ORCID Profile
0000-0003-1016-0588
Current Organisations
Karolinska University Hospital
,
University of Adelaide
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Biocatalysis and Enzyme Technology | Medical Biochemistry: Lipids | Food Sciences | Food Engineering
Health related to ageing | Preventive medicine | Nutrition |
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.BBADIS.2006.12.001
Abstract: Alzheimer's disease is the most prevalent form of dementia. Neuropathogenesis is proposed to be a result of the accumulation of amyloid beta peptides in the brain together with oxidative stress mechanisms and neuroinflammation. The presenilin proteins are central to the gamma-secretase cleavage of the amyloid prescursor protein (APP), releasing the amyloid beta peptide. Point mutations in the presenilin genes lead to cases of familial Alzheimer's disease by increasing APP cleavage resulting in excess amyloid beta formation. This review discusses the molecular mechanism of Alzheimer's disease with a focus on the presenilin genes. Alternative splicing of transcripts from these genes and how these may function in several disease states is discussed. There is an emphasis on the importance of animal models in elucidating the molecular mechanisms behind the development of Alzheimer's disease and how the zebrafish, Danio rerio, can be used as a model organism for analysis of presenilin function and Alzheimer's disease pathogenesis.
Publisher: Wiley
Date: 19-02-2009
DOI: 10.2164/JANDROL.108.006569
Abstract: The cytokine transforming growth factor beta1 (TGFB1) is implicated in male sexual function. Previous behavioral studies show that Tgfb1 null mutant mice mount and display limited intromission behavior with receptive females but are unable to complete successful copulation. The studies presented here explore the physiologic basis for sexual dysfunction in Tgfb1 null mutant males. Scanning electron microscopy revealed that the surface of the penis in Tgfb1 null mutant males was abnormally coated in superficial keratinized epithelial cells. There was a significant reduction in protrusion of penile spines through the superficial tissue in Tgfb1 null mutant mice in some mice, the spines were almost completely embedded. Histologic analysis revealed reduced skin thickness in the penis of Tgfb1 null mutant males. Nerve fibers, endothelial cells, smooth muscle actin, macrophages, and neuronal and inducible nitric oxide synthase were present in similar abundance and location in Tgfb1 null mutant mice compared with wild-type controls however, an increase in collagen I deposition was detected. Behavioral studies revealed that Tgfb1 null mutant males undergo spontaneous noncontact erections, albeit at a reduced rate compared with control mice, and engage in less frequent genital grooming activity. These studies suggest that Tgfb1 null mutation may adversely influence copulatory behavior through effects on both altered structural integrity of the penile skin and impaired tissue compliance leading to erectile dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 09-1987
DOI: 10.1007/BF00172679
Abstract: To assess cancer clinical trial recruitment and reasons for nonaccrual among a rural, medically underserved population served by a community-based cancer care center. We prospectively tracked clinical trial enrollment incidence among all new patients presenting at the Rapid City Regional Cancer Care Institute. Evaluating physicians completed questionnaires for each patient regarding clinical trial enrollment status and primary reasons for nonenrollment. Patients who identified as American Indian were referred to a program where patients were assisted in navigating the medical system by trained, culturally competent staff. Between September 2006 and January 2008, 891 new cancer patients were evaluated. Seventy-eight patients (9% 95% confidence intervals, 7-11%) were enrolled on a clinical treatment trial. For 73% (95% confidence intervals, 69-75%) of patients (646 of 891) lack of relevant protocol availability or protocol inclusion criteria restrictiveness was the reason for nonenrollment. Only 45 (5% 95% confidence intervals, 4-7%) patients refused enrollment on a trial. Of the 78 enrolled on a trial, 6 (8% 95% confidence intervals, 3-16%) were American Indian. Three additional American Indian patients were enrolled under a nontreatment cancer control trial, bringing the total percentage enrolled of the 94 American Indians who presented to the clinic to 10% (95% confidence intervals, 5-17%). Eligibility rates were unable to be calculated and cross validation of the number in the cohort via registries or ICD-9 codes was not performed. Clinical trial participation in this medically underserved population was low overall, but approximately 3-fold higher than reported national accrual rates. Lack of availability of protocols for common cancer sites as well as stringent protocol inclusion criteria were the primary obstacles to clinical trial enrollment. Targeted interventions using a Patient Navigation program were used to engage AI patients and may have resulted in higher clinical trial enrollment among this racial/ethnic group.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2014
Publisher: American Chemical Society (ACS)
Date: 11-04-2012
DOI: 10.1021/JF205168T
Abstract: The effects of protein oxidation, for ex le 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. β-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 β-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.
Publisher: Portland Press Ltd.
Date: 03-1996
DOI: 10.1042/BJ3140679
Abstract: The Ca2+-ATPase inhibitor thapsigargin (TG) activates bivalent-cation entry in human neutrophils via depletion of intracellular Ca2+ stores, but little is known about the underlying mechanism and the functional role of TG-induced cation entry. We studied the effects of TG on univalent- and bivalent-cation entry, lysozyme release and superoxide-anion (O2-) formation in human neutrophils. TG, like the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), stimulated entry of Ca2+, Mn2+, Ba2+, Sr2+ and Na+ in a 1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole hydrochloride (SK& F 96365)- and Gd3+-sensitive manner. The inhibitors of protein phosphatases 1/2A, calyculin A and okadaic acid, diminished TG-induced cation influxes, whereas the inhibitors of protein phosphatase 2B, cyclosporin A and FK-506, were potentiators. Pertussis toxin (PTX) partially inhibited the effects of TG on Ca2+ and Mn2+ entry. TG and fMLP activated inward currents with a linear current–voltage relationship and a reversal potential at about 0 mV. TG activated lysozyme release and potentiated fMLP-induced O2- formation. TG-induced lysozyme release was inhibited by SK& F 96365, PTX and the removal of extracellular Ca2+ or Na+. Our data show that TG activates a non-selective and SK& F 96365- and Gd3+-sensitive cation entry pathway and is a partial secretagogue. TG-stimulated cation entry involves PTX-sensitive G-proteins and protein phosphatases, with protein phosphatases 1/2A and 2B playing opposite roles.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2011
Publisher: Wiley
Date: 22-09-2008
DOI: 10.1002/RCM.3723
Abstract: The glandular skin secretion of the Eastern Dwarf Tree Frog Litoria fallax contains nine peptides named fallaxidins. The sequences of these peptides were elucidated using a combination of positive and negative electrospray mass spectrometry together with Edman sequencing. Among these peptides are: (i) fallaxidins 1.1 and 2.1 which have the sequences YFPIPI-NH2 and FWPFM-NH2. The activities of these peptides are unknown, but it has been shown that they are not smooth muscle active, opioids or antimicrobially active, nor do they effect proliferation of lymphocytes (ii) two weakly active antibiotics, fallaxidins 3.1 and 3.2 (e.g. fallaxidin 3.1, GLLDLAKHVIGIASKL-NH2), and a moderately active antibiotic fallaxidin 4.1 (GLLSFLPKVIGVIGHLIHPPS-OH). Fallaxidin 4.1 has an unusual sequence for an antibiotic, containing three Pro residues together with a C-terminal CO2H group. cDNA cloning has confirmed the identity of the nine isolated peptides from L. fallax, together with five additional peptides not detected in the peptide profile. The pre-regions of the nine preprofallaxidins are conserved and similar to those of the caerin peptides from L. caerulea and L. splendida, suggesting that the fallaxidin and caerin peptides, although significantly different in sequence, originated from a common ancestor gene.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.JFLM.2014.01.008
Abstract: A survey of herbal medicines available for internet and over-the-counter purchase in South Australia, Australia, was conducted looking specifically at those used for 'arthritis', 'cold and flu', 'gastrointestinal', 'stress' and 'premenstrual syndrome'. 121 products consisted of 29 in the 'arthritis' category, 33 in 'cold and flu', 19 in 'gastrointestinal' 30 in 'stress' and 10 in 'premenstrual syndrome'. Twenty two (18%) of 121 products were not registered with the Australian Register of Therapeutic Goods (ARTG), despite this being a legal requirement for their sale. Of the registered products 59 (60%) of 99 had differing ingredient concentrations on the website compared to their ARTG listing. Only three of the 15 purchased products had ingredient concentrations which were consistent between the website, ARTG listing and product packaging. These findings demonstrate that it may not be possible to determine what herbal substance an in idual has been exposed to prior to death and in what concentration, based on packaging from medications seized at the scene, or from examination of website data and the ARTG listing. These discrepancies may increase the problems that exist in attempting to determine what role herbal medicines may play in the mechanism of death in certain forensic cases.
Publisher: Wiley
Date: 08-1990
DOI: 10.1111/J.1749-6632.1990.TB31999.X
Abstract: Cilia and flagella are widespread cell organelles that have been highly conserved throughout evolution and play important roles in motility, sensory perception, and the life cycles of eukaryotes ranging from protists to humans. Despite the ubiquity and importance of these organelles, their composition is not well known. Here we use mass spectrometry to identify proteins in purified flagella from the green alga Chlamydomonas reinhardtii. 360 proteins were identified with high confidence, and 292 more with moderate confidence. 97 out of 101 previously known flagellar proteins were found, indicating that this is a very complete dataset. The flagellar proteome is rich in motor and signal transduction components, and contains numerous proteins with homologues associated with diseases such as cystic kidney disease, male sterility, and hydrocephalus in humans and model vertebrates. The flagellum also contains many proteins that are conserved in humans but have not been previously characterized in any organism. The results indicate that flagella are far more complex than previously estimated.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JNEUMETH.2016.08.012
Abstract: There is a paucity of detailed methods describing how to harvest and process motor neurons obtained from the adult rat spinal cord. Removal of intra-cardiac perfusion step. The spinal cord is extruded intact from the rat in under 60s post-decapitation then processed without differentiation of ventral and dorsal regions. The temperature during processing was maintained at room temperature (22°C) except during the Papain processing step where the temperature was increased to 30°C. Cell debris interfered with the counting of cells at the time of plating. Also, cell types could not be identified since they appear rounded structures with no projections. Cell viability counts reduced to 91% and 63% from day 7 to day 14 and days 7-28 respectively. Red blood cell counts in stepped density gradient layers 2 and 3 were low. No requirement for intra-cardiac perfusion. No requirement to cool to 4°C post harvesting, No requirement for specialized substrates. Reduces processing time by at least 2h and reduces the potential for processing errors through a reduction in complexity. Procedures are also explained suitable for those new to the culture of primary adult motor neurons. Cell viability counts indicate that removal of the perfusion step has a minimal effect on the viability of the cultured nerve cells, which may be due to the reduction in the spinal cord harvesting time and the inclusion of Hibernate based media during extrusion and processing.
Publisher: Informa UK Limited
Date: 20-03-2017
Publisher: Elsevier BV
Date: 1989
Publisher: SAGE Publications
Date: 25-02-2013
Abstract: The study investigated the use of serotonergic antidepressants (SSRIs: selective serotonin reuptake inhibitors SNRIs: serotonin–norepinephrine reuptake inhibitors) and St John’s wort in a large NSW-based community s le, and sought to identify a potentially dangerous concomitant use of these medications. Cross-sectional data from 266,848 participants from the ‘45 and Up’ study were used. The questionnaire captures self-reported treatment for depression or anxiety and antidepressant medications in the last four weeks. 5.8% of participants received treatment for depression or anxiety, with 4.7% taking an SSRI and 1.3% an SNRI. St John’s wort was taken by 0.3% of the participants. Use of SSRIs and SNRIs was reported more frequently by females than males (respectively, 64.1% vs 35.9%, 66.9% vs 33.1%). The gender difference was even more pronounced for St John’s wort (75.6% vs. 24.4%). Use of antidepressants decreased after the age of 65 years. One hundred and forty people reported concurrent use of an SSRI and an SNRI, and 11 people of an SSRI with St John’s wort. Around 7% of the study population aged 45–65 years reported the use of SSRIs or SNRIs, decreasing to 5% above 70 years of age. It is of concern that some in iduals used an SSRI concurrently with St John’s wort.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.ETAP.2016.09.020
Abstract: Saxitoxin (STX) and its analogs, the paralytic shellfish toxins (PSTs), are a group of potent neurotoxins well known for their role in acute paralytic poisoning by preventing the generation of action potentials in neuronal cells. They are found in both marine and freshwater environments globally and although acute exposure from the former has previously received more attention, low dose extended exposure from both sources is possible and to date has not been investigated. Given the known role of cellular electrical activity in neurodevelopment this pattern of exposure may be a significant public health concern. Additionally, the presence of PSTs is likely to be an ongoing and possibly increasing problem in the future. This review examines the neurodevelopmental toxicity of STX, the risk of extended or repeated exposure to doses with neurodevelopmental effects, the potential implications of this exposure and briefly, the steps taken and difficulties faced in preventing exposure.
Publisher: InTech
Date: 29-02-2012
DOI: 10.5772/31616
Publisher: Wiley
Date: 11-1996
DOI: 10.1111/J.1440-1681.1996.TB01156.X
Abstract: 1. Discrete, non‐adrenergic binding sites for imidazolines have been characterized in the brain and periphery. The 1 1 clonidine‐preferring site is mainly distributed in the brain and brain stem, while the 12 idazoxan‐preferring site is more widely distributed. 2. The 1 1 site appears to be associated with modulation of blood pressure. Imidazolines act within the rostral ventrolat ral medulla to produce hypotension. The underlying signal transduction mechanism is poorly understood. 3. The imidazolines clonidine and cirazoline inhibited nicotine‐stimulated calcium entry into rat phaeochromocytoma (PC‐12) cells by a non‐adrenergic mechanism. This effect was not attributable to the stimulation of protein kinases. 4. Similarly, clonidine and cirazoline inhibited nicotinestimulated inward currents into PC‐12 cells. This inhibitory action was not altered by inhibitors of signal transducing G‐proteins. 5. Clonidine and cirazoline displaced the ion channel ligand [ 3 H]‐phencyclidine from nicotinic acetylcholine receptors, suggesting that these drugs act by direct blockade of the intrinsic ion channel of the nicotinic acetylcholine receptor. 6. This ion channel‐blocking activity represents a novel action of these imidazolines and may underlie some of the proposed physiological actions of 1 1 sites.
Publisher: Wiley
Date: 11-1995
DOI: 10.1111/J.1476-5381.1995.TB17238.X
Abstract: 1. The role of protein kinase C in the modulation of noradrenaline release was investigated in mouse cortical slices which were pre-incubated with [3H]-noradrenaline. The aim was to investigate the hypothesis that protein kinase C is activated during high levels of transmitter release to maintain transmitter output. 2. The protein kinase C activators, phorbol myristate acetate (0.01-0.3 microM) and to a greater extent 4 beta-phorbol 12,13-dibutyrate (0.01-0.3 microM) significantly enhanced stimulation-induced noradrenaline release whereas 4 alpha-phorbol 12,13-dibutyrate (0.1 microM) which does not activate protein kinase C was without effect. The effect of the protein kinase C activator, phorbol myristate acetate, on noradrenaline release was attenuated by the protein kinase C inhibitor, polymyxin B (21 microM) which by itself inhibited stimulation-induced noradrenaline release. 3. Protein kinase C was down-regulated by 10 h exposure of the cortical slices to 4 beta-phorbol 12,13-dibutyrate (1 microM). In this case the facilitatory effect of 4 beta-phorbol 12,13-dibutyrate (0.1 microM) on noradrenaline release was abolished as was the inhibitory effect produced by polymyxin B. This indicates that polymyxin B was acting selectively at protein kinase C. 4. The inhibitory effect of polymyxin B on noradrenaline release, when expressed as a percentage of the appropriate frequency control, was constant at 1, 5 and 10 Hz. Furthermore, the ratio of release at 5 Hz to that at 10 Hz was not altered by protein kinase C down-regulation, indicating that there is no additional effect of protein kinase C at higher stimulation frequencies. 5. When transmitter release was elevated by blocking alpha 2-adrenoceptor auto-inhibition with idazoxan (0.1 microM) or K+ channels with tetraethylammonium (300 microM), the elevation in transmitter release was significantly attenuated by protein kinase C down-regulation, suggesting an involvement of protein kinase C. 6. We conclude that protein kinase C is involved in the modulation of noradrenaline release over a wide range of stimulation frequencies, in addition to a role when noradrenaline release is elevated by presynaptic mechanisms.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.NEULET.2013.10.027
Abstract: The native South American palm açaí berry (Euterpe oleraceae Mart.) has high polyphenolic and antioxidant levels. This study examined whether açaí berry extract afforded protection against β-amyloid (Aβ)-mediated loss of cell viability and oxidative stress associated with anti-fibrillar effects. PC12 cells were exposed to either Aβ1-42, Aβ25-35 or tert butyl hydroperoxide (t-BHP), alone or in the presence of açaí extract (0.5-50μg/ml). Thioflavin T (ThT) binding assay and transmission electron microscopy were used to determine effects of açaí extract on Aβ1-42 fibril morphology and compared to açaí phenolics gallic acid, cyanidin rutinoside and cyanidin glucoside. Exposure to Aβ1-42, Aβ25-35 or t-BHP decreased PC12 cell viability. Pretreatment with açaí extract significantly improved cell viability following Aβ1-42 exposure, however Aβ25-35 or t-BHP-mediated viability loss was unaltered. Açaí extract inhibited ThT fluorescence and disrupted Aβ1-42 fibril and aggregate morphology. In comparison with other phenolics, açaí was most effective at inhibiting Aβ1-42 aggregation. Inhibition of β-amyloid aggregation may underlie a neuroprotective effect of açaí.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.FORSCIINT.2014.05.021
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2010
Publisher: Springer Science and Business Media LLC
Date: 19-11-2013
Publisher: Elsevier BV
Date: 04-1990
DOI: 10.1016/0143-4179(90)90011-M
Abstract: In this study, we investigated the possible involvement of protein kinase C in the inhibitory effect of neuropeptide Y (NPY) on the electrical stimulation-induced release of radioactivity from mouse atria incubated with [3H]-noradrenaline. The protein kinase C activators, phorbol dibutyrate (PDB, 0.001-1 mumol/l) and phorbol myristate acetate (PMA, 0.001-1 mumol/l), increased the release of noradrenaline in a concentration-dependent manner. Interestingly, the maximum effect on noradrenaline release was significantly greater for phorbol dibutyrate compared to phorbol myristate acetate. The enhancement produced by both phorbol esters was significantly reduced by the protein kinase C inhibitor, K-252a (1 mumol/l). In the presence of the concentration of either phorbol ester (PMA, 0.1 mumol/l, PDB 1 mumol/l), that was supramaximal for increasing the release of noradrenaline, NPY (0.3 mumol/l) significantly inhibited the release of noradrenaline. Moreover, in the presence of the protein kinase C inhibitors, K-252a (1 mumol/l) or polymyxin B (70 mumol/l), NPY (0.3 mumol/l) also significantly inhibited the release of noradrenaline. Therefore, it is concluded that protein kinase C is not involved in the prejunctional inhibitory effect of NPY on noradrenaline release in the mouse atria. Furthermore, since K-252a also inhibits cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase and myosin light chain kinase, it is likely that these kinases are also not involved in the inhibitory mechanism of NPY.
Publisher: Wiley
Date: 12-1995
DOI: 10.1111/J.1445-5994.1995.TB02886.X
Abstract: Activation of receptors on postganglionic sympathetic nerve endings can alter the amount of noradrenaline release during a train of nerve impulses. These changes may be produced by the enzyme-linked synthesis of second messenger molecules within the nerve terminal. Cyclic AMP analogues enhance noradrenaline release and two hormones adrenaline and ACTH appear to enhance noradrenaline release through activation of adenylate cyclase. Activation of the phospholipase C rotein kinase C pathway also elevates stimulation-induced noradrenaline release and angiotensin enhancement of noradrenaline release appears to act through this pathway. On the other hand, receptors which inhibit noradrenaline release (alpha 2-adrenoceptors, muscarinic M2 receptors and neuropeptide Y receptors) do not act through either of these signal transduction pathways. Since these inhibitory systems are neurotransmitter activated and relay information on a nerve pulse to nerve pulse time scale back to the nerve ending a fast activation and deactivation rate of modulation is required. This may be better served by direct modulation of ion channels without a slow intervening enzyme step. Activation of protein kinase C by phorbol esters produces relatively large increases (two-threefold) in stimulation-induced noradrenaline release and this enzyme may also have a physiological role. Protein kinase C may be an appropriate target for drugs to manipulate transmitter release and development of selective activators and inhibitors of the many protein kinase C isoenzymes may prove clinically useful in diseases with inappropriate transmitter release profiles.
Publisher: Wiley
Date: 03-2000
Publisher: Elsevier BV
Date: 05-2022
Publisher: Springer Science and Business Media LLC
Date: 10-12-2015
DOI: 10.1038/SREP17475
Abstract: Globally, there has been an increase in the use of herbal remedies including traditional Chinese medicine (TCM). There is a perception that products are natural, safe and effectively regulated, however, regulatory agencies are h ered by a lack of a toolkit to audit ingredient lists, adulterants and constituent active compounds. Here, for the first time, a multidisciplinary approach to assessing the molecular content of 26 TCMs is described. Next generation DNA sequencing is combined with toxicological and heavy metal screening by separation techniques and mass spectrometry (MS) to provide a comprehensive audit. Genetic analysis revealed that 50% of s les contained DNA of undeclared plant or animal taxa, including an endangered species of Panthera (snow leopard). In 50% of the TCMs, an undeclared pharmaceutical agent was detected including warfarin, dexamethasone, diclofenac, cyproheptadine and paracetamol. Mass spectrometry revealed heavy metals including arsenic, lead and cadmium, one with a level of arsenic times the acceptable limit. The study showed 92% of the TCMs examined were found to have some form of contamination and/or substitution. This study demonstrates that a combination of molecular methodologies can provide an effective means by which to audit complementary and alternative medicines.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.NEUINT.2019.01.010
Abstract: Amyloid beta (Aβ) can aggregate and form plaques, which are considered as one of the major hallmarks of Alzheimer's disease. This study aims to directly compare the neuroprotective activities in vitro of two marine-derived carotenoids astaxanthin and fucoxanthin that have shown a spectrum of biological activities, including neuroprotection. The in vitro neuroprotective activities were investigated against Aβ
Publisher: American Chemical Society (ACS)
Date: 17-01-2012
DOI: 10.1021/BI201462U
Abstract: 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.
Publisher: Wiley
Date: 22-08-2006
Publisher: MDPI AG
Date: 17-10-2022
Abstract: 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.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.PEPTIDES.2012.10.001
Abstract: 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. 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.
Publisher: Wiley
Date: 02-2017
DOI: 10.5694/MJA16.00614
Abstract: Traditional herbal products are widely used in Australia to treat a broad range of conditions and diseases. It is popularly believed that these products are safer than prescribed drugs. While many may be safe, it is worrying that the specific effects and harmful interactions of a number of their components with prescription medications is not well understood. Some traditional herbal preparations contain heavy metals and toxic chemicals, as well as naturally occurring organic toxins. The effects of these substances can be dire, including acute hepatic and renal failure, exacerbation of pre-existing conditions and diseases, and even death. The content and quality of herbal preparations are not tightly controlled, with some ingredients either not listed or their concentrations recorded inaccurately on websites or labels. Herbal products may also include illegal ingredients, such as ephedra, Asarum europaeum (European wild ginger) and endangered animal species (eg, snow leopard). An additional problem is augmentation with prescription medications to enhance the apparent effectiveness of a preparation. Toxic substances may also be deliberately or inadvertently added: less expensive, more harmful plants may be substituted for more expensive ingredients, and processing may not be adequate. The lack of regulation and monitoring of traditional herbal preparations in Australia and other Western countries means that their contribution to illness and death is unknown. We need to raise awareness of these problems with health care practitioners and with the general public.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2010
Publisher: American Chemical Society (ACS)
Date: 20-02-2011
DOI: 10.1021/BI101678A
Abstract: Selenium compounds exhibit chemopreventative properties at supranutritional doses, but the efficacy of selenium supplementation in cancer prevention is dependent on the chemical speciation of the selenium supplement and its metabolites. The uptake, speciation, and distribution of the common selenoamino acid supplements, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys), in A549 human lung cancer cells were investigated using X-ray absorption and fluorescence spectroscopies. X-ray absorption spectroscopy of bulk cell pellets treated with the selenoamino acids for 24 h showed that while selenium was found exclusively in carbon-bound forms in SeMet-treated cells, a diselenide component was identified in MeSeCys-treated cells in addition to the carbon-bound selenium species. X-ray fluorescence microscopy of single cells showed that selenium accumulated with sulfur in the perinuclear region of SeMet-treated cells after 24 h, but microprobe selenium X-ray absorption near-edge spectroscopy in this region indicated that selenium was carbon-bound rather than sulfur-bound. X-ray absorption and X-ray fluorescence studies both showed that the selenium content of MeSeCys-treated cells was much lower than that of SeMet-treated cells. Selenium was distributed homogeneously throughout the MeSeCys-treated cells.
Publisher: Wiley
Date: 08-1991
DOI: 10.1111/J.1474-8673.1991.TB00319.X
Abstract: 1. Mouse atria were incubated with [3H]-noradrenaline and the outflow of radioactivity induced by electrical field stimulation (5 Hz, 60 s) was used as an index of noradrenaline release. Angiotensin II (1 x 10(-8) M) significantly enhanced the stimulation-induced (S-I) outflow of radioactivity. 2. Phorbol 12-myristate 13-acetate (0.001-1.0 x 10(-6) M) and phorbol 12, 13-dibutyrate (0.001-1.0 x 10(-6) M), protein kinase C activating phorbol esters, significantly enhanced the S-I outflow of radioactivity. Phorbol dibutyrate produced a greater maximal enhancement of S-I outflow of radioactivity than phorbol myristate acetate. The enhancement of S-I outflow of radioactivity produced by the combination of phorbol dibutyrate (1.0 x 10(-7) M) and phorbol myristate acetate (1.0 x 10(-7) M) was no greater than that produced by phorbol dibutyrate (1.0 x 10(-7) M) alone. The enhancement of S-I outflow of radioactivity produced by phorbol myristate acetate (1.0 x 10(-7) M) was constant whether the tissue was exposed for 15, 45 or 75 min. 3. When angiotensin II (1.0 x 10(-8) M) was present with the maximally effective concentration of phorbol dibutyrate (1.0 x 10(-7) M) it did not increase S-I outflow of radioactivity. 8-bromo-cyclic AMP (9.0 x 10(-5) M) by itself increased the S-I outflow of radioactivity and in the presence of the maximally effective concentration of phorbol dibutyrate the enhancement of S-I outflow of radioactivity produced by 8-bromo-cyclic AMP was maintained. 4. A protein kinase inhibitor, K-252a (1.0 x 10(-6) M), did not affect S-I outflow of radioactivity. K-252a significantly reduced the enhancement of S-I outflow of radioactivity produced by both phorbol myristate acetate (0.03 or 0.1 x 10(-6) M) and phorbol dibutyrate (0.01 or 1.0 x 10(-6) M). 5. K-252a (1.0 x 10(-6) M) blocked the enhancement of S-I outflow of radioactivity produced by angiotensin II (1.0 x 10(-8) M) and tetraethylammonium (1.0 x 10(-4) M). 6. These results suggest that angiotensin II receptors may enhance noradrenaline release through the pool of protein kinase C that is activated by phorbol dibutyrate.
Publisher: Wiley
Date: 29-07-2009
DOI: 10.1002/RCM.4164
Abstract: Positive and negative ion electrospray mass spectrometry together with Edman sequencing (when appropriate) has been used to sequence the host-defence peptides secreted from skin glands of the tree frog Litoria peronii. The peptide profiles are different in winter and summer. In winter, the frog produces small amounts of the known caerin 1.1 [GLLSVLGSVAKHVLPHVVPVIAEHL-NH(2)] (a wide-spectrum antibiotic) and caerin 2.1 [GLVSSIGRALGGLLADVVKSKQPA-OH], a narrow-spectrum antibiotic and an inhibitor of neuronal nitric oxide synthase. The major peptides produced throughout the year are the pGlu-containing peroniins 1.1 to 1.5 (e.g. peroniin 1.1 [pEPWLPFG-NH(2)], a smooth muscle contractor from 10(-7) M), and caerulein [pEQDY(SO(3)H)TGWMDF-NH(2)], a known and potent smooth muscle contractor from 10(-10) M. There are also some precursors to the peroniin 1 peptides, only detected in the skin secretion in summer, which are inactive and appear to be all (or part) of the spacer peroniin 1 peptides, e.g. peroniin 1.1b [SEEEKRQPWLPFG-NH(2)]. There are three members of the Litoria peronii Group of tree frogs classified in Australia, namely, L. peronii, L. rothii and L.tyleri. A comparison of the skin peptide profiles of L. peronii with those reported previously for L. rothii suggests that either these two species of tree frog are not as closely related as determined previously on morphological grounds, or that skin peptide ergence in tree frogs of this Group is more extensive than in others that have been studied.
Publisher: Wiley
Date: 06-1985
DOI: 10.1111/J.1440-1681.1985.TB02647.X
Abstract: Both resting and stimulated (straight-leg raising and head-up tilt) levels of arterial and venous plasma noradrenaline were significantly higher during low-dose adrenaline infusion in five mild hypertensive and four normotensive patients with one adrenal. Repeat adrenaline infusions in the five hypertensive patients while measuring noradrenaline clearance (3H-noradrenaline constant infusion) achieved similar levels of plasma adrenaline, and similar increases in plasma noradrenaline, within five min of achieving target infusion rate. Increased plasma noradrenaline was not explained by reduced clearance. These results are consistent with the hypothesis that physiological concentrations of adrenaline are capable of facilitating noradrenaline release in man.
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B512118N
Publisher: Springer Science and Business Media LLC
Date: 04-11-2022
Publisher: Wiley
Date: 03-1989
DOI: 10.1111/J.1476-5381.1989.TB11859.X
Abstract: 1. Mouse atria were incubated with [3H]-noradrenaline, and the outflow of radioactivity due to electrical field stimulation (5 Hz, 60 s) was used as an index of noradrenaline release. Angiotensin II (0.01 and 0.1 microM) significantly enhanced the stimulation-induced (S-I) outflow of radioactivity. 2. Phorbol 12-myristate 13-acetate (0.001, 0.03, 0.1 and 1.0 microM), a protein kinase C activating phorbol ester, significantly enhanced the S-I outflow of radioactivity. When angiotensin II (0.1 microM) was present with the concentration of phorbol 12-myristate 13-acetate that was maximally effective in increasing the S-I outflow (0.1 microM), the enhancement of S-I outflow produced by angiotensin II was maintained. 3. Polymyxin B (70 microM), an inhibitor of protein kinase C, significantly inhibited the S-I outflow. Polymyxin B also inhibited the enhancement of the S-I outflow produced by angiotensin II (0.1 microM). 4. In another series of experiments mice were injected with pertussis toxin (1.5 micrograms per mouse), 4 days before their atria were removed. The effectiveness of pertussis toxin pretreatment was determined indirectly using carbachol. Carbachol caused a concentration-dependent fall in both the rate and force of beating of isolated spontaneously beating atria from mice pretreated with vehicle. This effect of carbachol was not seen with atria from mice pretreated with pertussis toxin. 5. Pertussis toxin pretreatment did not alter the enhancement of the S-I outflow of radioactivity produced by angiotensin II (0.01 and 0.1 microM). 6. These results suggest that angiotensin II receptor modulation of noradrenaline release is not mediated through either a pertussis toxin sensitive guanine nucleotide-binding protein or activation of protein kinase C.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.BBRC.2014.10.062
Abstract: Protein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer's disease, Parkinson's disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C6MT00145A
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 1989
DOI: 10.1007/BF00165125
Publisher: The Optical Society
Date: 03-08-2011
DOI: 10.1364/OE.19.015824
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1016/S0165-1838(98)00098-8
Abstract: The molecular identity and structure of imidazoline receptors is still poorly understood. For ex le the I1-imidazoline binding site (I1-site) is localised to the plasma membrane, but it is not clear if this represents a conventional receptor. The I1-site reportedly has both high and low affinity binding states. Again it is not clear if these sites represent different states of the same receptor, or distinct molecular entities. The signal transduction mechanisms of I1-imidazoline receptors are beginning to be unravelled. There is clear evidence that ligands with high affinity for I1-sites stimulate phosphatidylcholine-selective phospholipase C in the rat adrenal medullary tumour cell line PC-12, but this may not be the case in all cell types. We investigated the possible role of this novel pathway in bovine adrenal medullary cells. Radioligand binding studies with [3H]clonidine confirmed the presence of I1-sites in membranes from these cells. Using microphysiometry, a recently developed technique for determining cellular activation, the extracellular acidification rates of cultured bovine adrenal medullary cells were unaffected by a number of imidazolines considered to be agonists at the I1-site. This suggests that there is no I1-site mediated stimulation of phosphatidylcholine specific phospholipase C in these cells. However, nicotine-stimulated increases in extracellular acidification were blocked by 100 microM clonidine. Ion channels have been suggested as another possible I1-imidazoline 'receptor' family, and may represent the low affinity I1-site detected in binding studies. I1-Site ligands can be shown to bind to, or block, several members of the ligand-gated ion channel superfamily, including the 5HT3, K+ATP, NMDA and nicotinic acetylcholine receptors. The I1-site ligands appear to be binding to, and acting at, the previously described phencyclidine binding site in these channels. Furthermore, molecular modelling suggests that I1-site selective ligands share a common three-dimensional structure with phencyclidine, and that I2-site selective ligands do not have this structure. This suggests that a phencyclidine-binding site motif may represent a novel site of action for I1-site ligands, and a search for receptors based on this motif may reveal novel imidazoline 'receptors'.
Publisher: Portland Press Ltd.
Date: 15-07-1994
DOI: 10.1042/BJ3010437
Abstract: We investigated whether maitotoxin activates non-selective cation channels, as was recently proposed [Soergel, Yasumoto, Daly and Gusovsky (1992) Mol. Pharmacol. 41, 487-493]. Stimulation of dibutyryl cyclic AMP-differentiated HL-60 cells with the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP 0.1 microM), the Ca(2+)-ATPase inhibitor thapsigargin (0.1 microM) or maitotoxin (25 ng/ml) resulted in an increase in cytoplasmic free calcium concentration ([Ca2+]i). Unlike fMLP and thapsigargin, maitotoxin produced no increase in [Ca2+]i in the absence of extracellular Ca2+. The increase in [Ca2+]i induced by fMLP was blocked by pretreatment with pertussis toxin (100 ng/ml for 24 h) but not that induced by maitotoxin. Similarly, the increase in [Ca2+]i produced by fMLP but not that produced by maitotoxin was inhibited by pretreatment with phorbol myristate acetate (100 ng/ml). Both fMLP- and maitotoxin-induced increases in [Ca2+]i were blocked by 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl)-1H-imid azole hydrochloride (SKF 96365) in a concentration-dependent manner. However, the maitotoxin-induced increase in [Ca2+]i was more sensitive to inhibition by SKF 96365 than the fMLP-induced increase. fMLP-induced increases in [Ca2+]i were blocked by cations with Gd3+ being more effective than Cd2+, whereas for maitotoxin Cd2+ was more effective than Gd3+. Both fMLP and thapsigargin stimulated quenching of Fura-2 fluorescence in the presence of extracellular Mn2+, whereas maitotoxin produced no Mn2+ quenching. Taken together these results suggest that maitotoxin does not stimulate the nonselective cation channel activated by fMLP, but instead activates Ca2+ influx by a different mechanism.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.REGPEP.2008.06.004
Abstract: The skin secretions of Crinia signifera, C. riparia and C. deserticola contain bioactive disulfide-containing peptides. Signiferin 1 (RLCIPYIIPC-OH) from C. signifera and C. deserticola) contracts smooth muscle at a concentration of 10(-9) M, and effects proliferation of lymphocytes at 10(-6) M. In contrast, riparin 1.1 (RLCIPVIFC-OH) and riparin 1.2 (FLPPCAYKGTC-OH) from C. riparia show lymphocyte activity but do not contract smooth muscle. The lymphocyte and smooth muscle activities involve CCK2R. 3D structures of signiferin 1 and riparin 1.1 have been established using 2D NMR methods: these studies show significant differences in the shapes of the disulfide rings and with the orientations of the N-terminal residues. cDNA cloning establishes that the pre sections of the precursor pre-pro-riparin 1.4-1.6 peptides are different from the conserved pre regions of disulfide-containing antimicrobial peptides from species of the genus Rana found in the northern hemisphere and caerin antimicrobial peptides isolated from Australian tree frogs of the genus Litoria. This suggests that (i) either that riparins 1 have converged to similar structure and function to the ranid and hyloid prepropeptides which were lost initially from the myobatrachid lineage, or (ii) the prepropeptides in all three groups were derived from a single ancestral form that has remained relatively conserved in the hyloid and ranoid lineages but has undergone substantial ergent evolution in the myobatrachids.
Publisher: Wiley
Date: 16-03-2009
DOI: 10.1002/RCM.3988
Abstract: Many species of frogs of the genus Litoria secrete bioactive peptides from their skin glands. These peptides are normally host-defence compounds and may have one, or more of the following activities smooth muscle contraction, analgesic, antimicrobial, antiviral, lymphocyte proliferator (immunomodulator) and neuronal nitric oxide synthase (nNOS) inactivation. Two frog species of the Litoria rubella Group that have been studied before, namely, Litoria electrica and Litoria rubella, are different from other species of the genus Litoria in that they produce small peptides that show neither membrane, lymphocyte nor nNOS activity. In this study we have used electrospray mass spectrometry together with Edman sequencing to identify eight skin peptides of the third member of this Group, Litoria dentata: surprisingly, none of these peptides show activity in our biological screening program. However, two major peptides (FPWL-NH(2) and FPWP-NH(2)) from L. electrica and L. rubella are opioids at the micromolar concentration.
Publisher: Wiley
Date: 2005
DOI: 10.1111/J.1742-4658.2004.04483.X
Abstract: Eugenin [pGluGlnAspTyr(SO(3))ValPheMetHisProPhe-NH(2)] has been isolated from the pouches of female Tammar wallabies (Macropus eugenii) carrying young in the early lactation period. The sequence of eugenin has been determined using a combination of positive and negative ion electrospray mass spectrometry. This compound bears some structural resemblance to the mammalian neuropeptide cholecystokinin 8 [AspTyr(SO(3))MetGlyTrpMetAspPhe-NH(2)] and to the hibian caerulein peptides [caerulein: pGluGlnAspTyr(SO(3))ThrGlyTrpMetAspPhe-NH(2)]. Eugenin has been synthesized by a route which causes only minor hydrolysis of the sulfate group when the peptide is removed from the resin support. Biological activity tests with eugenin indicate that it contracts smooth muscle at a concentration of 10(-9) M, and enhances the proliferation of splenocytes at 10(-7) M, probably via activation of CCK(2) receptors. The activity of eugenin on splenocytes suggests that it is an immunomodulator peptide which plays a role in the protection of pouch young.
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2FO30075C
Abstract: 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 β-amyloid protein (Aβ), 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 Aβ have not only improved our understanding of the pathogenic role of β-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses.
Publisher: Elsevier BV
Date: 12-2011
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.TOXICON.2009.06.009
Abstract: Two species of tree frog of the genus Litoria, namely L. splendida and L. rothii have been reported to change the compositions of their host-defence skin peptide profiles in summer and winter. L. splendida produces the potent smooth muscle active caerulein [pEQDY(SO(3)H)TGWMDF-NH(2)] in summer, but in winter much of the caerulein is hydrolysed to the less active desulfated form in addition, caerulein 1.2 [pEQDY(SO(3)H)TGWFDF-NH(2)] (which has only some 50% of the smooth muscle activity of caerulein) is released and acts via CCK2R. In contrast, Litoria rothii shows a most unexpected seasonal change of peptides. In summer it exudes caerulein together with a range of potent caerin antimicrobials and nNOS active peptides. In winter, none of the antibiotic or nNOS active caerin peptides are expressed. The major peptides produced by the skin glands in winter are caerulein 1.2 and rothein 1 (SVSNIPESIGF-OH). Like L. splendida, L. rothii has reduced the smooth muscle potency of caerulein by replacing it with caerulein 1.2. Rothein 1 is a lymphocyte proliferator acting via CCK2R. Activity testing and 2D NMR spectra of rothein 1 and some synthetic modifications indicate that both hydrophobic and hydrophilic interactions between rothein 1 and CCK2R are important.
Publisher: Wiley
Date: 07-1995
DOI: 10.1111/J.1749-6632.1995.TB32412.X
Abstract: Clonidine and cirazoline bind with high affinity to a nonadrenergic site in the brain stem, the so-called imidazoline I1 receptor. Our aim was to determine the mechanism by which these receptors act and their possible linkage to signal-transducing heterotrimeric G-proteins. We examined the effects of clonidine and cirazoline on PC-12 cells, a neuronal cell line that is reported to possess the I1 site and have no alpha 2-adrenoceptors. In undifferentiated PC-12 cells loaded with the Ca2+ indicator dye fura-2, clonidine and cirazoline (10-100 microM) inhibited the increase in [Ca2+]i produced by nicotine (10 microM). This inhibition was not reversed by yohimbine (100 microM), and adrenaline and BHT 920 were ineffective at 100 microM. This effect was not inhibited by pretreatment with pertussis toxin (24 hours, 100 ng/ml) and not modulated by pretreatment with IBMX (100 microM). The nicotine-induced increase in [Ca2+]i is apparently due to Ca2+ entering via the intrinsic ion channel of the nicotinic acetylcholine receptor. Clonidine and cirazoline inhibited the inward current produced by nicotine (10 microM) as measured by the whole cell patch-cl technique in differentiated PC-12 cells, recorded at a holding potential of -60 mV. In agreement with the results found with fura-2, inhibition of inward current was concentration dependent and not blocked by yohimbine (100 microM) or mimicked by adrenaline (100 microM). Pretreatment of PC-12 cells with pertussis toxin or infusion of GDP-beta-S (2 mM) via the patch pipette did not alter the inhibition of the nicotine-induced inward current by clonidine or cirazoline. Clonidine and cirazoline, but not adrenaline, displayed [3H]phencyclidine from Torpedo electroplaque membranes enriched in nicotinic acetylcholine receptors in a concentration-dependent manner (10-100 microM). Taken together, these results suggest that clonidine and cirazoline inhibit Na+ and Ca2+ entry through the nicotinic acetylcholine receptor via a nonadrenergic mechanism that is independent of G-proteins and cyclic nucleotides, presumably by direct blockade of the intrinsic ion channel of the nicotinic acetylcholine receptor.
Publisher: Wiley
Date: 07-2015
Abstract: Herbal medicines are perceived to be safe by the general public and medical practitioners, despite abundant evidence from clinical trials and case reports that show herbal preparations can have significant adverse effects. The overall impact of adverse events to herbal medicines in Australia is currently unknown. Post marketing surveillance of medications through spontaneous adverse drug reaction (ADR) reports to the Therapeutic Goods Administration (TGA) is one way to estimate this risk. The patterns of spontaneously reported ADRs provide insight to herbal dangers, especially when compared with patterns of a mechanistically similar conventional drug. The study compared the pattern of spontaneously reported ADRs to St. John's Wort (Hypericum perforatum), a common herbal treatment for depression which contains selective serotonin reuptake inhibitors (SSRI), to fluoxetine, a commonly prescribed synthetic SSRI antidepressant. Spontaneous ADR reports sent to the TGA between 2000-2013 for St. John's Wort (n = 84) and fluoxetine (n = 447) were obtained and analysed. The demographic information, types of interaction, severity of the ADR, and the body systems affected (using the Anatomical Therapeutic Chemical classification system) were recorded for in idual ADR cases. The majority of spontaneously reported ADRs for St. John's Wort and fluoxetine were concerning females aged 26-50 years (28.6%, 22.8%). The organ systems affected by ADRs to St John's Wort and fluoxetine have a similar profile, with the majority of cases affecting the central nervous system (45.2%, 61.7%). This result demonstrates that herbal preparations can result in ADRs similar to those of prescription medications.
Publisher: Elsevier BV
Date: 08-1984
DOI: 10.1016/0026-0495(84)90211-7
Abstract: In five males with mild essential hypertension, simultaneous hemodynamic and arterial and venous plasma catecholamine responses to three stimulation tests (mental arithmetic, isometric handgrip exercise, and cold) were studied. Plasma norepinephrine (NE), epinephrine (EPI), and dopamine (DA) were measured radioenzymatically. Isometric exercise was the best stimulus for systolic and diastolic blood pressure and NE. Mental arithmetic produced the highest levels of plasma EPI, but there was great intersubject variability. Dopamine levels did not increase with any of these stimuli. Consistent arterio-venous differences across the forearm were seen for EPI but not NE, consistent with local production of NE. Isometric exercise produced the closest correlations between peripheral plasma catecholamine levels, blood pressure, and heart rate. Good correlations were seen with mental arithmetic, but with the stimulus of cold correlation was poor.
Publisher: Wiley
Date: 12-2003
Abstract: IRAS, a putative clone of the I(1)-imidazoline receptor, possesses a proline-rich region (PRR) motif, which might interact with SH3 regions on tyrosine kinases, and an integrin-binding motif. Receptors with a PRR motif can generally assemble onto multi-element signaling complexes (eg., the beta(3)-receptor on the EGF receptor) and thereby modulate signal transduction. Integrins serve as scaffolds for multi-element signaling complexes, similar to that assembled with the EGF receptor. It is therefore possible that IRAS signals through a complex with other receptors.
Publisher: Wiley
Date: 19-05-2011
DOI: 10.1002/RCM.5041
Abstract: The Kyn-containing peptide FP-Kyn-L(NH(2)) is an unusual minor component of the skin peptide profile of the Australian red tree frog Litoria rubella collected from an area within a 20 kilometre radius of Alice Springs in central Australia. The structure was determined by electrospray mass spectrometry and synthesis. The major component of the skin secretion is the analogous tryptophyllin peptide FPWL(NH(2)). Both peptides show opioid activity at 10(-7) M, and are likely to act via the μ opioid receptor.
Publisher: Wiley
Date: 08-1987
DOI: 10.1111/J.1476-5381.1987.TB11275.X
Abstract: 1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM) ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0006-2952(94)90011-6
Abstract: Human neutrophils have been reported to possess both alpha 2- and beta 2-adrenoceptors. While activation of beta 2-adrenoceptors is known to inhibit N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion (O2-) production, the functional role of alpha 2-adrenoceptors is not known. We studied the effects of a range of structurally unrelated alpha 2-adrenoceptor agonists on fMLP-induced O2- production and UTP-induced increases in cytosolic free calcium concentration ([Ca2+]i) in human neutrophils. No effect of alpha 2-adrenoceptor agonists was seen on either fMLP-induced O2- production or UTP-induced increases in [Ca2+]i. alpha 2-Adrenoceptor agonists by themselves had no effect on either O2- production or [Ca2+]i. We then studied a model for neutrophils, differentiated HL-60 cells and human erythroleukaemia (HEL) cells, a cell line known to possess alpha 2-adrenoceptors. While the alpha 2-adrenoceptor agonists 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304) and 5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepin- dihydrochloride increased the [Ca2+]i in HEL cells, they had no effect by themselves on either [Ca2+]i or UTP-induced increases in [Ca2+]i in differentiated HL-60 cells. Activation of high-affinity GTPase by UK 14304 was seen in membranes from HEL cells but not in membranes from differentiated HL-60 cells. Similarly, a selective alpha 2-adrenoceptor antagonist, [3H]2-(2-methoxy-1,4-benzodioxan-2yl)-2 imidazoline, bound specifically and saturably to membranes from HEL cells, but not to membranes from HL-60 promyelocytes or differentiated HL-60 cells. Taken together, these data suggest that neither HL-60 promyelocytes nor differentiated HL-60 cells possess alpha 2-adrenoceptors, and that the lack of functional responses to alpha 2-adrenoceptor agonists in human neutrophils is due to the absence of alpha 2-adrenoceptors.
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1016/S0165-1838(98)00090-3
Abstract: In this article we outline the highlights of this special issue of the journal containing a series of articles covering many aspects of current interest in the field of imidazoline receptor research. This volume is the result of an international symposium held in September 1997 in Melbourne as an official satellite of the inaugural meeting of the International Society of Autonomic Neurosciences held in Cairns, Australia. A wide range of topics relating to imidazoline receptors were canvassed, including endogenous and synthetic ligands, identification and localisation of binding sites, putative transduction mechanisms and experimental and clinical functional studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-06-2022
DOI: 10.1002/HEP.32572
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1016/S0165-1838(98)00092-7
Abstract: A large scale extraction and isolation method was developed for the purification of clonidine-displacing substance (CDS) activity from bovine lung or brain. This optimised method used direct freeze drying of tissue, hexane removal of lipids, and methanol extraction of CDS activity. Using a bioassay directed isolation strategy a new CDS compound was purified from an extract of bovine lung. The isolation strategy involved subsequent steps of flash C-18 chromatography, ion exchange, size exclusion, and C-18 HPLC. An HPLC detection method was developed and applied to show that the new CDS is present in both lung and brain tissue. Spectroscopic data for this new CDS indicates that it is related to guanosine, but is not noradrenaline, adrenaline, histamine, agmatine, guanosine, GMP, GDP or GTP.
Publisher: Elsevier BV
Date: 1995
DOI: 10.1016/S0006-2952(94)00432-3
Abstract: Human erythroleukaemia (HEL) cells were investigated to characterize their alpha 2-adrenoceptor and imidazoline receptor sites. Membranes from HEL cells bound [3H]2-(2-methoxy-1, 4-benzodioxan-2yl)-2-imidazoline ([3H]RX821002) in a saturable and specific manner with a KD of 0.64 +/- 0.07 nM and a Bmax of 126 +/- 4 fmol/mg protein. [3H]RX821002 was displaced from HEL membranes by adrenergic drugs with the order of potency being yohimbine approximately oxymetazoline >> prazosin = 2-[2-[4-(o-methoxyphenyl)piperazin-1-yl]ethyl]-4,4-dimethyl- 1,3(2H,4H)-isochinolindione HCl (ARC 239), consistent with this site being an alpha 2A-adrenoceptor. HEL membranes also bound [3H]idazoxan in the presence of adrenaline to block alpha 2-adrenoceptors. This binding was saturable and specific with a KD of 3.5 +/- 1.0 nM and a Bmax of 31 +/- 6 fmol/mg protein. Adrenergic drugs from both the phenylethylamine and imidazoline classes increased high-affinity GTPase activity, an index of activation of regulatory heterotrimeric guanine-nucleotide binding proteins (G-proteins), and produced increases in cytosolic free calcium concentration ([Ca2+]i). The effects of these agonists in both systems were abolished by pertussis toxin pretreatment, and oxymetazoline and clonidine were antagonists. The potency of adrenergic drugs to inhibit 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304)-induced increases in [Ca2+]i was yohimbine approximately oxymetazoline >> ARC 239, consistent with the binding data and an action at alpha 2A-adrenoceptors. No evidence was found for a role of imidazoline receptors in stimulating G-proteins or modulating [Ca2+]i. The adrenergic agonist-induced increases in [Ca2+]i were due to both release of Ca2+ from intracellular stores and entry of extracellular Ca2+. Ca2+ entry was blocked by 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl)-1H- imidazole hydrochloride (SKF 96365), but not by nitrendipine. Adrenaline also stimulated Mn2+ entry in HEL cells. Taken together, these results suggest that HEL cells have alpha 2A-adrenoceptors that activate non-selective cation channels via pertussis toxin-sensitive G-proteins, i.e. Gi-proteins.
Publisher: Elsevier BV
Date: 09-2007
Publisher: American Chemical Society (ACS)
Date: 20-10-2011
DOI: 10.1021/JA206203C
Publisher: Wiley
Date: 22-02-2017
DOI: 10.1111/BCPT.12701
Abstract: 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.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5FO01281C
Abstract: Plant polyphenols such as the lignin honokiol pictured are able to bind to specific regions in the amyloid β oligomer and this may be associated with neuroprotective effects in neuronal cells.
Publisher: Wiley
Date: 16-12-2015
Abstract: The hibian 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 hibian 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.
Publisher: Informa UK Limited
Date: 30-03-2022
DOI: 10.1080/15376516.2022.2057267
Abstract: 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 rif icin 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 (
Publisher: Springer Science and Business Media LLC
Date: 1998
DOI: 10.1385/ENDO:9:1:71
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.BBAPAP.2014.06.006
Abstract: 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.
Publisher: Wiley
Date: 12-2003
Abstract: Agmatine and harmane have been proposed as endogenous ligands of imidazoline receptors. Agmatine has been reported to activate nitric oxide synthetase (NOS) in endothelial cells, so we sought to determine if agmatine or harmane and an analogue of harmane, propyl harmane, produced vasodilatation through an endothelium-dependent mechanism. The experiments were performed in endothelium-denuded and intact rat aortic rings preconstricted with phenylephrine (0.1 microM). Agmatine (0.3-1000 microM), harmane, and propyl harmane (0.3-100 microM) relaxed endothelium-intact rings in a concentration-dependent manner. Removal of endothelium inhibited the relaxant effect of agmatine, harmane, and propyl harmane. The NOS inhibitor L-NIO (100 microM) inhibited the relaxant effect of agmatine and harmane. The I(1)-receptor antagonist AGN (100 microM) partly inhibited the effect of harmane but not that of agmatine. These results suggest that the endogenous imidazoline ligands are capable of stimulating NOS largely by an I(1)-receptor-independent mechanism.
Publisher: Elsevier BV
Date: 11-2018
Publisher: CRC Press
Date: 22-07-1999
Publisher: The American Association of Immunologists
Date: 15-06-2006
DOI: 10.4049/JIMMUNOL.176.12.7489
Abstract: The aggregation of cell surface FcRs by immune complexes induces a number of important Ab-dependent effector functions. However, despite numerous studies that examine receptor function, very little is known about the molecular organization of these receptors within the cell. In this study, protein complementation, mutagenesis, and ligand binding analyses demonstrate that human FcγRIIa is present as a noncovalent dimer form. Protein complementation studies found that FcγRIIa molecules are closely associated. Mutagenesis of the dimer interface, as identified by crystallographic analyses, did not affect ligand binding yet caused significant alteration to the magnitude and kinetics of receptor phosphorylation. The data suggest that the ligand binding and the dimer interface are distinct regions within the receptor, and noncovalent dimerization of FcγRIIa may be an essential feature of the FcγRIIa signaling cascade.
Publisher: Wiley
Date: 25-02-2016
Abstract: Torso models for ballistics research require that the mechanical properties of simulant materials must match the heterogeneous nature of tissues/organs within the human thorax/abdomen. A series of energy loss experiments were conducted on fresh porcine organs/tissues at room temperature and 37°C, using steel 4.5 mm BBs fired from a Daisy(®) brand air rifle. They were compared to FBI and NATO specification ordnance gelatin and a candidate surrogate material called Simulant "A". Two CED M2 chronographs measured BB velocity. The resulting energy loss was established using KE = 1/2 mv² before and after target perforation. The combined results at room temperature and 37°C were as follows: FBI specification gelatin was similar (p > 0.05) to heart and lung, spleen was similar to NATO specification gelatin, Simulant "A" was similar to hindquarter muscle, and hindquarter muscle, kidney, and spleen were similar to each other regarding energy retardation. These results can be used as a basis for the development of simulant materials to create an anatomically correct heterogeneous model.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2016
DOI: 10.1007/S12024-016-9786-9
Abstract: Caffeine is considered a very safe stimulant and is widely consumed in a variety of forms, from pure caffeine to beverages and foods. Typically, death is only seen when gram quantities of caffeine are consumed, usually in suicide attempts. Even in this scenario, death is rare. However, there are special populations that need to be considered in forensic presentations, who may be at greater risk. These include poor metabolizers, people with liver disease, and people with cardiac conditions, who can die as a result of caffeine intake at levels well below what is ordinarily considered toxic. Also, caffeine intake may be hidden. For ex le, herbal medicines with substantial caffeine content may not disclose these concentrations on their product label. The role of caffeine in medicolegal deaths is yet to be defined, however, herbal medicines and herbal weight loss supplements may represent an underappreciated source of caffeine in this context.
Publisher: Wiley
Date: 06-1999
DOI: 10.1111/J.1749-6632.1999.TB09375.X
Abstract: Imidazoline binding sites are now generally accepted as being receptors. Despite this acceptance, the molecular structure and signal transduction mechanisms of these receptors are still poorly understood. The I1-imidazoline binding site (I1-receptor) is localized to the plasma membrane, but it is not clear if this represents a conventional receptor. It is also not clear if there are multiple forms of the I1-receptor. The signal transduction mechanisms of I1-receptors are similarly unclear, but much progress has been made. Evidence clearly indicates that ligands with high affinity for I1-receptors stimulate a novel signal transduction pathway, phosphatidylcholine-selective phospholipase C, in the rat adrenal medullary tumor cell line PC-12. However, this may not be the case in all cell types as microphysiometry, a novel technique for determining cellular activation, could not detect receptor activation in cultured bovine adrenal medullary cells exposed to a number of imidazolines considered to be agonists at the I1-receptor. This suggests that there is no I1-receptor-mediated stimulation of phosphatidylcholine-specific phospholipase C in these cells. By contrast, nicotine-stimulated increases in ion entry were blocked by clonidine. Ion channels have been suggested as another possible I1-imidazoline "receptor" family and may represent the low affinity I1-receptor. I1-Receptor ligands can be shown to bind to, or block, the following members of the ligand-gated ion channel super family, the 5HT3, K+ATP, NMDA, and nicotinic acetylcholine receptors. The site of action appears to be the phencyclidine binding site in these channels, but other possibilities cannot be excluded. Molecular modeling suggests that I1-receptor-selective ligands share a common three-dimensional structure with phencyclidine, providing a basis for these actions. This suggests that a phencyclidine-binding site motif may represent a novel site of action for I1-receptor ligands and that searches for receptors based on this motif may reveal novel imidazoline "receptors."
Publisher: Informa UK Limited
Date: 03-01-2022
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.BMCL.2013.09.071
Abstract: Many protein misfolding diseases, for ex le, 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.
Publisher: Wiley
Date: 08-03-1993
DOI: 10.1016/0014-5793(93)80517-X
Abstract: Superoxide anion (O2-.) production from human neutrophils stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP, 1 microM) was inhibited by preparations of the inhibitor of cAMP-dependent protein kinase, Rp-cyclic adenosine 3',5'-phosphorothioate (Rp-cAMPS, 100 microM). This effect of Rp-cAMPS was reversed by xanthine amine congener (0.1 microM), an adenosine receptor antagonist, and by low concentrations of adenosine desaminase (0.02 mg/ml). HPLC analysis shows that these preparations of Rp-cAMPS contained concentrations of adenosine which could produce significant inhibition of fMLP-induced O2-. production. These results suggest that Rp-cAMPS should be used with caution in cells or tissues containing adenosine receptors, and that preparations of Rp-cAMPS should be treated with adenosine desaminase before use to avoid activation of adenosine receptors.
Publisher: Wiley
Date: 08-1997
DOI: 10.1111/J.1440-1681.1997.TB02102.X
Abstract: 1. Protein kinase C (PKC) is an important second messenger-activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca2+ entry, presumably those involved in vesicle dynamics. 2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions. 3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high-frequency stimulation and not during low-frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca2+ and a consequent activation of PKC. 4. Activation of PKC by phorbol esters produces a large enhancement in action potential-evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NEURO.2011.12.015
Abstract: 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, β-amyloid (Aβ) in neuronal cell lines. PC12 or SH-SY5Y cells were selectively exposed to either hydrogen peroxide, tert-butyl hydroperoxide or Aβ, 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. Aβ exposure evoked a loss of cell viability in PC12 cells. Of the cannabinoids tested, only anandamide was able to inhibit Aβ-evoked neurotoxicity. ACEA had no effect on Aβ-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 Aβ exposure. None of the cannabinoids directly inhibited or disrupted preformed Aβ fibrils and aggregates. In conclusion, the endocannabinoid anandamide protects neuronal cells from Aβ exposure via a pathway unrelated to CB1 or CB2 receptor activation. The protective effect of cannabidiol against oxidative stress does not confer protection against Aβ exposure, suggesting ergent pathways for neuroprotection of these two cannabinoids.
Start Date: 2010
End Date: 2012
Funder: Australian Research Council
View Funded ActivityStart Date: 11-2010
End Date: 12-2015
Amount: $470,000.00
Funder: Australian Research Council
View Funded Activity