IR, HR-ESI-MS, 1D and 2D NMR spectra. Compounds 1 and 4-7 inhibited nitric oxide (NO) production in lipopolysaccharide activated RAW 264.7 cells with IC50 values ranging from 19.03±1.84 to 67.92±3.81â µM, whereas compounds 2 and 3 were inactive with IC50 values over 100â µM.
Assuntos
Dracaena , Lipopolissacarídeos , Saponinas , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Óxido Nítrico , Células RAW 264.7 , Trientina , Saponinas/farmacologia , Saponinas/química , Estrutura MolecularRESUMO
BACKGROUND: Triterpenoids have shown a wide range of biological activities including antitumor and antiviral effects. Typically, triterpenes are synthesized through the mevalonate pathway and are extracted from natural plants and fungi. In this work, triterpenoids, ganoderic acids (GAs) were discovered to be produced via biotransformation of a diterpene, 15,16-dihydrotanshinone I (DHT) in the liquid cultured Ganoderma sessile mycelium. RESULTS: Firstly, the biotransformation products, two rare GAs were isolated and purified by column chromatography, and characterized using HR-ESI-MS spectrometry and NMR spectrometry. The two compounds were Lanosta-7,9(11),24-trien-15α,22,ß-diacetoxy-3ß-hydroxy-26-oic acid (LTHA) and Lanosta-7,9(11),24-trien-15α,22,ß-diacetoxy-3ß-carbonyl-26-oic acid (LTCA). Then, transcriptome and proteome technologies were employed to measure the expression of mRNA and protein, which further confirmed that triterpenoid GAs could be transformed from exogenous diterpenoid DHT. At the molecular level, we proposed a hypothesis of the mechanism by which DHT converted to GAs in G. sessile mycelium, and the possible genes involved in biotransformation were verified by RT-qPCR. CONCLUSIONS: Two rare GAs were obtained and characterized. A biosynthetic pathway of GAs from DHT was proposed. Although the synthetic route was not confirmed, this study provided important insights into omics resources and candidate genes for studying the biotransformation of diterpenes into triterpenes.
Assuntos
Trientina , Triterpenos , Triterpenos/metabolismo , BiotransformaçãoRESUMO
The intrinsic hydrophilicity of metal compounds, such as copper ferrite (CuFe2 O4 ), and organic compounds, including graphene oxide (GO) and triethylenetetramine (TETA), make them promising adsorbents for heavy metals removal. The presence of lone pairs in these compounds is observed in modified polyethersulfone membranes used for the separation of arsenic (As) and total dissolved solids (TDS), including mono and divalent salts from aqueous solutions. The objective of this study was to investigate the performance of GO-TETA-CuFe2 O4 membranes for wastewater treatment applications. The membranes were characterized for their optimal mechanical strength (tensile strength) and high negative charge (zeta potential) on the surface. Separation tests were conducted at different pressures and pH levels to evaluate the membrane's effectiveness in removing contaminants. In addition, the membranes were examined for their antibacterial properties. The modified membrane exhibited superior performance compared with the control membrane, with TDS removal rates of 93.8%, As3+ removal rates of 81.2%, and As5+ removal rates of 87.9%. The contact angle of the modified membrane was reduced, resulting in an increase in pure water flux from 13.11 to 27.87 L/m2 .h. The modified membrane also demonstrated significantly higher resistance to fouling than the control membrane, with a resistance increase from 6.78 × 10+12 to 2.07 × 10+12 m-1 . This contributed to the improved separation performance of As and TDS in a cross-flow setup. The results suggest that the GO-TETA-CuFe2 O4 modified membrane has great potential for use in water treatment applications. PRACTITIONER POINTS: GO-TETA-CuFe2 O4 was successfully used for modification of PES NF membrane structure. The efficiency of blended NF membranes with GO-TETA-CuFe2 O4 significantly increased. The modified membranes exhibited significant water flux and antifouling properties. The GO-TETA-CuFe2 O4 /PES membranes showed high rejection of heavy metal ions and TDS than PES. The GO-TETA-CuFe2 O4 /PES membranes exhibited desirable antibacterial activity.
Assuntos
Arsênio , Incrustação Biológica , Metais Pesados , Cobre , Incrustação Biológica/prevenção & controle , Membranas Artificiais , Antibacterianos/farmacologia , TrientinaRESUMO
INTRODUCTION: Neurological deterioration, soon after anti-copper treatment initiation, is problematic in the management of Wilson's disease (WD) and yet reports in the literature are limited. The aim of our study was to systematically assess the data according to early neurological deteriorations in WD, its outcome and risk factors. METHODS: Using PRISMA guidelines, a systematic review of available data on early neurological deteriorations was performed by searching the PubMed database and reference lists. Random effects meta-analytic models summarized cases of neurological deterioration by disease phenotype. RESULTS: Across the 32 included articles, 217 cases of early neurological deterioration occurred in 1512 WD patients (frequency 14.3%), most commonly in patients with neurological WD (21.8%; 167/763), rarely in hepatic disease (1.3%; 5/377), and with no cases among asymptomatic individuals. Most neurological deterioration occurred in patients treated with d-penicillamine (70.5%; 153/217), trientine (14.2%; 31/217) or zinc salts (6.9%; 15/217); the data did not allow to determine if that reflects how often treatments were chosen as first line therapy or if the risk of deterioration differed with therapy. Symptoms completely resolved in 24.2% of patients (31/128), resolved partially in 27.3% (35/128), did not improve in 39.8% (51/128), with 11 patients lost to follow-up. CONCLUSIONS: Given its occurrence in up to 21.8% of patients with neurological WD in this meta-analysis of small studies, there is a need for further investigations to distinguish the natural time course of WD from treatment-related early deterioration and to develop a standard definition for treatment-induced effects.
Assuntos
Degeneração Hepatolenticular , Doenças do Sistema Nervoso , Humanos , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/diagnóstico , Penicilamina/uso terapêutico , Trientina/uso terapêutico , Cobre , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/diagnósticoRESUMO
AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. METHODS: The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. CONCLUSION: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM. TRIAL REGISTRATION NUMBERS: NCT04706429 and ISRCTN57145331.
Assuntos
Cardiomiopatia Hipertrófica , Trientina , Humanos , Trientina/uso terapêutico , Cobre/uso terapêutico , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/complicações , Coração , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/prevenção & controle , FibroseRESUMO
BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS: From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS: In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.
Assuntos
Degeneração Hepatolenticular , Feminino , Humanos , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/tratamento farmacológico , Penicilamina/uso terapêutico , Penicilamina/efeitos adversos , Trientina , Zinco/uso terapêutico , CobreRESUMO
The WEEL for triethylenetetramine (TETA; CAS No. 112-24-3) was originally established in 1991 and updated in 1998 and 2009. Recent literature searches to identify new toxicity information were performed in 2016 and January 2021. No new studies or data relevant to the WEEL were identified. TETA is used in manufacturing; the hydrochloride salt of TETA is used as a copper-chelating drug in the treatment of Wilson's disease. TETA is severely irritating to the skin and eyes and produces skin sensitization; however, it is of low to moderate acute toxicity via the oral and dermal routes of exposure. In subchronic studies, signs of toxicity included multi-organ effects (lung, liver, and spleen) in mice, but not rats. TETA was genotoxic/mutagenic in short-term in vitro assays but not in in vivo assays. No data on reproductive toxicity were available. Embryo/fetal toxicity occurred at maternally toxic doses and was associated with copper deficiency. In humans, the use of TETA·2HCl for treatment of Wilson's disease during pregnancy resulted in no miscarriages or fetal abnormalities. No evidence of carcinogenicity was noted in a lifetime dermal study in mice. Based on a subchronic drinking water study in mice, 600 ppm (95 mg/kg-day) was determined to be the no-observed-adverse-effect level (NOAEL) and the point of departure (POD). This NOAEL was converted to an equivalent inhalation concentration by adjusting for respiratory rate, interindividual variability, and uncertainty. The resulting 8-h time-weighted average WEEL value of 1 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to airborne TETA.
Assuntos
Degeneração Hepatolenticular , Trientina , Humanos , Animais , Camundongos , Trientina/uso terapêutico , Trientina/toxicidade , Cobre , Nível de Efeito Adverso não ObservadoRESUMO
Photocatalysis has been widely used for the removal of hexavalent chromium from wastewater as an efficient and environmental friendly method. However, conventional photocatalysts generally exhibit poor adsorption properties toward Cr(VI), resulting in unsatisfactory performance in high concentrated wastewaters. In this study, we synthesized a novel composite material with high Cr(VI) adsorption ability by blending prepared CuS nanocrystals into triethylenetetramine modified sodium alginate for the enhanced photocatalytic removal of Cr(VI). Effect of CuS dosage, pH value, light source and intensity were discussed for the optimum Cr(VI) removal conditions. The synthesized composite has shown good adsorption performance toward Cr(VI) and the overall removal rate reached 98.99 % within 50 min under UV light irradiation with citric acid as hole scavenger. Adsorption isotherm, thermodynamics, and kinetics with corresponding model fitting were discussed, which suggested that the monolayer and chemical adsorption dominated the adsorption process. Characterization results indicated that amino and hydroxyl groups contributed electrons in the photocatalysis reaction for the reduction of Cr(VI) to Cr(III). CuS nanocrystals can enhance the surface charge and light absorbance ability of the composite, and the Cr(VI) removal was governed by electrostatic interaction and photo-induced redox reaction.
Assuntos
Nanopartículas , Poluentes Químicos da Água , Trientina , Alginatos , Cromo/química , Águas Residuárias , Adsorção , Poluentes Químicos da Água/química , Cinética , Concentração de Íons de HidrogênioRESUMO
Gertia stigmatica is a recently described member of the Kareniaceae with a peridinin-containing plastid rather than the aberrant, haptophyte-derived, tertiary plastid found in canonical Kareniaceae genera such as Karenia, Karlodinium, and Takayama. G. stigmatica provides a unique opportunity to compare biochemical traits, such as sterol composition, between these two fundamentally different types of Kareniaceae. To this point, canonical members of the Kareniaceae have been observed to typically produce a set of 4α-methyl-substituted, Δ8(14)-nuclear-unsaturated major sterols, such as (24R)-4α-methyl-5α-ergosta-8(14),22-dien-3ß-ol (gymnodinosterol) and 27-nor-(24R)-4α-methyl-5α-ergosta-8(14),22-dien-3ß-ol (brevesterol), which are very uncommon throughout other members of the class Dinophyceae. Our objective was to compare the sterols of G. stigmatica to canonical Kareniaceae to elucidate whether these same distinctive sterols are found, with our hypothesis being that they would because G. stigmatica is indeed a member of the Kareniaceae. Contrary to our hypothesis, G. stigmatica lacks gymnodinosterol and brevesterol, with its sterols instead dominated by 4-desmethyl sterols, such as cholesterol, 24-methylcholesta-5,22E-dien-3ß-ol, and the unusual tri-unsaturated sterols ergosta-5,8(14),22E-trien-3ß-ol and cholesta-5,8(14),22E-trien-3ß-ol. No sterols were found to possess a 4α-methyl substituent or a single Δ8(14) nuclear unsaturation. Thus, G. stigmatica's sterol composition as a member of the Kareniaceae is atypical.
Assuntos
Dinoflagellida , Haptófitas , Esteróis , Trientina , PlastídeosRESUMO
An elegant approach to unknown secosteroid-quinoline hybrids is disclosed. A series of 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-(iso)quinolylmethylene]hydrazides was prepared and these novel type of secosteroids was screened for antiproliferative activity against estrogen-responsive human breast cancer cell line MCF-7. Most of the synthesized compounds showed a cytotoxic effect superior to that of reference drug cisplatin; the lead compound exhibits the highest activity with the IC50 value of about 0.8 µM and is 7 times more active than cisplatin. A high selectivity index was observed for the hit 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-quinolylmethylene]hydrazides 2a and 2c. Compounds 2a and 2c evaluated in luciferase reporter assays exhibited high antiestrogenic potency which was superior to that of tamoxifen. These hit compounds were characterized by high activity against MCF-7 cells that retained towards multidrug-resistant NCI/ADR-RES cells.
Assuntos
Antineoplásicos , Quinolinas , Secoesteroides , Humanos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Trientina/farmacologia , Antineoplásicos/farmacologia , Quinolinas/farmacologia , Secoesteroides/farmacologia , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Estrutura MolecularRESUMO
BACKGROUND: The main mechanism underlying cancer dissemination is the epithelial to mesenchymal transition (EMT). This process is orchestrated by cytokines like TGFß, involving "non-canonical" AKT- or STAT3-driven pathways. Recently, the alteration of copper homeostasis seems involved in the onset and progression of cancer. METHODS: We expose different breast cancer cell lines, including two triple negative (TNBC) ones, an HER2 enriched and one cell line representative of the Luminal A molecular subtype, to short- or long-term copper-chelation by triethylenetetramine (TRIEN). We analyse changes in the expression of EMT markers (E-cadherin, fibronectin, vimentin and αSMA), in the levels and activity of extracellular matrix components (LOXL2, fibronectin and MMP2/9) and of copper homeostasis markers by Western blot analyses, immunofluorescence, enzyme activity assays and RT-qPCR. Boyden Chamber and wound healing assays revealed the impact of copper chelation on cell migration. Additionally, we explored whether perturbation of copper homeostasis affects EMT prompted by TGFß. Metabolomic and lipidomic analyses were applied to search the effects of copper chelation on the metabolism of breast cancer cells. Finally, bioinformatics analysis of data on breast cancer patients obtained from different databases was employed to correlate changes in kinases and copper markers with patients' survival. RESULTS: Remarkably, only HER2 negative breast cancer cells differently responded to short- or long-term exposure to TRIEN, initially becoming more aggressive but, upon prolonged exposure, retrieving epithelial features, reducing their invasiveness. This phenomenon may be related to the different impact of the short and prolonged activation of the AKT kinase and to the repression of STAT3 signalling. Bioinformatics analyses confirmed the positive correlation of breast cancer patients' survival with AKT activation and up-regulation of CCS. Eventually, metabolomics studies demonstrate a prevalence of glycolysis over mitochondrial energetic metabolism and of lipidome changes in TNBC cells upon TRIEN treatment. CONCLUSIONS: We provide evidence of a pivotal role of copper in AKT-driven EMT activation, acting independently of HER2 in TNBC cells and via a profound change in their metabolism. Our results support the use of copper-chelators as an adjuvant therapeutic strategy for TNBC.
Assuntos
Transição Epitelial-Mesenquimal , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Fibronectinas/metabolismo , Fibronectinas/farmacologia , Fibronectinas/uso terapêutico , Cobre/farmacologia , Cobre/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Disponibilidade Biológica , Trientina/farmacologia , Trientina/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Fator de Crescimento Transformador beta/metabolismo , Aminoácido Oxirredutases/metabolismo , Aminoácido Oxirredutases/farmacologia , Aminoácido Oxirredutases/uso terapêuticoRESUMO
Structurally novel 2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized from N-(2-propyn-1-yl) amides and 1,3,5-trimethoxybenzenes by a tandem method consisting of a Tf2O-promoted amide activation and a TfOH-promoted Friedel-Crafts ipso-cyclization. The method offered the first example of using N-(2-propyn-1-yl) amides as substrates in both Tf2O-promoted secondary amide activation and the synthesis of azaspiro[4.5]deca-6,9-diene-8-ones.
Assuntos
Amidas , Trientina , Estrutura Molecular , CiclizaçãoRESUMO
BACKGROUND AND AIM: This retrospective, multicenter study aims to assess the efficacy and safety in Wilson disease (WD) patients treated with trientine tetrahydrochloride (TETA 4HCl) after switch from trientine dihydrochloride (TETA 2HCl). METHODS: In total, 68 WD patients with stable copper metabolism were identified to receive TETA 4HCl (Cuprior™) after previous treatment with TETA 2HCl. We analyzed biochemical markers such as urinary copper, serum copper, non-coeruloplasmin bound copper (NCC), and transaminases as well as clinical scores (APRI; FIB-4 score) at baseline with a follow-up (FU) of 12 months. Safety of TETA 4HCl treatment was based on reported adverse events (AEs). RESULTS: The study cohort reflects a common WD cohort with a mean age of 20.3 years at diagnosis and 38.3 years at baseline. There are no significant differences concerning serum copper, NCC, transaminases, APRI, and FIB-4 score in the 3-month FU. Six-month FU revealed a decreased AST (P = 0.008), APRI (P = 0.042), and FIB-4 score (P = 0.039). GGT varied only borderline significantly in the 3-month, but not in the 6-month FU. Comparison of urinary copper within the subsets did not reveal a difference to baseline in all FUs, suggesting stable control of copper metabolism. Few AEs during TETA 4HCl treatment were reported, most commonly gastrointestinal discomfort. Only three treatments with TETA 4HCl were discontinued. CONCLUSION: Copper parameters and liver function were stable after treatment switch to TETA 4HCl. Treatment with TETA 4HCl was generally well tolerated. This study indicates that the switch from TETA 2HCl to TETA 4HCl is safe and viable.
Assuntos
Degeneração Hepatolenticular , Trientina , Humanos , Adulto Jovem , Adulto , Trientina/efeitos adversos , Degeneração Hepatolenticular/tratamento farmacológico , Cobre , Estudos Retrospectivos , Quelantes/efeitos adversos , TransaminasesRESUMO
The focus point of this current work is to evaluate the anticancer and growth inhibitory efficacy of compounds 5α,8α-epidioxy-24á¶-methylcholesta-6,22-dien-3ß-ol (LT1), and Ergosta-5,7,22-trien-3ß-ol (LT2) of Lentinus tuberregium (Fr.) on three cell lines such as A673 (Rhabdomyosarcoma), MCF7 (breast cancer), and HCT116 (colorectal carcinoma) by MTT assay. LT1 and LT2 exerted maximal growth inhibition in the order as A673 > HCT116 > MCF7. Comparatively, LT1 was more potent in causing cell growth inhibition than LT2 in the A673 cancer cell line. Based on the MTT assay, A673 cells alone proceeded further as a model to evaluate the anticancer potential of LT1 and LT2 at three different semilogarithmic concentrations (3, 10, 30 µM). The cells exposed with compounds at 24 and 48 h were analyzed by flow cytometry. Exposure of LT1 at 3 and 10 µM concentrations for 24 h caused a G2-M arrest. At 10 µM concentration, cells also accumulated in the G0-G1 phase, indicating a G1 block. These effects were only transient as prolonged exposure (48 h) of LT1 treatment brought back the cell population to normalcy. Both the compounds only at 30 µM concentration have the potential to induce a hypodiploid peak (sub G0), indicating an induction of apoptosis which was explicit by nuclear condensation and fragmentation of nuclei in cells. The dose-dependent and compound-specific apoptotic induction was further confirmed by caspase activity higher in LT1 than LT2. The results highlight the significant growth inhibitory activity and anticancer potential of LT1 and LT2 which are recommended for further in-depth analysis.
Assuntos
Agaricales , Lentinula , Trientina , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo CelularRESUMO
A 7 yr old castrated male Cavalier King Charles spaniel presented for evaluation of liver enzyme elevations. Abdominal ultrasound revealed a small liver with mixed echogenicity, small hypoechoic nodules, and an irregular surface. Histologic examination and copper quantification of the liver obtained by laparoscopy diagnosed copper-associated hepatitis. One month later the dog developed hyperkeratosis of all four foot pads and ulcerations of feet, legs, and rectum. Punch biopsies confirmed superficial necrolytic dermatitis. After a total of 2 mo of chelation with no changes to medications, skin lesions began to improve, continuing over the following 6 wk to almost complete resolution. At this point the skin lesions returned and had minimal response to four amino acids infusions. The dog was switched from penicillamine to trientine. Zinc acetate was initiated 6 wk after the switch to trientine, and skin improvement was noted soon thereafter. At the time of death, skin lesions were improving and the dog was clinically comfortable. Copper-associated hepatitis should be considered as a possible etiology for superficial necrolytic dermatitis. Treatment of superficial necrolytic dermatitis is often unrewarding, and copper chelation, when copper-associated hepatitis has been confirmed, represents another therapeutic option.