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1.
Cells ; 11(20)2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36291126

RESUMO

Clusterin is a glycoprotein present at high concentrations in many extracellular fluids, including semen. Its increased expression accompanies disorders associated with extracellular amyloid fibril accumulation such as Alzheimer's disease. Clusterin is an extracellular molecular chaperone which prevents the misfolding and amorphous and amyloid fibrillar aggregation of a wide variety of unfolding proteins. In semen, amyloid fibrils formed from a 39-amino acid fragment of prostatic acid phosphatase, termed Semen-derived Enhancer of Virus Infection (SEVI), potentiate HIV infectivity. In this study, clusterin potently inhibited the in vitro formation of SEVI fibrils, along with dissociating them. Furthermore, clusterin reduced the toxicity of SEVI to pheochromocytoma-12 cells. In semen, clusterin may play an important role in preventing SEVI amyloid fibril formation, in dissociating SEVI fibrils and in mitigating their enhancement of HIV infection.


Assuntos
Amiloide , Clusterina , Infecções por HIV , HIV-1 , Fragmentos de Peptídeos , Proteínas Tirosina Fosfatases , Humanos , Amiloide/metabolismo , Clusterina/metabolismo , Infecções por HIV/metabolismo , HIV-1/metabolismo , Sêmen/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Tirosina Fosfatases/metabolismo
2.
Forensic Sci Med Pathol ; 18(4): 403-406, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35749044

RESUMO

Unexpected hepatic failure with liver necrosis is sometimes encountered during a forensic autopsy. Determining the etiology may sometimes be difficult, although increasingly herbal medicines are being implicated. To determine whether such effects might also be caused by foodstuffs, the following in vitro study was undertaken. Four formulations of traditional herbal soup advertised as bak kut teh were prepared and added to cultures of liver carcinoma cells (HepG2). Cell viability was assessed using an MTT colorimetric assay at 48 h demonstrating that all formulations had significant toxicity prior to dilution (p < 0.05). Formulation #1 showed 21% cell death (p = 0.023), Formulation #2 30% (p = 0.009), and Formulation #3 41% (p < 0.0001). Formulations #1-3 showed no significant toxicity once diluted (p > 0.05). Formulation 4 showed approximately 83% cell death before dilution (p < 0.0001) and persistent toxicity even with dilutions at 1:10 (15% ± 3.7, p = 0.023) and 1:1000 (14% ± 3.8, p = 0.024). This study has shown that herbal foodstuffs such as bak kut teh may be responsible for variable degrees of in vitro hepatotoxicity, thus extending the range of herbal products that may be potentially injurious to the liver. If unexpected liver damage is encountered at autopsy, information on possible recent ingestion of herbal food preparations should be sought, as routine toxicology screening will not identify the active components. Liver damage may therefore be caused not only by herbal medicines but possibly by herbal products contained in food.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Plantas Medicinais , Humanos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Autopsia , Preparações de Plantas
3.
Toxicol Mech Methods ; 32(8): 606-615, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35354423

RESUMO

Hepatotoxicity is a well-known adverse effect of many substances, with toxicity often resulting from interactions of drugs with other drug-like substances. With the increased availability of complementary and alternative medicines, including herbal medicines, the likelihood of adverse interactions between drugs and drug-like substances in herbs increases. However, the impact of potential herb-herb interactions is little understood. To assess the potential of two cytochrome P450 enzyme modulating phytochemicals common to many herbal medicines, atractylenolide I (ATR-I) and astragaloside IV (AST-IV), to interact with coumarin, another phytochemical common in many foods, a hepatocyte function model with a liver carcinoma cell line, HepG2, was exposed to these agents. To determine the effects of cytochrome P450 modulation by these phytochemicals certain cells were induced with rifampicin to induce cytochrome P450. Increasing concentrations of ATR-I combined with a fixed, nontoxic concentration of coumarin (200 µM), demonstrated significant additive interactions. 300 µM ATR-I produced a 31% reduction in cell viability (p < 0.01) with coumarin in rifampicin uninduced cells. In rifampicin-induced cells, ATR-I (100-300 µM) produced a significant reduction in cell viability (p < 0.01) with coumarin (200 µM). AST-IV with fixed coumarin (200 µM) showed 27% toxicity at 300 µM AST-IV in rifampicin uninduced cells (p < 0.05) and 30% toxicity in rifampicin induced cells (p < 0.05). However, when fixed coumarin and AST-IV were combined with increasing concentrations of ATR-I no further significant increase in toxicity was observed (p > 0.05). These results demonstrate the potential toxic interactive capabilities of common traditional Chinese herbal medicine phytochemicals and underline the potential importance of coumarin-mediated toxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cumarínicos/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Ervas-Drogas , Humanos , Lactonas , Compostos Fitoquímicos , Polimedicação , Rifampina , Saponinas , Sesquiterpenos , Triterpenos
4.
Life Sci ; 291: 119975, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34560084

RESUMO

3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary treatment for hyperlipidemic cardiovascular diseases which are a leading global cause of death. Statin therapy is life saving and discontinuation due to adverse events such as myotoxicity may lead to unfavourable outcomes. There is no known mechanism for statin-induced myotoxicity although it is theorized that it is due to inhibition of downstream products of the HMG-CoA pathway. It is known that drug-drug interactions with conventional medicines exacerbate the risk of statin-induced myotoxicity, though little attention has been paid to herb-drug interactions with complementary medicines. Flavonoids are a class of phytochemicals which can be purchased as high dose supplements. There is evidence that flavonoids can raise statin plasma levels, increasing the risk of statin-induced myopathy. This could be due to pharmacokinetic interactions involving hepatic cytochrome 450 (CYP450) metabolism and organic anion transporter (OATP) absorption. There is also the potential for flavonoids to directly and indirectly inhibit HMG-CoA reductase which could contraindicate statin-therapy. This review aims to discuss what is currently known about the potential for high dose flavonoids to interact with the hepatic CYP450 metabolism, OATP uptake of statins or their ability to interact with HMG-CoA reductase. Flavonoids of particular interest will be covered and the difficulties of examining herbal products will be discussed throughout.


Assuntos
Flavonoides/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Doenças Cardiovasculares/metabolismo , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas/fisiologia , Flavonoides/efeitos adversos , Humanos , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Fígado/metabolismo , Ácido Mevalônico/metabolismo , Doenças Musculares , Miotoxicidade/etiologia , Transportadores de Ânions Orgânicos/efeitos dos fármacos , Transportadores de Ânions Orgânicos/metabolismo , Fatores de Risco
5.
Leg Med (Tokyo) ; 47: 101740, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32634765

RESUMO

Hepatotoxicity from paracetamol/acetaminophen has occasionally been reported at lower than expected doses. As herbal preparations may interact with pharmaceutical drugs the following in vitro study was undertaken to determine whether the toxic effects of paracetamol on liver cell growth in culture would be exacerbated by the addition of psoralen, a furanocoumarin compound that is present in Psoralea corylifolia, a common Chinese herb. The following study utilising a liver carcinoma cell line (HepG2) showed that Psoralea corylifolia was significantly toxic from 0.3 mg/ml to 5 mg/ml (p < 0.05), whereas paracetamol was not toxic below 50 mM (p = 0.0026). Interactions between previously non-toxic levels of 0.1 mg/ml of Psoralea corylifolia and increasing concentrations of paracetamol (0-50 mM), however, were observed, with a significant increase in toxicity compared to paracetamol alone (30% cell death vs. 72% cell death with Psoralea corylifolia). A significant synergistic interaction was observed at 40 mM paracetamol with 0.1 mg/ml of Psoralea (p = 0.038). This study has, therefore, shown significantly increased hepatotoxicity in cell cultures exposed to paracetamol when herbal compounds containing furanocoumarins were added. Fulminant acute liver failure occurring after the ingestion of low doses of paracetamol may not, therefore, always be due to an occult idiosyncratic response to paracetamol, but instead possibly to the combined effects of paracetamol and herbal preparations. Given the widespread use of both paracetamol and herbal preparations this possibility should be considered in cases of unexplained hepatic necrosis and liver failure that present for medicolegal investigation.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ficusina/toxicidade , Fígado/patologia , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sinergismo Farmacológico , Ficusina/isolamento & purificação , Células Hep G2 , Humanos , Falência Hepática/induzido quimicamente , Necrose/induzido quimicamente , Psoralea/química
6.
Dalton Trans ; 48(38): 14505-14515, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31531475

RESUMO

Linear and non-linear tetranuclear ruthenium(ii) complexes containing the bridging ligand bis[4(4'-methyl-2,2'-bipyridyl)]-1,7-heptane have been synthesised and their biological properties examined. The minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC) of the ruthenium(ii) complexes were determined against six strains of bacteria: Gram-positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA); and the Gram-negative Escherichia coli (E. coli) strains MG1655, APEC, UPEC and Pseudomonas aeruginosa (P. aeruginosa). The results showed that both tetranuclear complexes had significant antimicrobial activity, with the non-linear (branched) species (Rubb7-TNL) having slightly higher activity than the corresponding linear analogue (Rubb7-TL). The corresponding toxicity against three eukaryotic cell lines - BHK (baby hamster kidney), Caco-2 (heterogeneous human epithelial colorectal adenocarcinoma) and Hep-G2 (liver carcinoma) - have also been determined. Interestingly, both Rubb7-TNL and Rubb7-TL were as toxic to the eukaryotic cells as they were to the bacteria, a rarity for kinetically-inert cationic polypyridylruthenium(ii) complexes, and exhibited lower IC50 values than cisplatin over 24-, 48- or 72-hour incubation times. Fluorescence spectroscopy was used to study the binding of the ruthenium complexes with human serum albumin (HSA). Rubb7-TNL and Rubb7-TL exhibited strong HSA binding, with equilibrium binding constants in the order of 107 M-1. Confocal microscopy was used to examine the cellular localisation of Rubb7-TNL in BHK cells. The results indicated that the ruthenium complex localised in the nucleolus. Significant accumulation was also observed in the cytoplasm, but not in the mitochondria. Taken together, the results of this study suggest that Rubb7-TNL is an unlikely candidate as an antimicrobial agent, but may have potential as an anticancer drug.


Assuntos
2,2'-Dipiridil/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Heptanos/farmacologia , Piridinas/química , Rutênio/farmacologia , 2,2'-Dipiridil/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Heptanos/química , Humanos , Ligantes , Rutênio/química
7.
Front Chem ; 6: 595, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30560120

RESUMO

The toxicity (IC50) of a series of mononuclear ruthenium complexes containing bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (bbn) as a tetradentate ligand against three eukaryotic cell lines-BHK (baby hamster kidney), Caco-2 (heterogeneous human epithelial colorectal adenocarcinoma) and Hep-G2 (liver carcinoma)-have been determined. The results demonstrate that cis-α-[Ru(Me4phen)(bb7)]2+ (designated as α-Me4phen-bb7, where Me4phen = 3,4,7,8-tetramethyl-1,10-phenanthroline) showed little toxicity toward the three cell lines, and was considerably less toxic than cis-α-[Ru(phen)(bb12)]2+ (α-phen-bb12) and the dinuclear complex [{Ru(phen)2}2{µ-bb12}]4+. Fluorescence spectroscopy was used to study the binding of the ruthenium complexes with human serum albumin (HSA). The binding of α-Me4phen-bb7 to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. Large upfield 1H NMR chemical shift changes observed for the methylene protons in the bb7 ligand upon addition of Q[10], coupled with the observation of several intermolecular ROEs in ROESY spectra, indicated that α-Me4phen-bb7 bound Q[10] with the bb7 methylene carbons within the cavity and the metal center positioned outside one of the portals. Simple molecular modeling confirmed the feasibility of the binding model. An α-Me4phen-bb7-Q[10] binding constant of 9.9 ± 0.2 × 106 M-1 was determined by luminescence spectroscopy. Q[10]-encapsulation decreased the toxicity of α-Me4phen-bb7 against the three eukaryotic cell lines and increased the binding affinity of the ruthenium complex for HSA. Confocal microscopy experiments indicated that the level of accumulation of α-Me4phen-7 in BHK cells is not significantly affected by Q[10]-encapsulation. Taken together, the combined results suggest that α-Me4phen-7 could be a good candidate as a new antimicrobial agent, and Q[10]-encapsulation could be a method to improve the pharmacokinetics of the ruthenium complex.

8.
Basic Clin Pharmacol Toxicol ; 120(4): 390-397, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28224710

RESUMO

The potent neurotoxin saxitoxin (STX) belongs to a group of structurally related analogues produced by both marine and freshwater phytoplankton. The toxins act by blocking voltage-gated sodium channels stopping the inflow of sodium ions and the generation of action potentials. Exposure from marine sources occurs as a result of consuming shellfish which have concentrated the toxins, and freshwater exposure can occur from drinking water although there have been no acute poisonings from the latter source to date. Previously, the majority of research into this group of toxins, collectively known as the paralytic shellfish toxins, has focused on acute exposure resulting in paralytic shellfish poisoning. While acute exposure guidelines exist for both sources, there are no chronic exposure guidelines and there has been minimal research into this pattern of exposure despite the known role of electrical activity in neurogenesis. We aimed to investigate this pattern of exposure and its potential effects on neurodevelopment using model neuronal cells. PC12 and SH-SY5Y cells were exposed to STX (0.25-3 µg/l) for 7 days, after which time they were stained with TRITC-Phalloidin, to observe adverse morphological effects. Cells exposed to STX had a significant decrease (18-85%) in long axonlike projections, instead exhibiting a significant increase in shorter projections classified as filopodia (p < 0.05). The results suggest that extended low-dose exposure to STX can inhibit proper neurite outgrowth at concentrations well below guideline levels for both sources of exposure making it a potential public health concern.


Assuntos
Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Saxitoxina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Neurônios/patologia , Células PC12 , Ratos
9.
Metallomics ; 8(8): 762-73, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27460862

RESUMO

NAMI-A and KP1019 are Ru(III)-based anti-metastatic and cytotoxic anti-cancer drugs, respectively, and have been proposed to be activated by reduction to Ru(II). The potential reduction of NAMI-A and KP1019 in the hypoxic environment of a tumour model of neuroblastoma was examined. Normoxic, hypoxic and necrotic tumour tissues were modelled by multicellular spheroids of SH-SY5Y human neuroblastoma cells of various diameters (50-800 µm). The variation in spheroid environment was confirmed with pimonidazole staining. Laser-ablation inductively-coupled plasma mass spectrometry showed KP1019 and NAMI-A penetration into the spheroid hypoxic region. XANES showed that the speciation of NAMI-A biotransformation products did not change significantly as hypoxia levels increased. KP1019 metabolites showed a correlation between the degree of spheroid hypoxia and the Ru K-edge energy consistent with either partial reduction of Ru(III) to Ru(II) in tumour microenvironments, increased S/Cl coordination or a reduced fraction of polynuclear Ru species. EXAFS spectroscopy was undertaken in an attempt to distinguish between these scenarios but was inconclusive.


Assuntos
Antineoplásicos/farmacologia , Dimetil Sulfóxido/análogos & derivados , Hipóxia/fisiopatologia , Indazóis/farmacologia , Neuroblastoma/patologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Esferoides Celulares/patologia , Antineoplásicos/química , Dimetil Sulfóxido/química , Dimetil Sulfóxido/farmacologia , Humanos , Indazóis/química , Neuroblastoma/tratamento farmacológico , Compostos Organometálicos/química , Rutênio/química , Compostos de Rutênio , Esferoides Celulares/efeitos dos fármacos , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Espectroscopia por Absorção de Raios X
10.
Food Funct ; 7(2): 1138-46, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26815043

RESUMO

In this study we compared the effects of a diverse set of natural polyphenolics ligands on in silico interactive modelling, in vitro anti-aggregative properties and neuronal toxicity of ß amyloid. The ß amyloid-binding characteristics of optimised structural conformations of polyphenols with ascribed neuroprotective actions including punicalagin, myricetin, luteolin and honokiol were determined in silico. Thioflavin T and transmission electron microscopy were used to assess in vitro inhibitory effects of these polyphenols on Aß1-42 fibril and aggregation formation. Phaeochromocytoma (PC12) cells were exposed to Aß1-42, alone and in combination with test concentrations of each polyphenol (100 µM) and viability measured using MTT assay. Aß1-42 evoked a concentration-dependent loss of cell viability in PC12 cells, in which all four polyphenols demonstrated significant inhibition of neurotoxicity. While all compounds variably altered the morphology of Aß aggregation, the flavonoids luteolin and myricetin and the lignan honokiol all bound in a similar hydrophobic region of the amyloid pentamer and exerted the most pronounced inhibition of Aß1-42 aggregation. Each of the polyphenols demonstrated neuroprotective effects in PC12 cells exposed to Aß1-42, including punicalagin. These findings highlight some structure-activity insights that can be gleaned into the anti-aggregatory properties of bioactive polyphenols based on modelling of their binding to ß-amyloid, but also serve to highlight the more general cellular neuroprotective nature of such compounds.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Polifenóis/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Benzotiazóis , Compostos de Bifenilo/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Flavonoides/farmacologia , Corantes Fluorescentes/análise , Taninos Hidrolisáveis/farmacologia , Lignanas/farmacologia , Luteolina/farmacologia , Microscopia Eletrônica de Transmissão , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Ratos , Tiazóis/análise
11.
Chembiochem ; 17(3): 239-46, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26676975

RESUMO

The amphibian skin is a vast resource for bioactive peptides, which form the basis of the animals' innate immune system. Key components of the secretions of the cutaneous glands are antimicrobial peptides (AMPs), which exert their cytotoxic effects often as a result of membrane disruption. It is becoming increasingly evident that there is a link between the mechanism of action of AMPs and amyloidogenic peptides and proteins. In this work, we demonstrate that the broad-spectrum amphibian AMP uperin 3.5, which has a random-coil structure in solution but adopts an α-helical structure in membrane-like environments, forms amyloid fibrils rapidly in solution at neutral pH. These fibrils are cytotoxic to model neuronal cells in a similar fashion to those formed by the proteins implicated in neurodegenerative diseases. The addition of small quantities of 2,2,2-trifluoroethanol accelerates fibril formation by uperin 3.5, and is correlated with a structural stabilisation induced by this co-solvent. Uperin 3.5 fibril formation and the associated cellular toxicity are inhibited by the polyphenol (-)-epigallocatechin-3-gallate (EGCG). Furthermore, EGCG rapidly dissociates fully formed uperin 3.5 fibrils. Ion mobility-mass spectrometry reveals that uperin 3.5 adopts various oligomeric states in solution. Combined, these observations imply that the mechanism of membrane permeability by uperin 3.5 is related to its fibril-forming properties.


Assuntos
Anfíbios/metabolismo , Amiloide/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Sequência de Aminoácidos , Amiloide/química , Animais , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Catequina/análogos & derivados , Catequina/química , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Células PC12 , Estrutura Secundária de Proteína , Ratos , Espectrometria de Massas por Ionização por Electrospray
12.
Biochim Biophys Acta ; 1844(9): 1591-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24948476

RESUMO

Semen-derived enhancer of viral infection (SEVI) is the term given to the amyloid fibrils formed by a 39-amino acid fragment (PAP248-286) of prostatic acidic phosphatase (PAP) found in human semen. SEVI enhances human immunodeficiency virus (HIV) infectivity by four to five orders of magnitude (Münch et al., 2007). Here, we show by various biophysical techniques including Thioflavin T fluorescence, circular dichroism spectroscopy and transmission electron microscopy that fragments encompassing the central region of SEVI, i.e. PAP248-271 and PAP257-267, form fibrils of similar morphology to SEVI. Our results show that the central region, residues PAP267-271, is crucially important in promoting SEVI fibril formation. Furthermore, SEVI and fibrillar forms of these peptide fragments are toxic to neuronal pheochromocytoma 12 cells but not to epithelial colon carcinoma cells. These findings imply that although SEVI assists in the attachment of HIV-1 to immune cells, it may not facilitate HIV entry by damaging the epithelial cell layer that presents a barrier to the HIV.


Assuntos
Amiloide/química , HIV-1/química , Fragmentos de Peptídeos/química , Proteínas Tirosina Fosfatases/química , Sêmen/química , Fosfatase Ácida , Motivos de Aminoácidos , Amiloide/farmacologia , Animais , Benzotiazóis , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes , HIV-1/metabolismo , Humanos , Microscopia Eletrônica de Transmissão , Dados de Sequência Molecular , Especificidade de Órgãos , Células PC12 , Fragmentos de Peptídeos/farmacologia , Ratos , Sêmen/enzimologia , Sêmen/virologia , Espectrometria de Fluorescência , Tiazóis , Ligação Viral
13.
Forensic Sci Int ; 241: 138-40, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24915453

RESUMO

Following a short treatment for irritable bowel with the following herbs: Astragalus propinquus, Codonopsis pilosula, Paeonia sp., Atractylodes macrocephala, Pueraria sp., Poria cocos, Dioscorea opposita, Patriniae, Psoralea corylifolia, Alpinia katsumadai, Glycyrrhiza uralensis and Dolomiaea souliei sp. a 43-year-old woman developed acute severe liver failure requiring liver transplantation. Histopathological examination of the liver showed massive hepatic necrosis in keeping with drug/chemical toxicity. Surgery was followed by multiorgan failure and death. While numerous studies have evaluated the effect of polypharmacy, the study of multiple concurrent herb use is only just emerging, despite the popularity of herbal medicine use in the western world. As this case demonstrates that fulminant hepatic failure and death may be caused by the concomitant use of a number of herbal products, the possibility of untoward effects from herbal polypharmacy must be increasingly considered in the evaluation of medicolegal cases.


Assuntos
Necrose Hepática Massiva/induzido quimicamente , Fitoterapia/efeitos adversos , Adulto , Evolução Fatal , Feminino , Hepatite B Crônica/complicações , Humanos , Transplante de Fígado , Necrose Hepática Massiva/patologia , Polimedicação
14.
Bioorg Med Chem Lett ; 23(23): 6336-40, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24157371

RESUMO

Many protein misfolding diseases, for example, Alzheimer's, Parkinson's and Huntington's, are characterised by the accumulation of protein aggregates in an amyloid fibrillar form. Natural products which inhibit fibril formation are a promising avenue to explore as therapeutics for the treatment of these diseases. In this study we have shown, using in vitro thioflavin T assays and transmission electron microscopy, that grape seed extract inhibits fibril formation of kappa-casein (κ-CN), a milk protein which forms amyloid fibrils spontaneously under physiological conditions. Among the components of grape seed extract, gallic acid was the most active component at inhibiting κ-CN fibril formation, by stabilizing κ-CN to prevent its aggregation. Concomitantly, gallic acid significantly reduced the toxicity of κ-CN to pheochromocytoma12 cells. Furthermore, gallic acid effectively inhibited fibril formation by the amyloid-beta peptide, the putative causative agent in Alzheimer's disease. It is concluded that the gallate moiety has the fibril-inhibitory activity.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Ácido Gálico/química , Ácido Gálico/farmacologia , Extrato de Sementes de Uva/química , Extrato de Sementes de Uva/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Extrato de Sementes de Uva/análise , Camundongos , Dobramento de Proteína
15.
Peptides ; 38(2): 427-36, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23069634

RESUMO

The Asp and isoAsp isomers of three bioactive peptides, Crinia angiotensin 11 [APGDRIYHPF(OH)], uperin 1.1 [pEADPNAFYGLM(NH(2))] and citropin 1.1 [GLFDVIKKVASVIGGL(NH(2))] were tested for changes in (i) susceptibility towards proteolytic cleavage, (ii) activity (smooth muscle activity for Crinia angiotensin 11 and uperin 1.1 isomers, and antimicrobial activity for the two isomers of citropin 1.1), and (iii) 3D structures in water, trifluoroethanol-d(3)/water (1:1) and DPC micelles as determined by 2D nuclear magnetic resonance spectroscopy. Proteolytic cleavage with trypsin was identical for each pair of Asp/isoAsp isomers. Cleavage with chymotrypsin was the same for the Crinia angiotensin and uperin 1.1 isomeric pairs, but different for the two Asp/isoAsp citropin 1.1 isomers. Chymotrypsin cleaved at Phe3 (adjacent to Asp4) for citropin 1.1, but not at Phe3 (adjacent to isoAsp4) for isoAsp citropin 1.1. The smooth muscle activity of the isoAsp isomer of Crinia angiotensin 11 was less than that of the Asp isomer. The smooth muscle activity of isoAsp3-uperin 1.1 is greater than that of the Asp isomer at low concentration (<10(-9)M) but no different from the Asp isomer at concentrations>10(-9) M. Citropin 1.1 is a wide-spectrum antibiotic against Gram positive organisms, while the isoAsp isomer is inactive against the test pathogens Staphylococcus aureus and Bacillus subtilis. The observed changes in activity are accompanied by changes in the 3D structures of isomers as determined by 2D nuclear magnetic resonance spectroscopy.


Assuntos
Ácido Aspártico/química , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Peptídeos/farmacologia , Animais , Anuros , Ácido Aspártico/metabolismo , Cobaias , Modelos Moleculares , Peptídeos/química , Peptídeos/metabolismo , Conformação Proteica , Proteólise , Relação Estrutura-Atividade
16.
Food Funct ; 3(12): 1242-50, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22929970

RESUMO

Polyphenolic compounds derived mainly from plant products have demonstrated neuroprotective properties in a number of experimental settings. Such protective effects have often been ascribed to antioxidant capacity, but specific augmentation of other cellular defences and direct interactions with neurotoxic proteins have also been demonstrated. With an emphasis on neurodegenerative conditions, such as Alzheimer's disease, we highlight recent findings on the neuroprotection ascribed to bioactive polyphenols capable of directly interfering with the Alzheimer's disease hallmark toxic ß-amyloid protein (Aß), thereby inhibiting fibril and aggregate formation. This includes compounds such as the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and the phytoalexin resveratrol. Targeted studies on the biomolecular interactions between dietary polyphenolics and Aß have not only improved our understanding of the pathogenic role of ß-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses.


Assuntos
Peptídeos beta-Amiloides/efeitos adversos , Dieta , Doenças Neurodegenerativas/prevenção & controle , Polifenóis/farmacologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Antioxidantes , Catequina/análogos & derivados , Catequina/química , Catequina/metabolismo , Catequina/farmacologia , Linhagem Celular , Curcumina , Humanos , Modelos Moleculares , Neurônios , Fármacos Neuroprotetores , Plantas/química , Polifenóis/administração & dosagem , Polifenóis/metabolismo , Resveratrol , Estilbenos/administração & dosagem , Chá/química
17.
J Agric Food Chem ; 60(16): 4144-55, 2012 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-22443319

RESUMO

The effects of protein oxidation, for example of methionine residues, are linked to many diseases, including those of protein misfolding, such as Alzheimer's disease. Protein misfolding diseases are characterized by the accumulation of insoluble proteinaceous aggregates comprised mainly of amyloid fibrils. Amyloid-containing bodies known as corpora amylacea (CA) are also found in mammary secretory tissue, where their presence slows milk flow. The major milk protein κ-casein readily forms amyloid fibrils under physiological conditions. Milk exists in an extracellular oxidizing environment. Accordingly, the two methionine residues in κ-casein (Met(95) and Met(106)) were selectively oxidized and the effects on the fibril-forming propensity, cellular toxicity, chaperone ability, and structure of κ-casein were determined. Oxidation resulted in an increase in the rate of fibril formation and a greater level of cellular toxicity. ß-Casein, which inhibits κ-casein fibril formation in vitro, was less effective at suppressing fibril formation of oxidized κ-casein. The ability of κ-casein to prevent the amorphous aggregation of target proteins was slightly enhanced upon methionine oxidation, which may arise from the protein's greater exposed surface hydrophobicity. No significant changes to κ-casein's intrinsically disordered structure occurred upon oxidation. The enhanced rate of fibril formation of oxidized κ-casein, coupled with the reduced chaperone ability of ß-casein to prevent this aggregation, may affect casein-casein interaction within the casein micelle and thereby promote κ-casein aggregation and contribute to the formation of CA.


Assuntos
Amiloide/química , Caseínas/química , Metionina/química , Amiloide/metabolismo , Animais , Caseínas/metabolismo , Bovinos , Metionina/metabolismo , Oxirredução , Células PC12 , Ratos
18.
Neurotoxicology ; 33(1): 138-46, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22233683

RESUMO

Cannabinoids have been widely reported to have neuroprotective properties in vitro and in vivo. In this study we compared the effects of CB1 and CB2 receptor-selective ligands, the endocannabinoid anandamide and the phytocannabinoid cannabidiol, against oxidative stress and the toxic hallmark Alzheimer's protein, ß-amyloid (Aß) in neuronal cell lines. PC12 or SH-SY5Y cells were selectively exposed to either hydrogen peroxide, tert-butyl hydroperoxide or Aß, alone or in the presence of the CB1 specific agonist arachidonyl-2'-chloroethylamide (ACEA), CB2 specific agonist JWH-015, anandamide or cannabidiol. Cannabidiol improved cell viability in response to tert-butyl hydroperoxide in PC12 and SH-SY5Y cells, while hydrogen peroxide-mediated toxicity was unaffected by cannabidiol pretreatment. Aß exposure evoked a loss of cell viability in PC12 cells. Of the cannabinoids tested, only anandamide was able to inhibit Aß-evoked neurotoxicity. ACEA had no effect on Aß-evoked neurotoxicity, suggesting a CB1 receptor-independent effect of anandamide. JWH-015 pretreatment was also without protective influence on PC12 cells from either pro-oxidant or Aß exposure. None of the cannabinoids directly inhibited or disrupted preformed Aß fibrils and aggregates. In conclusion, the endocannabinoid anandamide protects neuronal cells from Aß exposure via a pathway unrelated to CB1 or CB2 receptor activation. The protective effect of cannabidiol against oxidative stress does not confer protection against Aß exposure, suggesting divergent pathways for neuroprotection of these two cannabinoids.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Canabinoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/ultraestrutura , Análise de Variância , Animais , Antioxidantes/farmacologia , Ácidos Araquidônicos/farmacologia , Benzotiazóis , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromanos/farmacologia , Interações Medicamentosas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Indóis/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Neuroblastoma/patologia , Células PC12/efeitos dos fármacos , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Tiazóis
19.
Biochemistry ; 51(3): 736-8, 2012 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-22242710

RESUMO

The selenoamino acids methylselenocysteine (MeSeCys) and selenomethionine (SeMet) have disparate efficacies as anticancer agents. Herein, we use X-ray absorption spectroscopy to determine the chemical form of selenium in human neuroblastoma cells. Cells treated with MeSeCys contain a significant diselenide component, which is absent from SeMet-treated cells and suggests that metabolites of MeSeCys are capable of altering the redox status of the cells. The differences in the speciation of Se in the selenoamino acid-treated cells may provide insight into the differing anticancer activities of MeSeCys and SeMet.


Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/metabolismo , Cisteína/análogos & derivados , Compostos Organosselênicos/metabolismo , Compostos Organosselênicos/farmacologia , Linhagem Celular Tumoral , Cisteína/farmacologia , Humanos , Compostos de Selênio/metabolismo , Selenocisteína/análogos & derivados , Espectroscopia por Absorção de Raios X/métodos
20.
J Am Chem Soc ; 133(45): 18272-9, 2011 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-21957893

RESUMO

Selenite is an inorganic form of selenium that has a cytotoxic effect against several human cancer cell lines: one or more selenite metabolites are considered to be responsible for its toxicity. X-ray absorption spectroscopy was used to monitor Se speciation in A549 human lung cancer cells incubated with selenite over 72 h. As anticipated, selenodiglutathione and elemental Se both comprised a large proportion of Se in the cells between 4 and 72 h after treatment, which is in accordance with the reductive metabolism of selenite in the presence of glutathione and glutathione reductase/NADPH system. Selenocystine was also present in the cells but was only detected as a significant component between 24 and 48 h concomitant with a decrease in the proportion of selenocysteine and the viability of the cells. The change in speciation from the selenol, selenocysteine, to the diselenide, selenocystine, is indicative of a change in the redox status of the cells to a more oxidizing environment, likely brought about by metabolites of selenite. X-ray fluorescence microscopy of single cells treated with selenite for 24 h revealed a punctate distribution of Se in the cytoplasm. The accumulation of Se was associated with a greater than 2-fold increase in Cu, which was colocalized with Se. Selenium K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy revealed Se-Se and Se-S bonding, but not Se-Cu bonding, despite the spatial association of Se and Cu. Microprobe X-ray absorption near-edge structure spectroscopy (µ-XANES) showed that the highly localized Se species was mostly elemental Se.


Assuntos
Antineoplásicos/metabolismo , Neoplasias Pulmonares/metabolismo , Selenito de Sódio/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Selenito de Sódio/química , Selenito de Sódio/farmacologia , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Espectroscopia por Absorção de Raios X
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