Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64 Cu PET/CT study in healthy humans.

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.

Four New Steroidal Saponins from the Roots of Dracaena cambodiana with NO Production Inhibition Activity in LPS Activated RAW 264.7 Cells.

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-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-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-(1→3)-ß-D-glucopyranoside (2), (23R,25R)-16,23-cyclocholesta-5,16,20(22)-trien-3ß,22,26-triol-3-O-α-L-rhamnopyranosyl-(1→3)-ß-D-glucopyranoside (3), 3ß-[(O-α-L-rhamnopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-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±3.81 µM, whereas compounds 2 and 3 were inactive with IC50 values over 100 µM.

Neurological worsening in Wilson disease - clinical classification and outcome.

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.

Biotransformation of triterpenoid ganoderic acids from exogenous diterpene dihydrotanshinone I in the cultures of Ganoderma sessile.

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.

Tandem Synthesis of 2-Azaspiro[4.5]deca-1,6,9-trien-8-ones Based on Tf2O-Promoted Activation of N-(2-Propyn-1-yl) Amides.

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.

Experience on switching trientine formulations in Wilson disease: Efficacy and safety after initiation of TETA 4HCl as substitute for TETA 2HCl.

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.

In vitro evaluation of growth reticence and anticancer potential of 5α,8α-epidioxy-24ᶓ-methylcholesta-6,22-dien-3ß-ol and ergosta-5,7,22-trien-3ß-ol bioactive isolated from an edible mushroom Lentinus tuberregium (fr.).

The focus point of this current work is to evaluate the anticancer and growth inhibitory efficacy of compounds 5α,8α-epidioxy-24ᶓ-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.

Early neurological deterioration in Wilson's disease: a systematic literature review and meta-analysis.

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.

Triethylenetetramine (TETA).

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.

Treatment of Superficial Necrolytic Dermatitis with Copper Chelationina Dog with Copper-Associated Hepatitis.

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.

Photochemistry and photophysics of cholesta-5,7,9(11)-trien-3ß-ol: a fluorescent analogue of cholesterol.

Cholesta-5,7,9(11)-trien-3ß-ol (9,11-dehydroprovitamin D3, CTL) is used as a fluorescent probe to track the presence and migration of cholesterol in vivo. CTL is known to be photochemically active, but little consideration has been given to the formation efficiency and possible toxicity of its photoproducts. In degassed tetrahydrofuran (THF) solution, we isolated the photoproduct of CTL and of its 25-hydroxy derivative (HOCTL), and X-ray crystal structures were obtained for HOCTL and the photorearrangement product. The X-ray crystal structure and its 1H NMR spectrum confirm the product structure as a pentacyclic HOCTL isomer. In the presence of air in THF, endoperoxide formation via [2+4] addition of 1O2* across the B ring of CTL or HOCTL becomes the dominant photoreaction. The UV spectrum and decay kinetics of the triplet state of HOCTL, the precursor of 1O2*, are determined by transient absorption spectroscopy. We confirm the proposed structure of the endoperoxide by X-ray crystallography. Kinetics analysis of quantum yields provides rate constants for photophysical and photochemical events.

Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer's disease.

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aß deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aß levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.

Multifaced Assessment of Antioxidant Power, Phytochemical Metabolomics, In-Vitro Biological Potential and In-Silico Studies of Neurada procumbens L.: An Important Medicinal Plant.

This work was undertaken to explore the phytochemical composition, antioxidant, and enzyme-inhibiting properties of Neurada procumbens L. extracts/fractions of varying polarity (methanol extract and its fractions including n-hexane, chloroform, n-butanol, and aqueous fractions). A preliminary phytochemical study of all extracts/fractions, HPLC-PDA polyphenolic quantification, and GC-MS analysis of the n-hexane fraction were used to identify the phytochemical makeup. Antioxidant (DPPH), enzyme inhibition (against xanthine oxidase, carbonic anhydrase, and urease enzymes), and antibacterial activities against seven bacterial strains were performed for biological investigation. The GC-MS analysis revealed the tentative identification of 22 distinct phytochemicals in the n-hexane fraction, the majority of which belonged to the phenol, flavonoid, sesquiterpenoid, terpene, fatty acid, sterol, and triterpenoid classes of secondary metabolites. HPLC-PDA analysis quantified syringic acid, 3-OH benzoic acid, t-ferullic acid, naringin, and epicatechin in a significant amount. All of the studied extracts/fractions displayed significant antioxidant capability, with methanol extract exhibiting the highest radical-scavenging activity, as measured by an inhibitory percentage of 81.4 ± 0.7 and an IC50 value of 1.3 ± 0.3. For enzyme inhibition experiments, the n-hexane fraction was shown to be highly potent against xanthine oxidase and urease enzymes, with respective IC50 values of 2.3 ± 0.5 and 1.1 ± 0.4 mg/mL. Similarly, the methanol extract demonstrated the strongest activity against the carbonic anhydrase enzyme, with an IC50 value of 2.2 ± 0.4 mg/mL. Moreover, all the studied extracts/fractions presented moderate antibacterial potential against seven bacterial strains. Molecular docking of the five molecules ß-amyrin, campesterol, ergosta-4,6,22-trien-3ß-ol, stigmasterol, and caryophyllene revealed the interaction of these ligands with the investigated enzyme (xanthine oxidase). The results of the present study suggested that the N. procumbens plant may be evaluated as a possible source of bioactive compounds with multifunctional therapeutic applications.

Adherence to treatment, a challenge even in treatable metabolic rare diseases: A cross sectional study of Wilson's disease.

Wilson's disease (WD), a rare genetic disorder responsible for copper accumulation in the body, is fatal if left untreated. Although there are effective treatments, adherence to treatment tends to be low. We evaluated the medication adherence of 139 patients using the Morisky scale. Adherence was correlated with age at diagnosis and at inclusion in the study, the form of the disease, the treatment, the duration of treatment, delivery and storage problems, depression, anxiety, the level of education, and the biological data. 32.4% of the patients had low adherence; their levels of exchangeable copper were significantly higher than those of the patients with high or medium adherence (P = .049). The average age of the patients at the time of the study was significantly higher in those with high adherence than in those with medium or low adherence (P = .043). 75.9% of the patients with high adherence had a neurological form and 26.7% of the patients with low adherence were asymptomatic (P = .0090). The duration of treatment was significantly longer in the patients with high adherence than in those with medium or low adherence (P = .0192). The type of treatment (chelators or zinc) had no impact on the level of adherence. Forty-four percent of the patients experienced problems dispensing and storing medications. Despite the availability of effective treatments for this rare disease, adherence problems occur with Wilson's disease in particular in asymptomatic patients. Although different factors are involved, sustained multidisciplinary management on a case-by-case basis is necessary.

Optimized Trientine-dihydrochloride Therapy in Pediatric Patients With Wilson Disease: Is Weight-based Dosing Justified?

OBJECTIVES: The aim of the study was to investigate the efficacy and safety of trientine-dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight-based dosages on their clinical and biochemical outcome. METHODS: We retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight-based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg ·â€Škg-1 ·â€Šday-1. RESULTS: Median follow-up was 60 (5-60) months in the total study group. During TD therapy, nonceruloplasmin-bound copper was reduced from mean 1.53 (0.01-6.95) at baseline to 0.62 (0.01-4.57) µmol/l. 24h-urinary copper excretion diminished to 1.85 (0.8-9.6) µmol/day approximating the therapeutic goal of 1.6 µmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases).Investigations about weight-based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg ·â€Škg-1 ·â€Šday-1, median follow-up 60 [9-60] months), whereas in group 2 (>20 mg ·â€Škg-1 ·â€Šday-1, median follow-up 60 [14-60] months), it was 63.6%. CONCLUSIONS: TD proves to be an efficacious alternative chelating agent for children with WD. Weight-based dosages above the recommended 20 mg ·â€Škg-1 ·â€Šday-1 may increase the rate of adverse effects in pediatric patients.

N,N'-1,10-Bis(Naringin) Triethylenetetraamine, Synthesis and as a Cu(II) Chelator for Alzheimer's Disease Therapy.

The bis-Schiff base of N,N'-1,10-bis(naringin) triethylenetetraamine (1) was prepared, as a copper(II) ion chelator, compound 1 was used for Alzheimer's disease therapy in vitro. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of compound 1 showed that this Schiff base could promote PC12 cells proliferation, and also, compound 1 could inhibit Cu2+-amyloid-ß (Aß)1-42 mediated cytotoxicity on PC12 cells. The thioflavine T (ThT) assay showed that 1 can effectively attenuate Cu2+-induced Aß1-42 aggregation. In addition, compound 1 is determined to be potent antioxidants on the basis of in vitro antioxidant assay, it can effectively decease the level of reactive oxygen species (ROS) in Cu2+-Aß1-42-treated PC12 cells and elevate the superoxide dismutase (SOD) activity in Cu2+-Aß1-42-treated PC12 cells. The results show that N,N'-1,10-bis(naringin) triethylenetetraamine is a potential agent for therapy of Alzheimer's disease.

Effects of Superoxide Dismutase Inhibitors and Glucose on Cell Death and Generation of Reactive Oxygen Species in Pea Leaves.

The effects of superoxide dismutase (SOD) inhibitors, diethyldithiocarbamate (DDC), triethylenetetramine (trien), and their combination with glucose on cells of the epidermis from pea leaves of different age (rapidly growing young leaves and slowly growing old leaves) was investigated. DDC and trien caused death of the guard cells as determined by destruction of their nuclei. Glucose did not affect destruction of the nuclei induced by SOD inhibitors in the cells from old leaves, but intensified it in the cells from young leaves. 2-Deoxyglucose, an inhibitor of glycolysis, and propyl gallate, SOD-mimic and antioxidant, suppressed destruction of the nuclei that was caused by SOD inhibitors and glucose in cells of the epidermis from the young, but not from the old leaves. Glucose and trien stimulated, and propyl gallate reduced generation of reactive oxygen species (ROS) in the pea epidermis as determined by the fluorescence of 2',7'-dichlorofluorescein (DCF). Carbonyl cyanide m-chlorophenylhydrazone (CCCP), a protonophoric uncoupler of oxidative and photosynthetic phosphorylation, suppressed the DCF fluorescence in the guard cells. Treatment of the cells with CCCP followed by its removal with washing increased destruction of the nuclei caused by SOD inhibitors and glucose. In young leaves, CCCP was less effective than in old ones. The findings demonstrate the effects of SOD inhibitors and glucose on the cell death and generation of ROS and could indicate glycolysis-dependent ROS production.

Adsorption and Release of Sulfamethizole from Mesoporous Silica Nanoparticles Functionalised with Triethylenetetramine.

Mesoporous silica nanoparticles (MSN) were synthesised and functionalised with triethylenetetramine (MSN-TETA). The samples were fully characterised (transmission electron microscopy, small angle X-ray scattering, Fourier transform infrared spectroscopy, thermogravimetric analysis, zeta potential and nitrogen adsorption/desorption isotherms) and used as carriers for the adsorption of the antimicrobial drug sulphamethizole (SMZ). SMZ loading, quantified by UV-Vis spectroscopy, was higher on MSN-TETA (345.8 mg g-1) compared with bare MSN (215.4 mg g-1) even in the presence of a lower surface area (671 vs. 942 m2 g-1). The kinetics of SMZ adsorption on MSN and MSN-TETA followed a pseudo-second-order model. The adsorption isotherm is described better by a Langmuir model rather than a Temkin or Freundlich model. Release kinetics showed a burst release of SMZ from bare MSN samples (k1 = 136 h-1) in contrast to a slower release found with MSN-TETA (k1 = 3.04 h-1), suggesting attractive intermolecular interactions slow down SMZ release from MSN-TETA. In summary, the MSN surface area did not influence SMZ adsorption and release. On the contrary, the design of an effective drug delivery system must consider the intermolecular interactions between the adsorbent and the adsorbate.

LC-MS proteomic profiling of Caco-2 human intestinal cells exposed to the copper-chelating agent, triethylenetetramine: A preliminary study.

Homeostasis of metal micronutrients such as copper is tightly regulated to ensure deficiency does not occur while restricting damage resulting from excess accumulation. Using LC-MS the effect on the proteome of intestinal Caco-2 cells of exposure to the chelator triethylenetetramine (TETA) was investigated. Continuous exposure of TETA at 25 µM to Caco-2 cells caused decreased cell yields and morphological changes. These effects were reversed when cells were no longer exposed to TETA. Quantitative proteomic analysis identified 957 mostly low-fold differentially expressed proteins, 41 of these returned towards control Caco-2 expression following recovery. Proteins exhibiting this "reciprocal" behaviour included upregulated deoxyhypusine hydroxylase (DOHH, 15.69- fold), a protein essential for eIF-5A factor hypsuination, a post translational modification responsible for eIF-5A maturation, which in turn is responsible for translation elongation. Exposure to TETA also resulted in 87 proteins, the expression of which was stable and remained differentially expressed following recovery. This study helps to elucidate the stable and transient proteomic effects of TETA exposure in intestinal cells.

Phase Splitting Agent Regulated Biphasic Solvent for Efficient CO2 Capture with a Low Heat Duty.

A biphasic solvent features high absorption capacity and low heat duty for CO2 capture. Phase separation behavior is essential to cut down energy penalty. Four phase splitting agents with different hydrophobicities, such as 1,3-dimethyl-2-imidazolidinone (DMI), 1-methyl-2-pyrrolidinone (NMP), N,N-dimethylformamide, and sulfolane, were dosed to biphasic solvents, triethylenetetramine and 2-(diethylamino)ethanol. Experimental results revealed that they can tune the phase separation behavior during CO2 absorption. Generally, under the same CO2 loading, the volume ratio of the rich phase increased with their hydrophobicity (log P), which accounts for over 50%. Moreover, their influences on absorption capacity, kinetics, and thermodynamics were also investigated. After dosing NMP, the heat duty was decreased by 22%. Furthermore, a phase splitting agent with a positive log P was more conducive to reducing the heat duty, and one with a negative log P enhanced the absorption rate. With DMI, the absorption rate was 114% higher than that of MEA at rich loading. The 13C NMR analysis showed that the agents were not involved in CO2 absorption and did not affect the reaction mechanism. Furthermore, quantum calculation was used to verify the reaction mechanism, confirming that the phase splitting agent increases the reaction equilibrium constant and makes it proceed more thoroughly.