Publications by authors named "Gerald Münch"

117 Publications

Eupomatenes A - E: Neolignans isolated from the leaves of Australian rainforest plant Eupomatia laurina.

Fitoterapia 2021 Jun 17:104972. Epub 2021 Jun 17.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia.

A detailed phytochemical investigation of the leaves of the Australian rainforest tree Eupomatia laurina, led to the discovery of five new neolignans, eupomatenes A - E and eight known compounds, eupomatenoid-2, trans-(2'S)-2-[1'-(4-methoxyphenyl)prop-2'-yl]anethol, chlorogenic acid, chlorogenic acid-methyl ester, tyrosol-1-O-β-xylopyranosyl-1(1 → 6)-O-β-glucopyranoside, leucoside, kaempferol-3-O-neohesperidoside, and pachypodol. The structures of all the compounds were determined by detailed spectroscopic analysis. All compounds were also evaluated for their anti-inflammatory properties by assessing their inhibitory effects on nitric oxide (NO) production and TNF- α release in RAW 264.7 macrophages. Whilst slight anti-inflammatory activity (in terms of inhibition of NO production) was observed with eupomatenes A - E, this was also associated with high levels of cell growth inhibition.
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http://dx.doi.org/10.1016/j.fitote.2021.104972DOI Listing
June 2021

Therapeutic Opportunities for Food Supplements in Neurodegenerative Disease and Depression.

Front Nutr 2021 14;8:669846. Epub 2021 May 14.

Psychiatric Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.

Emerging evidence is showing nutrition as a crucial factor in the high prevalence and incidence of neurodegenerative mental disorders. Preventive interventions on neuroinflammation seem to be able to interfere with neurodegeneration. Supplementation of essential nutrients, such as long-chain-polyunsaturated fatty acids, vitamin E and mineral elements, may minimize inflammation, enhancing antioxidative defense, and lowering the risk and incidence of age-related diseases, such as cardiovascular diseases and neurodegenerative diseases. This manuscript reviews the current evidence on the role of neuroinflammation in the pathophysiology of neurodegenerative and mental disorders, and preventive strategies for food supplementation in these neuropsychiatric diseases. Dietary supplementation-based strategies have been demonstrated to be effective in subjects with mild cognitive impairment, while weaker results have been obtained in patients with advance neurodegenerative disease. Adjunctive supplementation has also been demonstrated to improve depression, this being of marked benefit considering the comorbidity between cognitive impairment/dementia and depression. Further research is needed to improve the prescriptive precision of supplementation in patients, and to better understand potential interactions with clinical and pharmacokinetic factors.
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http://dx.doi.org/10.3389/fnut.2021.669846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160227PMC
May 2021

The effect of aging and chronic microglia activation on the morphology and numbers of the cerebellar Purkinje cells.

Neurosci Lett 2021 04 8;751:135807. Epub 2021 Mar 8.

Department of Pharmacology, School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. Electronic address:

Reduced cerebellar volume and motor dysfunction have previously been observed in the GFAP-IL6 murine model of chronic neuroinflammation. This study aims to extend these findings by investigating the effect of microglial activation and ageing on the total number of Purkinje cells and the morphology of their dendritic arborization. Through comparison of transgenic GFAP-IL6 mice and their wild-type counterparts at the ages of 12 and 24-months, we were able to investigate the effects of ageing and chronic microglial activation on Purkinje cells. Unbiased stereology was used to estimate the number of microglia in Iba1 stained tissue and Purkinje cells in calbindin stained tissue. Morphological analyses were made using 3D reconstructions of images acquired from the Golgi-stained cerebellar tissue. We found that the total number of microglia increased by approximately 5 times in the cerebellum of GFAP-IL6 mice compared to their WT littermates. The number of Purkinje cells decreased by as much as 50 % in aged wild type mice and 83 % in aged GFAP-IL6 mice. The remaining Purkinje cells in these cohorts were found to have significant reductions in their total dendritic length and number of branching points, indicating how the complexity of the Purkinje cell dendritic arbor reduces through age and inflammation. GFAP-IL6 mice, when compared to WT mice, had higher levels of microglial activation and more profound neurodegenerative changes in the cerebellum. The presence of constitutive IL6 production, driving chronic neuroinflammation, may account for these neurodegenerative changes in GFAP-IL6 mice.
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http://dx.doi.org/10.1016/j.neulet.2021.135807DOI Listing
April 2021

Identification of tetragocarbone C and sideroxylin as the most potent anti-inflammatory components of Syncarpia glomulifera.

Fitoterapia 2021 Apr 1;150:104843. Epub 2021 Feb 1.

Pharmacology Unit, School of Medicine, Western Sydney University, Building 30, Campbelltown, NSW, Australia; NICM Health Research Institute, Western Sydney University, Sydney, NSW, Australia. Electronic address:

In contrast to ancient Western and Asian cultures, medicinal plants of the Aboriginal and Torres Strait Islanders in Australia have not been as intensively studied for their molecular composition and molecular bioactivity. Syncarpia glomulifera subsp. glomulifera is a species in the plant family Myrtaceae. The resin of the plant has been traditionally used by the D'harawal people of Western Sydney to heal inflamed sores and ulcers. Hence, the anti-inflammatory activity of its leaf extract was investigated in RAW 264.7 macrophage and N11 microglia cell lines to isolate and identify the most active compounds. One new compound, tetragocarbone C, and three known compounds, tetragocarbone B, sideroxylin, and lumaflavanone A showed potent anti-inflammatory activity by downregulating nitric oxide and TNF-α production in LPS and IFN-γ stimulated cells. Except for the less potent tetragocarbone B, all compounds had an IC value (for nitric oxide downregulation) of <10 μg/mL and moderate cytotoxicity in both cell lines. The molecular targets along pro-inflammatory signaling pathways were further investigated in RAW 264.7 cells. All four compounds suppressed phosphorylation of ERK, c-Jun, and limited the phosphorylation of STAT-1 and STAT-3 in response to LPS and IFN-γ activation. The four compounds also suppressed NF-κB activation by preventing the translocation of the p65 subunit into the nucleus. Collectively, these findings suggest that the compounds isolated from Syncarpia glomulifera, especially tetragocarbone C and sideroxylin are promising anti-inflammatory agents, and could be further investigated for the treatment of diseases characterized by chronic inflammation.
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http://dx.doi.org/10.1016/j.fitote.2021.104843DOI Listing
April 2021

Potential anti-neuroinflammatory compounds from Australian plants - A review.

Neurochem Int 2021 01 10;142:104897. Epub 2020 Nov 10.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia. Electronic address:

Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators, such as cytokines and chemokines, and generation of reactive oxygen and nitrogen species. Even though it is considered an event secondary to neuronal death or dysfunction, neuro-inflammation comprises a majority of the non-neuronal contributors to the cause and progression of neurodegenerative diseases like Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), Chronic Traumatic Encephalopathy (CTE) and others. As a result of the lack of effectiveness of current treatments for neurodegenerative diseases, neuroinflammation has become a legitimate therapeutic target for drug discovery, leading to the study of various in vivo and in vitro models of neuroinflammation. Several molecules sourced from plants have displayed anti-inflammatory properties in the study of neurodegenerative diseases. A group of these anti-inflammatory compounds has been classified as cytokine-suppressive anti-inflammatory drugs (CSAIDs), which target the pro-inflammatory AP1 and nuclear factor-κB signaling pathways and inhibit the expression of many pro-inflammatory cytokines, such as interleukin IL-1, IL-6, TNF-α, or nitric oxide. Australian plants, thriving amid the driest inhabited continent of the world, are an untapped source of chemical diversity in the form of secondary metabolites. These compounds are produced in response to biotic and abiotic stresses that the plants are exposed to in the highly biodiverse environment. This review is an attempt to highlight anti-inflammatory compounds isolated from Australian plants.
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http://dx.doi.org/10.1016/j.neuint.2020.104897DOI Listing
January 2021

Ternstroenols A - E: Undescribed pentacyclic triterpenoids from the Australian rainforest plant Ternstroemia cherryi.

Phytochemistry 2020 Aug 9;176:112426. Epub 2020 Jun 9.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia. Electronic address:

Chromatographic separation of the extracts of the Australian rainforest plant Ternstroemia cherryi led to the isolation of five undescribed barrigenol-like triterpenoids, ternstroenols A - E, from the fruits and three known ones from the leaves. Ternstroenols A - E represent a new form of structural diversity, being the first in its kind to incorporate a trans- 2, 4, 6- decatrienoyl moiety at C-22. The structures of the ternstroenols were assigned by detailed spectroscopic analysis, degradation and chemical derivatization. All compounds exhibited potent anti-inflammatory activity in LPS and IFN- γ activated RAW 264.7 macrophages, with IC values as low as 0.7 μM. Despite the remarkable potency, high levels of unwanted cell growth inhibition was also observed, which prompted their cytotoxic evaluation in U87/U251 human glioblastoma cell lines.
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http://dx.doi.org/10.1016/j.phytochem.2020.112426DOI Listing
August 2020

Mulgravanols A and B, rare oxidized xanthenes and a new phloroglucinol isolated from the Australian rainforest plant Waterhousea mulgraveana (Myrtaceae).

Fitoterapia 2020 Jun 22;143:104595. Epub 2020 Apr 22.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia.

Phytochemical investigation of the Australian rainforest plant leaves Waterhousia mulgraveana, yielded two rare oxidized xanthenes, mulgravanols A (1) and B (2) along with a new phloroglucinol, mulgravanol C (3). Mulgravanol A (1) is the first reported example of a complex xanthene flanked by a methine bridged phloroglucinol unit. All the compounds displayed moderate inhibitory effects on nitric oxide production and TNF-α release in RAW 264.7 macrophages (IC) 42-55 μM. The structures of the new compounds were assigned based on a detailed spectroscopic interpretation.
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http://dx.doi.org/10.1016/j.fitote.2020.104595DOI Listing
June 2020

The reciprocal EC value as a convenient measure of the potency of a compound in bioactivity-guided purification of natural products.

Fitoterapia 2020 Jun 21;143:104598. Epub 2020 Apr 21.

Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; NICM Health Research Institute, Western Sydney University, Sydney, Campbelltown, NSW 2560, Australia. Electronic address:

Identification of potent natural products is a challenging task in which sophisticated separation processes including HPLC are employed. The bioactivity of HPLC fractions is determined with a bioassay, and the most potent compounds are progressed to structural elucidation. In pharmacology, the potency of a compound is expressed as the half-maximal effective concentration (EC), which refers to the concentration of a drug that induces a response halfway between the baseline and maximum. While expressing the potency of a compound by its EC value makes sense in a clinical context, it is counterintuitive in the context of bioactivity-guided purification, as the potency of a compound is inversely related to its EC value, and the most potent compound is the one with the lowest EC. In natural products chemistry, it would be more logical if an increase in potency would be reflected by an increase of a parameter reflecting the potency. In this study, we introduce the term "effective dilution volume (EDV)" as the reciprocal of the EC (1/EC). We show how the EDV can be used to identify potent compounds in chromatographic separations, allowing to easily graph and identify anti-inflammatory compounds. We show two examples of this approach by overlaying an HPLC chromatogram with the EDV to point out the most potent compounds. We hope that the EDV will make the illustration of active fractions containing potent compounds in a chromatogram obvious for the reader and will become a useful graphic tool in the natural products literature in the future.
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http://dx.doi.org/10.1016/j.fitote.2020.104598DOI Listing
June 2020

Evaluation of Phytosomal Curcumin as an Anti-inflammatory Agent for Chronic Glial Activation in the GFAP-IL6 Mouse Model.

Front Neurosci 2020 12;14:170. Epub 2020 Mar 12.

Department of Pharmacology, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia.

Chronic glial activation is characterized by an increased number of activated microglia and astroglia; these secrete free radicals and cytotoxic cytokines, subsequently causing neuronal damage. This study investigated the hypothesis that a soy-lecithin based phytosomal curcumin formulation can decrease glial activation in the brains of GFAP-IL6 mice, a model of chronic glial activation, which exhibits gliosis in various regions of the brain. Three doses of Meriva curcumin (MC) (874, 436, and 218 PPM) were fed to 3-month-old GFAP-IL6 and wild-type (WT) mice for 4 weeks. As markers of glial activation, the total numbers of Iba-1 and TSPO microglia and macrophages, and GFAP astrocytes, were determined in the cerebellum and hippocampus by immunohistochemistry and unbiased stereology. Furthermore, the morphology of the glial cells was assessed by confocal microscopy and Sholl analysis. Administration of phytosomal curcumin led to a dose-dependent reduction in neuroinflammatory markers. Phytosomal curcumin (874 PPM) decreased the number of microglia by 26.2% in the hippocampus and by 48% in the cerebellum of the GFAP-IL6 mice compared with the GFAP-IL6 mice on normal food. Additionally, GFAP astrocyte numbers in the hippocampus of the GFAP-IL6 mice were decreased by 42%. The GFAP-IL6 mice exhibited a different microglial morphology to the WT mice, showing an increased soma size and perimeter. This difference was significantly reduced by the 874 PPM phytosomal curcumin dose. Our findings demonstrate that phytosomal curcumin is able to attenuate the inflammatory pathology, and potentially reverse the detrimental effects of chronic glial activation.
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http://dx.doi.org/10.3389/fnins.2020.00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081170PMC
March 2020

Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model.

Sci Rep 2020 02 11;10(1):2365. Epub 2020 Feb 11.

Department of Pharmacology, School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, New South Wales, 2751, Australia.

Chronic glial activation is characterized by increased numbers of activated glial cells, secreting free radicals and cytotoxic cytokines, subsequently causing neuronal damage. In order to investigate the anti-inflammatory activity of Longvida Optimised Curcumin (LC), we fed 500 ppm of LC to 2-month-old wild type and GFAP-IL6 mice for 6 months. LC feeding led to a significant reduction in the number of Iba-1 microglia by 26% in the hippocampus and by 48% in the cerebellum, GFAP astrocytes by 30%, and TSPO cells by 24% in the hippocampus and by 31% in the cerebellum of the GFAP-IL6 mice. The morphology of the cells was assessed and LC significantly decreased the dendritic length of microglia and the convex area, convex perimeter, dendritic length, nodes and number of processes of astrocytes in the hippocampus while decreasing the soma area and perimeter in the cerebellum, in LC-fed GFAP-IL6 mice. In addition, LC feeding increased pre- and postsynaptic protein levels and improved balance measured by Rotarod. Together, these data suggest that LC is able to attenuate the inflammatory pathology and ameliorate neurodegeneration and motor deficits in GFAP-IL6 mice. For patients with neuro-inflammatory disorders, LC might potentially reverse the detrimental effects of chronic glial activation.
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http://dx.doi.org/10.1038/s41598-020-58838-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012877PMC
February 2020

In search of an anti-inflammatory drug for Alzheimer disease.

Nat Rev Neurol 2020 03;16(3):131-132

Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, Australia.

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http://dx.doi.org/10.1038/s41582-019-0307-9DOI Listing
March 2020

The differential impact of acute microglia activation on the excitability of cholinergic neurons in the mouse medial septum.

Brain Struct Funct 2019 Sep 13;224(7):2297-2309. Epub 2019 Jun 13.

School of Medicine, Western Sydney University, Campbelltown, NSW, 2560, Australia.

The medial septal nucleus is one of the basal forebrain nuclei that projects cholinergic input to the hippocampus and cortex. Two of the hallmarks of Alzheimer's disease (AD) are a significant loss of cholinergic transmission and neuroinflammation, and it has been suggested that these two hallmarks are causally linked to the medial septum. Therefore, we have investigated the age-related susceptibility of medial septal cholinergic neurons to glial activation, mediated via peripheral administration of lipopolysaccharide (500 μg/kg) into ChAT(BAC)-eGFP mice at different ages (3-22 months). Our results show that during normal aging, cholinergic neurons experience a bi-phasic excitability profile, in which increased excitability at adulthood (ages ranging between 9 and 12 months) decreases in aged animals (> 18 months). Moreover, activation of glia had a differential impact on mice from different age groups, affecting K conductances in young and adult animals, without affecting aged mice. These findings provide a potential explanation for the increased vulnerability of cholinergic neurons to neuroinflammation with aging as reported previously, thus providing a link to the impact of acute neuroinflammation in AD.
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http://dx.doi.org/10.1007/s00429-019-01905-wDOI Listing
September 2019

Efficacy of Cognition Support Formula® on cognitive function in older adults with subjective cognitive impairment: a protocol for a 26-week, randomised, double-blind, placebo-controlled trial.

Trials 2019 Jun 10;20(1):345. Epub 2019 Jun 10.

NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia.

Background: Due to an ageing population in Australia there has been an increase in the number of older adults with subjective cognitive impairment (SCI), a self-reported decline in cognitive function associated with an increased risk of mild cognitive impairment and dementia. There is no current, recommended treatment for SCI; therefore, the effectiveness of a supplement approved by the Therapeutic Goods Association that has the potential to enhance cognitive function in an at-risk cohort should be tested. The primary aim of this proposed research is to determine the efficacy of 6 months of treatment with BioCeuticals Cognition Support Formula® (containing Bacopa monniera (brahmi), Ginkgo biloba, Panax ginseng and alpha-lipoic acid) on cognition in older adults with SCI (utilising the CogState® one card learning and identification tests as co-primary outcome measures of visual short-term memory and attention; mean speed (ms), accuracy (%), and total number of hits, misses, and anticipations) compared with placebo. The secondary aims are to assess an improvement in other cognitive domains (executive functioning, processing speed, and working memory), evaluate safety, adverse effects, and determine efficacy on mood, fatigue, and neurocognition. It is expected that improvements across the study timepoints in the co-primary outcomes in the active treatment group (compared with placebo) will be evident.

Method: One-hundred and twenty participants will be recruited for the randomised, double-blind, placebo-controlled study. Participants will be randomly assigned to one of the treatment groups (active or placebo) at a 1:1 ratio, and will be required to complete a series of cognitive (using CogState®), mood (using the Depression, Anxiety, Stress Scale (DASS-42) and Short Health Anxiety Inventory (SHAI)), and fatigue (using the Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F)) tasks at baseline (0 months), the midpoint (3 months), and the endpoint (6 months). These tasks will be evaluated between timepoints (baseline vs. midpoint, midpoint vs. endpoint, and baseline vs. endpoint). Neurocognition will be measured by electroencephalography at baseline and at the endpoint in half of the participants. Adverse effects will be documented over the 6-month trial period.

Discussion: This is the first study to test the efficacy of Cognition Support Formula® on cognition in older adults with SCI. As people with SCI have an increased risk of dementia, and there are limited treatments options for this population, it is important to assess a supplement that has the potential to enhance cognitive function.

Trial Registration: Universal Trial Number (UTN), U1111-1196-9548. Australian New Zealand Clinical Trials Registry, ACTRN12617000945325 . Registered on 30 June 2017.
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http://dx.doi.org/10.1186/s13063-019-3431-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558749PMC
June 2019

A pharmacokinetic assessment of optimal dosing, preparation, and chronotherapy of aspirin in pregnancy.

Am J Obstet Gynecol 2019 09 30;221(3):255.e1-255.e9. Epub 2019 Apr 30.

School of Medicine, Western Sydney University, NSW, Australia; Department of Renal Medicine, South Western Sydney Local Health District, NSW, Australia; Heart Research Institute, University of Sydney, NSW, Australia; Women's Health Initiative Translational Unit (WHITU), South Western Sydney Local Health District, NSW, Australia.

Background: The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin.

Objective: We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non-enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups.

Materials And Methods: Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non-enteric-coated, 150 mg non-enteric-coated morning dosing, and 150 mg non-enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography-mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software.

Results: Pregnant women had a 40% ± 4% reduction in area under the curve from time point 0 to 24 hours (P < .01) and 29% ± 3% reduction in point of maximum concentration (P < .01) with a 44% ± 8% increase in clearance (P < .01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P < .01) in the time of maximum concentration, a 47% ± 3% reduction in point of maximum concentration (P < .01) and a 48% ± 1% increase in volume of distribution (P < .01) with the use of 100 mg enteric-coated aspirin compared to non-enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing.

Conclusion: There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non-enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.
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http://dx.doi.org/10.1016/j.ajog.2019.04.027DOI Listing
September 2019

Chronic Microglial Activation in the GFAP-IL6 Mouse Contributes to Age-Dependent Cerebellar Volume Loss and Impairment in Motor Function.

Front Neurosci 2019 3;13:303. Epub 2019 Apr 3.

Pharmacology Unit, School of Medicine, Western Sydney University, Penrith, NSW, Australia.

Chronic microglial activation is a prominent feature of many chronic neurodegenerative diseases, including Parkinson's and Alzheimer's disease. To investigate the effects of chronic microglial activation on cerebellar structure and motor function throughout the lifespan, the transgenic GFAP-IL6 mouse model was used. The aim of the study was to examine inflammatory markers and neuronal degeneration while simultaneously characterizing the motor performance of GFAP-IL6 mice at 3, 6, 14, and 24 months of age in comparison to WT (C57BL/6) mice. In respect to markers of neuroinflammation in the cerebellum, increased numbers of Iba1 microglia were observed as early as at 3 months of age. In addition, TNF-α levels proved to be significantly higher in the GFAP-IL6 compared to WT mice at all time points. A difference in cerebellar volume between the GFAP-IL6 and WT mice was observed later in life, starting at 6 months and increasing to a loss of about 50% in aged (24 months old) GFAP-IL6 mice. Synaptic deficits were also assessed by using pre- (synaptophysin) and post-synaptic (PSD95) markers. While synaptophysin levels remained unchanged, PSD95 levels decreased in the aging GFAP-IL6 mice compared to their WT littermates from 14 months onward. To assess the effect of microglia activation and neurodegeneration on behavior, a variety of motor function tests, semi-quantitative cerebellar ataxia score, accelerod, beam walking, and open field tests were performed. An age-dependent difference between the genotypes was observed in many of the motor function tests. For example, reduced performance on the accelerod and higher ataxia scores were observed at 6 months of age, followed by the beam walking test showing differences at 14 months of age. In summary, this study constitutes a comprehensive, age-dependent examination of inflammatory, synaptic and neurodegenerative changes in the brains of GFAP-IL6 mice leading to a deterioration in motor performance. The results also indicate that early chronic microglia activation in the GFAP-IL6 mouse leads to observable cerebellar volume loss and motor deficits later in life.
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http://dx.doi.org/10.3389/fnins.2019.00303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456818PMC
April 2019

Hydrogen peroxide mediates pro-inflammatory cell-to-cell signaling: a new therapeutic target for inflammation?

Neural Regen Res 2019 Aug;14(8):1430-1437

Department of Pharmacology, School of Medicine, Western Sydney University, Penrith, NSW, Australia.

Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study, we present proof that hydrogen peroxide - like nitric oxide - acts as a true first (intercellular) messenger for a multitude of pro-inflammatory ligands. RAW 264.7 macrophages were activated with three different ligands, lipopolysaccharide, interferon-gamma or advanced glycation end products in the presence of increasing concentrations of (hydrogen peroxide scavenging) catalase. As inflammatory readouts, nitric oxide and tumor necrosis factor were determined. We hypothesize that hydrogen peroxide travels between cells propagating the signal, then a certain percentage of the readout should be inhibited by catalase in a concentration-dependent manner. The experiment showed concentration-dependent inhibition of nitric oxide and tumor necrosis factor-α production in response to all three ligands/ligand combinations (interferon-gamma, lipopolysaccharide, and chicken egg albumin-derived advanced glycation end product) in the presence of increasing concentration of catalase. For example, catalase inhibited 100% of nitric oxide and 40% of tumor necrosis factor-α production at its highest concentration. Our results suggest that hydrogen peroxide travels through cell membranes into the extracellular space and enters and activates adjacent cells. Like nitric oxide, we suggest that it is a ubiquitous first messenger, able to transmit cell-to-cell pro-inflammatory signals such as nitric oxide and tumor necrosis factor-α. In a therapeutic setting, our data suggest that compounds acting as hydrogen peroxide scavengers might not even need to enter the cell to act as anti-inflammatory drugs.
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http://dx.doi.org/10.4103/1673-5374.253529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524506PMC
August 2019

Targeting Inflammatory Pathways in Alzheimer's Disease: A Focus on Natural Products and Phytomedicines.

CNS Drugs 2019 05;33(5):457-480

Department of Pharmacology, School of Medicine, Western Sydney University, Campbelltown, NSW, 2560, Australia.

Studies of the brains of Alzheimer's disease (AD) patients have revealed key neuropathological features, such as the deposition of aggregates of insoluble amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs). These pathological protein deposits, including Aβ peptides (which form senile plaques) and hyperphosphorylated tau (which aggregates into NFTs), have been assumed to be 'the cause of AD'. Aβ has been extensively targeted to develop an effective disease-modifying therapy, but with limited clinical success. Emerging therapies are also now targeting further pathological processes in AD, including neuroinflammation. This review focuses on the inflammatory and oxidative stress-related changes that occur in AD, and discusses some emerging anti-inflammatory natural products and phytomedicines. Many of the promising compounds are cytokine-suppressive anti-inflammatory drugs (CSAIDs), which target the proinflammatory AP1 and nuclear factor-κB signalling pathways and inhibit the expression of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, tumour necrosis factor-α, or nitric oxide produced by inducible nitric oxide synthase. However, many of these phytomedicines have not been tested in rigorous clinical trials in AD patients. It is not yet clear if the active compounds reach an effective concentration in the brain (due to limited bioavailability) or if they can slow down AD progression in long-term trials. The authors suggest that it is crucial for both the pharmacological and complementary medicine industries to conduct and fund those studies to significantly advance the field.
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http://dx.doi.org/10.1007/s40263-019-00619-1DOI Listing
May 2019

Determination of glyoxal and methylglyoxal in serum by UHPLC coupled with fluorescence detection.

Anal Biochem 2019 05 20;573:51-66. Epub 2019 Feb 20.

Department of Pharmacology, School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia; NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia. Electronic address:

Glyoxal (GO) and methylglyoxal (MGO) are two important biomarkers in diabetes. Analytical methods for determination of GO and MGO in serum samples are either HPLC with UV-Vis (low sensitivity) or MS/MS (expensive) detection. These disadvantages have hampered the introduction of these biomarkers as a routine analyte for diabetes diagnostics into the clinical laboratory. In this study, we introduce a UHPLC method with fluorescence detection for the measurement of GO and MGO in serum samples by pre-column derivatization at neutral pH with 5, 6-diamino-2,4-dihydroxypyrimidine sulfate (DDP) to form lumazines. The method was validated as per FDA guidelines. Using this method, we have determined GO and MGO in a variety of animal serum samples, and for example, determined the GO and MGO concentration in adult bovine serum to be 852 ± 27 and 192 ± 10 nmol/L, respectively. In human serum, GO and MGO levels in non-diabetic subjects (n = 14) were determined to be 154 ± 88 and 98 ± 27 nmol/L, and in serum samples from subjects with diabetes (n = 14) 244 ± 137 and 190 ± 68 nmol/L, respectively. In addition, interference studies showed that physiological serum components did not lead to an artificial increase in the levels of GO and MGO.
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http://dx.doi.org/10.1016/j.ab.2019.02.014DOI Listing
May 2019

Costatamins A - C, new 4-phenylcoumarins with anti-inflammatory activity from the Australian woodland tree Angophora costata (Myrtaceae).

Fitoterapia 2019 Mar 14;133:171-174. Epub 2019 Jan 14.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia.

The bioassay-guided isolation of new anti-inflammatory metabolites from the Australian Indigenous plant Angophora costata led to the discovery of three new 4-phenylcoumarins, costatamins A - C (1-3). The structures were determined by detailed spectroscopic analysis. Costatamins A - C were evaluated for their inhibitory effects on (a) NO production and (b) TNF-α release in RAW 264.7 macrophages, displaying an IC(50) value of 20-30 μg/mL for both the inflammatory markers.
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http://dx.doi.org/10.1016/j.fitote.2019.01.004DOI Listing
March 2019

Assessment of diets containing curcumin, epigallocatechin-3-gallate, docosahexaenoic acid and α-lipoic acid on amyloid load and inflammation in a male transgenic mouse model of Alzheimer's disease: Are combinations more effective?

Neurobiol Dis 2019 04 2;124:505-519. Epub 2019 Jan 2.

School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia; Molecular Medicine Research Group, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia; National Institute of Complementary Medicine, University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia. Electronic address:

Increasingly, evidence is accumulating pointing at a protective role of a healthy diet at decreasing the risk of Alzheimer's disease. To test the effectiveness of nutritional components, the following food-derived compounds: curcumin alone (curcumin), curcumin combined with (-)epigallocatechin-3-gallate (EGCG), docosahexaenoic acid (DHA) and α-lipoic acid (ALA) (curcumin + EDA), or a combination of EGCG, DHA and ALA (EDA) were assessed in male Tg2576 transgenic mice on amyloid plaque load, amyloid levels (Aβ40/Aβ42, but not oligomers due to tissue limitations), microglial activation and memory using the contextual and cued fear conditioning test. The combination diet EDA, resulted in the strongest reduction of amyloid plaque load in both the cortical (p < .0001) and hippocampal (p < .0001) areas of the Tg2576 mouse brain, along with lower Aβ/Aβ levels in the frontal cortex (p = .000129 and p = .000039, respectively) and Aβ levels in the temporal lobe (p = .000082). A curcumin only diet was shown to lower amyloid plaque load (p = .028), but when combined with EGCG, DHA and ALA did not result in further decreases in amyloid plaque load. The EDA combination group showed the most prominent decrease in microglial activation (number of microglia around plaques: p < .05 and p < .0001, respectively, for the cortex and hippocampus). Analysing the hippocampal associated contextual fear conditioning revealed that both the curcumin+EDA (p < .0001) and EDA groups (p = .001) spent increased time on freezing compared to the control group. In addition, the curcumin+EDA group showed a significant increase in time spent freezing compared with the curcumin only group. In the amygdala associated cued test, all mice demonstrated the ability to associate the conditioned stimulus with the unconditioned stimulus as evidenced by a significant increase in freezing behaviour in response to the presentation of the cue (p < .0001). Post-hoc analysis showed that only curcumin+EDA (p < .0001) and EDA groups (p < .0001) developed a significant increase in freezing during the cue presentation. The results from this study show that the combination of EGCG, DHA and ALA (EDA) appeared to have the most potent anti-inflammatory and neuroprotective effect. Our results also demonstrate that interactions between nutraceutical products might result in counterproductive outcomes, highlighting the fact that manufacturers of nutraceuticals containing multiple compounds should be careful not to claim additive or synergistic effects of their combination products in vivo without having tested it in animal models and/or human clinical trials.
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http://dx.doi.org/10.1016/j.nbd.2018.11.026DOI Listing
April 2019

Investigation Into the Effects of Tenilsetam on Markers of Neuroinflammation in GFAP-IL6 Mice.

Pharm Res 2018 01 5;35(1):22. Epub 2018 Jan 5.

Department of Pharmacology, School of Medicine, Western Sydney University, Building 30, Goldsmith Ave, Campbelltown, NSW, 2560, Australia.

Purpose: To test the short- and long-term effects of Tenilsetam on chronic neuroinflammation in the GFAP-IL6 mouse.

Methods: From 3 months of age, GFAP-IL6 mice were divided into 2 groups and fed with Tenilsetam enriched food pellets or control food pellets, respectively, for either 5 or 15 months. Total numbers of Iba-1 microglia, TSPO cells were determined using an unbiased stereological method. Levels of methylglyoxal and TNF-α in the cerebellar homogenate were tested using HPLC and ELISA, respectively.

Results: Tenilsetam decreased the total number of Iba-1 microglia in both the cerebellum and the hippocampus of GFAP-IL6 mice at 8 months and in the cerebellum at 18 months. In the cerebellum, it decreased the density of microglia in GFAP-IL6 mice to a similar level after 5 and 15 months' feeding. Tenilsetam prevented the volume loss of the cerebellum at 8 months. It also significantly decreased TNF-α in the cerebellum of GFAP-IL6 mice to a similar level of WT mice after 15 months of feeding.

Conclusion: Tenilsetam has anti-inflammatory effects evidenced by the decreased number of microglia in both the cerebellum and hippocampus, and decreased TNF-α levels in the GFAP-IL6 Tenilsetam fed animals.
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http://dx.doi.org/10.1007/s11095-017-2326-9DOI Listing
January 2018

The Effects of Different Isocaloric Oral Nutrient Solutions on Psychophysical, Metabolic, Cognitive, and Olfactory Function in Young Male Subjects.

Front Psychol 2017 23;8:1988. Epub 2017 Nov 23.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen Nürnberg, Erlangen, Germany.

Food intake influences human cognition, olfaction, hunger, and food craving. However, little research has been done in this field to elucidate the effects of different nutrients. Thus, the goal of our study was to investigate the effects of oral ingestion of different nutrient solutions on olfactory, cognitive, metabolic and psychophysical function. Twenty healthy men participated in our study employing a double-blind, cross-over, repeated measurement design. Participants were tested on four different study days. Each day participants received, in randomized order, one of three isocaloric (protein, carbohydrate or fat 600 kcal, 1,500 mL) solutions or a placebo. Olfactory and cognitive tests (monitoring only) were conducted three times, i.e., 60 min before the beginning of nutrient intake, following oral ingestion of the solution and 60, and 240 min after. Psychophysical and metabolic function tests (active grehlin, desacyl ghrelin, insulin, glucagon, glucose, triglyceride, urea) were performed 7 times on each examination day (observation period: -60 min, 0 = solution intake, +60, +120, +180, +240, and +300 min). Ratings of hunger and food craving significantly differed over the observation period with lowest ratings following application of the protein solution. Highest ratings of craving were found following placebo intake. We further observed a significant positive correlation of active grehlin with hunger and fat, protein and sweets craving for each nutrient solution. Active grehlin significantly correlated with carbohydrate craving for carbohydrate and fat solution and with vegetable craving for fat solution only. Hunger hormone levels, hunger and food craving ratings demonstrated that the hierarchical order that appears in satiating efficiencies of isovolumetric-isocaloric ingested macronutrients is protein > fat > carbohydrate. Our study reveals that the type of nutrient exerts a significant influence on metabolic parameters, hunger and food craving.
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http://dx.doi.org/10.3389/fpsyg.2017.01988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704390PMC
November 2017

The Effects of a Normal Rate versus a Slow Intervalled Rate of Oral Nutrient Intake and Intravenous Low Rate Macronutrient Application on Psychophysical Function - Two Pilot Studies.

Front Psychol 2017 28;8:1031. Epub 2017 Jun 28.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-NürnbergErlangen, Germany.

Stomach distension and energy per time are factors influencing satiety. Moreover, different rates of nutrient intake induce different stomach distension. The goal of our studies was to elucidate the influence of different oral rates of nutrient intake (normal rate versus slow intervalled rate; study I) and intravenous low rate macronutrient application (protein, carbohydrate, fat) or placebo (study II) on psychophysical function. The pilot studies investigated the effects of 1) study I: a mixed nutrient solution (1/3 protein, 1/3 fat, 1/3 carbohydrates) 2) study II: intravenous macronutrient infusions (protein, carbohydrate, fat) or placebo on psychophysical function (mood, hunger, food craving, alertness, smell intensity ratings and hedonic ratings) in human subjects. In study I 10 male subjects (age range: 21-30 years) completed the study protocol participating in both test conditions and in study II 20 male subjects (age range: 19-41 years) completed the study protocol participating in all test conditions. Additionally, metabolic function was analyzed and cognitive and olfactory tests were conducted twice starting 100 min before the beginning of the intervention and 240 min after. Psychophysical (mood, hunger, fat-, protein-, carbohydrate-, sweets- and vegetable-craving), alertness and metabolic function tests were performed seven times on each examination day. Greater effects on hunger and food cravings were observed for normal rate of intake compared to slow intervalled rate of intake and intravenous low rate macronutrient application. Our findings potentially confirm that volume of the food ingested and a higher rate of energy per time contribute to satiety during normal rate of food intake, while slow intervalled rate of food intake and intravenous low rate macronutrient application showed no effects on satiation. Our results motivate the view that a certain amount of volume of the food ingested and a certain energy per time ratio are necessary to reduce hunger and food craving.
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http://dx.doi.org/10.3389/fpsyg.2017.01031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487446PMC
June 2017

Activation of Macrophages and Microglia by Interferon-γ and Lipopolysaccharide Increases Methylglyoxal Production: A New Mechanism in the Development of Vascular Complications and Cognitive Decline in Type 2 Diabetes Mellitus?

J Alzheimers Dis 2017 ;59(2):467-479

Department of Pharmacology, School of Medicine, Western Sydney University, Penrith, NSW, Australia.

Methylglyoxal (MGO), a dicarbonyl compound derived from glucose, is elevated in diabetes mellitus and contributes to vascular complications by crosslinking collagen and increasing arterial stiffness. It is known that MGO contributes to inflammation as it forms advanced glycation end products (AGEs), which activate macrophages via the receptor RAGE. The aim of study was to investigate whether inflammatory activation can increase MGO levels, thereby completing a vicious cycle. In order to validate this, macrophage (RAW264.7, J774A.1) and microglial (N11) cells were stimulated with IFN-γ and LPS (5 + 5 and 10 + 10 IFN-γ U/ml or μg/ml LPS), and extracellular MGO concentration was determined after derivatization with 5,6-Diamino-2,4-dihydroxypyrimidine sulfate by HPLC. MGO levels in activated macrophage cells (RAW264.7) peaked at 48 h, increasing 2.86-fold (3.14±0.4 μM) at 5 U/ml IFN-γ+5 μg/ml LPS, and 4.74-fold (5.46±0.30 μM) at 10 U/ml IFN-γ+10 μg/ml LPS compared to the non-activated controls (1.15±0.02 μM). The other two cell lines, J774A.1 macrophages and N11 microglia, showed a similar response. We suggest that inflammation increases MGO production, possibly exacerbating arterial stiffness, cardiovascular complications, and diabetes-related cognitive decline.
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http://dx.doi.org/10.3233/JAD-161152DOI Listing
April 2018

Analysis of different innovative formulations of curcumin for improved relative oral bioavailability in human subjects.

Eur J Nutr 2018 Apr 16;57(3):929-938. Epub 2017 Feb 16.

National Institute of Complementary Medicine, Western Sydney University, Campbelltown, NSW, 2560, Australia.

Purpose: The optimal health benefits of curcumin are limited by its low solubility in water and corresponding poor intestinal absorption. Cyclodextrins (CD) can form inclusion complexes on a molecular basis with lipophilic compounds, thereby improving aqueous solubility, dispersibility, and absorption. In this study, we investigated the bioavailability of a new γ-cyclodextrin curcumin formulation (CW8). This formulation was compared to a standardized unformulated curcumin extract (StdC) and two commercially available formulations with purported increased bioavailability: a curcumin phytosome formulation (CSL) and a formulation of curcumin with essential oils of turmeric extracted from the rhizome (CEO).

Methods: Twelve healthy human volunteers participated in a double-blinded, cross-over study. The plasma concentrations of the individual curcuminoids that are present in turmeric (namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were determined at baseline and at various intervals after oral administration over a 12-h period.

Results: CW8 showed the highest plasma concentrations of curcumin, demethoxycurcumin, and total curcuminoids, whereas CSL administration resulted in the highest levels of bisdemethoxycurcumin. CW8 (39-fold) showed significantly increased relative bioavailability of total curcuminoids (AUC) in comparison with the unformulated StdC.

Conclusion: The data presented suggest that γ-cyclodextrin curcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.
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http://dx.doi.org/10.1007/s00394-016-1376-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861163PMC
April 2018

High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation.

Arch Toxicol 2017 Apr 15;91(4):1623-1634. Epub 2017 Feb 15.

Department of Pharmacology, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia.

Neuroinflammation is a pathophysiological process present in a number of neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, traumatic brain injury including chronic traumatic encephalopathy and other age-related CNS disorders. Although there is still much debate about the initial trigger for some of these neurodegenerative disorders, during the progression of disease, broad range anti-inflammatory drugs including cytokine suppressive anti-inflammatory drugs (CSAIDs) might be promising therapeutic options to limit neuroinflammation and improve the clinical outcome. One of the most promising CSAIDs is curcumin, which modulates the activity of several transcription factors (e.g., STAT, NF-κB, AP-1) and their pro-inflammatory molecular signaling pathways. However, normal curcumin preparations demonstrate low bioavailability in vivo. To increase bioavailability, preparations of high bioavailability curcumin have been introduced to achieve therapeutically relevant concentrations in target tissues. This literature review aims to summarize the pharmacokinetic and toxicity profile of different curcumin formulations.
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http://dx.doi.org/10.1007/s00204-017-1939-4DOI Listing
April 2017

Medicinal Plants of the Australian Aboriginal Dharawal People Exhibiting Anti-Inflammatory Activity.

Evid Based Complement Alternat Med 2016 27;2016:2935403. Epub 2016 Dec 27.

Department of Pharmacology, School of Medicine, Western Sydney University, Sydney, NSW, Australia.

Chronic inflammation contributes to multiple ageing-related musculoskeletal and neurodegenerative diseases, cardiovascular diseases, asthma, rheumatoid arthritis, and inflammatory bowel disease. More recently, chronic neuroinflammation has been attributed to Parkinson's and Alzheimer's disease and autism-spectrum and obsessive-compulsive disorders. To date, pharmacotherapy of inflammatory conditions is based mainly on nonsteroidal anti-inflammatory drugs which in contrast to cytokine-suppressive anti-inflammatory drugs do not influence the production of cytokines such as tumour necrosis factor- or nitric oxide. However, their prolonged use can cause gastrointestinal toxicity and promote adverse events such as high blood pressure, congestive heart failure, and thrombosis. Hence, there is a critical need to develop novel and safer nonsteroidal anti-inflammatory drugs possessing alternate mechanism of action. In this study, plants used by the Dharawal Aboriginal people in Australia for the treatment of inflammatory conditions, for example, asthma, arthritis, rheumatism, fever, oedema, eye inflammation, and inflammation of bladder and related inflammatory diseases, were evaluated for their anti-inflammatory activity in vitro. Ethanolic extracts from 17 spp. (Myrtaceae) were assessed for their capacity to inhibit nitric oxide and tumor necrosis factor- production in RAW 264.7 macrophages. showed the most potent nitric oxide inhibitory effect (IC  5.57 ± 1.4 g/mL), whilst exhibited nitric oxide inhibition values between 7.58 and 19.77 g/mL.
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http://dx.doi.org/10.1155/2016/2935403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223016PMC
December 2016

Anti-Inflammatory Chemical Profiling of the Australian Rainforest Tree Alphitonia petriei (Rhamnaceae).

Molecules 2016 Nov 11;21(11). Epub 2016 Nov 11.

School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.

Chronic inflammation is an important pathological condition in many human diseases, and due to the side effects of the currently used non-steroidal anti-inflammatory drugs, discovery of novel anti-inflammatory drugs is of general interest. Anti-inflammatory activity guided compound isolation from the plant led to the isolation of the known plant sterols emmolic acid (), alphitolic acid (), and -coumaroyl esters of alphitolic acid ( and ) and betulinic acid (). A detailed spectroscopic analysis led to the structure elucidation of the alphitolic acid derivatives (-), and the semi-synthetic emmolic acid acetate (). When tested in LPS (Lipopolysaccharides) + IFN-γ (Interferon gamma) activated RAW 264.7 macrophages, all compounds except () exhibited potent anti-inflammatory activity (IC values as low as 1.7 μM) in terms of downregulation of NO and TNF-α production, but also demonstrated some considerable cytotoxicity.
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http://dx.doi.org/10.3390/molecules21111521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273140PMC
November 2016

Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer's disease.

Sci Rep 2016 08 12;6:31450. Epub 2016 Aug 12.

Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, yet current therapeutic treatments are inadequate due to a complex disease pathogenesis. The plant polyphenol apigenin has been shown to have anti-inflammatory and neuroprotective properties in a number of cell and animal models; however a comprehensive assessment has not been performed in a human model of AD. Here we have used a human induced pluripotent stem cell (iPSC) model of familial and sporadic AD, in addition to healthy controls, to assess the neuroprotective activity of apigenin. The iPSC-derived AD neurons demonstrated a hyper-excitable calcium signalling phenotype, elevated levels of nitrite, increased cytotoxicity and apoptosis, reduced neurite length and increased susceptibility to inflammatory stress challenge from activated murine microglia, in comparison to control neurons. We identified that apigenin has potent anti-inflammatory properties with the ability to protect neurites and cell viability by promoting a global down-regulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition, we show that apigenin is able to protect iPSC-derived AD neurons via multiple means by reducing the frequency of spontaneous Ca(2+) signals and significantly reducing caspase-3/7 mediated apoptosis. These data demonstrate the broad neuroprotective action of apigenin against AD pathogenesis in a human disease model.
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http://dx.doi.org/10.1038/srep31450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981845PMC
August 2016

Revelation of molecular basis for chromium toxicity by phenotypes of Saccharomyces cerevisiae gene deletion mutants.

Metallomics 2016 05;8(5):542-50

School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. and Department of Pharmacology, School of Medicine and Molecular Medicine Research Group, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.

Chromium toxicity is increasingly relevant to living organisms such as humans, due to the environmental contamination of chromium and the application of stainless steel-based medical devices like hip prostheses. Despite the investigations in past years, the molecular details for chromium toxicity remain to be delineated. In this study, we seek to gain insights into the molecular aspects of chromium toxicity by screening a genome-wide deletion set of individual genes in Saccharomyces cerevisiae against hexavalent chromium [Cr(vi)] using chromium trioxide. From the primary data collected in this study, two lists of deletion mutants in response to Cr(vi) exposure were obtained, one for the sensitive phenotype and the other for the resistant phenotype. The functional analysis of the genes corresponding to the sensitive mutants reveals the key features of Cr(vi) toxicity, which include genotoxicity, protein damage, disruption of energy and sulfur metabolisms. DNA repair, ubiquitination-mediated protein degradation, iron homeostasis and growth attenuation are the intrinsic facets of the cell's detoxification mechanisms. Protein kinase CK2 is, for the first time, found to be involved in regulating chromium toxicity by reducing the uptake of Cr(vi). Taken together, the findings provide meaningful details into the basic understanding of chromium toxicity in terms of its uptake, modes of action, cellular detoxification and molecular regulatory mechanisms.
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http://dx.doi.org/10.1039/c6mt00039hDOI Listing
May 2016