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1.
J Nat Prod ; 87(7): 1817-1825, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-38964296

ABSTRACT

Our ongoing exploration of Australian rainforest plants for the biodiscovery of anti-inflammatory agents led to the isolation and structural elucidation of eight new arylalkenyl α,ß-unsaturated-δ-lactones, triplinones A-H (1-8), from the leaves of the Australian rainforest plant Cryptocarya triplinervis B. Hyland (Lauraceae). The chemical structures of these compounds were established by NMR spectroscopic data analysis, while their relative and absolute configurations were established using a combination of Mosher ester analysis utilizing both Riguera's and Kishi's methods, ECD experiments, and X-ray crystallography analysis. Compounds 1-8 exhibited good inhibitory activities toward nitric oxide (NO) production in lipopolysaccharide (LPS) and interferon (IFN)-γ induced RAW 264.7 macrophages, in particular compounds 1-3 and 5, with IC50 values of 7.3 ± 0.5, 6.0 ± 0.3, 5.6 ± 0.3, and 5.4 ± 2.5 µM, respectively.


Subject(s)
Anti-Inflammatory Agents , Cryptocarya , Lactones , Nitric Oxide , Plant Leaves , Rainforest , Plant Leaves/chemistry , Mice , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Australia , RAW 264.7 Cells , Molecular Structure , Lactones/pharmacology , Lactones/chemistry , Lactones/isolation & purification , Nitric Oxide/biosynthesis , Nitric Oxide/antagonists & inhibitors , Cryptocarya/chemistry , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Crystallography, X-Ray
2.
Chem Biodivers ; 21(7): e202400492, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38700281

ABSTRACT

Inflammation represents the inherent protective reaction of the human body to various harmful agents and noxious stimuli. Standard anti-inflammatory therapy including nonsteroidal anti-inflammatory drugs are associated with several side effects. In the past decades, people rely on medicinal plants for the treatment of inflammation. The traditional utilization of medicinal plants is regarded as a safe, cost-effective, and broadly accepted approach. In this study, anti-inflammatory activity of plants traditionally utilized by the D'harawal people in Australia has been assessed in vitro. Eighty Australian native plants were screened based on the Dharawal Pharmacopeia for their inhibitory effect on the nitric oxide (NO) production in lipopolysaccharides (LPS) and interferon (IFN)-γ stimulated RAW 264.7 murine macrophages for their anti-inflammatory activity. From the eighty ethanolic extracts screened, seventeen displayed potent NO inhibition with an IC50 recorded below 15 µg/mL. The aim of this review was to utilise the ethnopharmacological knowledge and to correlate the anti-inflammatory activity of the seventeen plants with either their known or unknown phytochemicals reported in the literature. In doing so, we have created a snapshot of Australian native plant candidates that warrant further chemical investigation associated with their anti-inflammatory activity.


Subject(s)
Anti-Inflammatory Agents , Lipopolysaccharides , Nitric Oxide , Plant Extracts , Plants, Medicinal , Mice , Australia , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/metabolism , Animals , RAW 264.7 Cells , Plants, Medicinal/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/isolation & purification , Humans , Ethnopharmacology , Macrophages/drug effects , Macrophages/metabolism , Interferon-gamma/metabolism
3.
Fitoterapia ; 173: 105815, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38168569

ABSTRACT

Anti-inflammatory bioassay-guided compound isolation from the exocarp of the Australian rainforest tree Endiandra insignis (family Lauraceae) has led to the discovery and structural elucidation of unusual α, ß-unsaturated twenty-four carbon fatty acids and their positional isomers, insignoic acids A - E (1a - 5c). The stereochemistry and position of the double bond within the aliphatic chain were independently determined via NMR spectroscopy and Ozone-Induced Dissociation (OzID) Mass Spectrometry, respectively. Compounds (1a - 5c) displayed good to moderate anti-inflammatory activity in the range of 8-84 µM. The low therapeutic index observed when assessing the cell viability in the RAW macrophage cell lines, prompted us to investigate the anticancer potential of these unusual fatty acids. The anti-cancer activity was assessed in A-431 carinoma cell lines and MM649 melanoma cell lines. Insignoic acid C (3a-f) exhibited the highest level of potency with an IC50 value of 5-7 µM against both the cell lines. The insignoic acids are the first of their kind known for incorporating an alpha-beta unsaturated system flanked next to a keto group with an additional level of oxygenation at C-6 in a 24­carbon fatty acid backbone.


Subject(s)
Lauraceae , Trees , Molecular Structure , Rainforest , Australia , Fatty Acids, Unsaturated , Fatty Acids , Anti-Inflammatory Agents , Carbon
4.
Int J Mol Sci ; 24(13)2023 Jul 04.
Article in English | MEDLINE | ID: mdl-37446262

ABSTRACT

The Australian rainforest is a rich source of medicinal plants that have evolved in the face of dramatic environmental challenges over a million years due to its prolonged geographical isolation from other continents. The rainforest consists of an inherent richness of plant secondary metabolites that are the most intense in the rainforest. The search for more potent and more bioavailable compounds from other plant sources is ongoing, and our short review will outline the pathways from the discovery of bioactive plants to the structural identification of active compounds, testing for potency, and then neuroprotection in a triculture system, and finally, the validation in an appropriate neuro-inflammatory mouse model, using some examples from our current research. We will focus on neuroinflammation as a potential treatment target for neurodegenerative diseases including multiple sclerosis (MS), Parkinson's (PD), and Alzheimer's disease (AD) for these plant-derived, anti-inflammatory molecules and highlight cytokine suppressive anti-inflammatory drugs (CSAIDs) as a better alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) to treat neuroinflammatory disorders.


Subject(s)
Neurodegenerative Diseases , Neuroprotective Agents , Animals , Mice , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Neuroprotective Agents/chemistry , Australia , Neurodegenerative Diseases/drug therapy , Brain , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
5.
Nat Prod Res ; : 1-8, 2023 Jul 28.
Article in English | MEDLINE | ID: mdl-37505279

ABSTRACT

Phytochemical investigation of the leaves of Polyscias australiana (F.Muell.) Philipson (family Araliaceae) led to the isolation and identification of two new analogues belonging to the rare dammarane-type triterpene glycosides, polysciasosides B (1) and C (2). Also isolated in high yields from this plant was the known saponin, ß-hedrin (3). The two new polysciasoside analogues exhibited no anti-inflammatory activity (inhibitory effects on NO inhibition and cell viability in RAW 264.7 macrophages) or cytotoxic activity against AGS gastric adenocarcinoma or the MCF7 breast adenocarcinoma cell lines. In contrast, the known compound ß-hedrin exhibited potent anti-inflammatory and cytotoxicity in these biological assays.

6.
Int J Mol Sci ; 24(7)2023 Apr 06.
Article in English | MEDLINE | ID: mdl-37047821

ABSTRACT

Identification of bioactive natural products from plants starts with the screening of extracts for a desired bioactivity such as antimicrobial, antifungal, anti-cancer, anti-inflammatory, or neuroprotective. When the bioactivity shows sufficient potency, the plant material is subjected to bio-activity-guided fractionation, which involves, e.g., sequential extraction followed by chromatographic separation, including HPLC. The bioactive compounds are then structurally identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR). One of the questions that come up during the purification process is how much of the bioactivity originally present in the crude extract is preserved during the purification process. If this is the case, it is interesting to investigate if the loss of total bioactivity is caused by the loss of material during purification or by the degradation or evaporation of potent compounds. A further possibility would be the loss of synergy between compounds present in the mixture, which disappears when the compounds are separated. In this publication, a novel formula is introduced that allows researchers to calculate total bioactivity in biological samples using experimental data from our research into the discovery of anti-inflammatory compounds from Backhousia myrtifolia (Grey Myrtle). The results presented show that a raw ethanolic extract retains slightly more bioactivity than the sum of all sequential extracts per gram of starting material and that-despite a large loss of material during HPLC purification-the total bioactivity in all purified fractions is retained, which is indicative of rather an additive than a synergistic principle.


Subject(s)
Anti-Infective Agents , Biological Products , Plant Extracts/chemistry , Biological Products/chemistry , Plants , Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents/pharmacology
7.
Molecules ; 28(5)2023 Feb 25.
Article in English | MEDLINE | ID: mdl-36903406

ABSTRACT

Our in-house ethnopharmacological knowledge directed our anti-inflammatory investigation into the leaves of Backhousia mytifolia. Bioassay guided isolation of the Australian indigenous plant Backhousia myrtifolia led to the isolation of six new rare peltogynoid derivatives named myrtinols A-F (1-6) along with three known compounds 4-O-methylcedrusin (7), 7-O-methylcedrusin (8) and 8-demethylsideroxylin (9). The chemical structures of all the compounds were elucidated by detailed spectroscopic data analysis, and absolute configuration was established using X-ray crystallography analysis. All compounds were evaluated for their anti-inflammatory activity by assessing the inhibition of nitric oxide (NO) production and tumor necrosis factor- α (TNF-α) in lipopolysaccharide (LPS) and interferon (IFN)-γ activated RAW 264.7 macrophages. A structure activity relationship was also established between compounds (1-6), noting promising anti-inflammatory potential by compounds 5 and 9 with an IC50 value of 8.51 ± 0.47 and 8.30 ± 0.96 µg/mL for NO inhibition and 17.21 ± 0.22 and 46.79 ± 5.87 µg/mL for TNF-α inhibition, respectively.


Subject(s)
Flavonoids , Tumor Necrosis Factor-alpha , Animals , Mice , Flavonoids/pharmacology , Plant Extracts/chemistry , Australia , Anti-Inflammatory Agents/pharmacology , Nitric Oxide , Lipopolysaccharides/pharmacology , Plant Leaves/chemistry , RAW 264.7 Cells
8.
Nat Prod Res ; 37(14): 2421-2426, 2023 Jul.
Article in English | MEDLINE | ID: mdl-35142583

ABSTRACT

A detailed close phytochemical investigation of the fruits of Ternstroemia cherryi led to the isolation and identification of the minor metabolite, ternstroenol F, which possessed the usual barrigenol-like terpenoid backbone. The notable difference was that this minor metabolite had the 2(E)-4(Z)-6(E)-decatrienoic acid forming an ester bond at C-22 of the oleanane backbone. Ternstroenol F was evaluated for its inhibitory effects on NO inhibition, cell viability and TNF- α release in RAW 264.7 macrophages, displaying an IC50 values of 0.23, 0.81 and 1.84 µM respectively.


Subject(s)
Ericales , Saponins , Triterpenes , Australia , Molecular Structure , Plant Extracts/chemistry , Rainforest , Saponins/pharmacology , Saponins/chemistry , Triterpenes/pharmacology , Triterpenes/chemistry , Tumor Necrosis Factor-alpha
9.
Planta Med ; 89(1): 30-45, 2023 Jan.
Article in English | MEDLINE | ID: mdl-35764305

ABSTRACT

Various age-related chronic diseases have been linked to oxidative stress. The cellular antioxidant response pathway is regulated by the transcription factor nuclear erythroid factor 2. Therefore, plant-derived nuclear erythroid factor 2 activators might be useful therapeutics to stimulate the body's defense mechanisms. Our study focused on the discovery of potent nuclear erythroid factor 2 activators from medicinal plants. Initially, a variety of medicinal plant extracts were screened for nuclear erythroid factor 2 activity using a nuclear erythroid factor 2 luciferase reporter cell line. Among these, Valerian (Valeriana officinalis) root was identified as a potent candidate. Sequential extraction and bioassay-guided fractionation led to the isolation of four nuclear erythroid factor 2-active compounds, which were structurally identified by NMR and LC/HRMS as the known compounds isovaltrate, valtrate, jatamanvaltrate-P, and valerenic acid. These four compounds were then tested in relevant biological assays. Firstly, their effects on the expression of glutathione S-transferase, glutamate-cysteine ligase catalytic subunit, glutathione peroxidase, and heme oxygenase 1 were determined in HepG2 cells. Glutathione S-transferase P1 and glutamate-cysteine ligase catalytic subunit were upregulated by isovaltrate, valtrate, and jatamanvaltrate-P, while heme oxygenase 1 was upregulated by isovaltrate, jatamanvaltrate-P, and valerenic acid. The four compounds also increased the levels of glutathione and its metabolite, CysGly. As glutathione aids in the detoxification of hydrogen peroxide, cytoprotective effects of these four nuclear erythroid factor 2 activators against hydrogen peroxide toxicity were investigated, and indeed, the compounds significantly improved cell survival. This study provides evidence that four valepotriates from the roots of V. officinalis are activators of nuclear erythroid factor 2-mediated antioxidant and detoxification pathways. Our data might expand the medical use of this plant beyond its current application as a sleep aid.


Subject(s)
Antioxidants , Valerian , Antioxidants/chemistry , NF-E2-Related Factor 2/metabolism , Valerian/chemistry , Glutamate-Cysteine Ligase/metabolism , Glutamate-Cysteine Ligase/pharmacology , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/pharmacology , Hydrogen Peroxide/pharmacology , Oxidative Stress , Glutathione/metabolism
10.
Molecules ; 27(19)2022 Oct 05.
Article in English | MEDLINE | ID: mdl-36235129

ABSTRACT

Inspired by ethnopharmacological knowledge, we conducted a bioassay-guided fractionation of the leaves of Tristaniopsis laurina which led to the discovery of a new anti-inflammatory compound, tristaenone A (1). The structure was elucidated by detailed spectroscopic data analysis, and the absolute configuration was established using X-ray crystallography analysis. Tristaenone A (1) suppressed LPS and IFN-γ-induced NO, TNF-α and IL-6 production in RAW 264.7 cells with IC50 values of 37.58 ± 2.45 µM, 80.6 ± 5.82 µM and 125.65 ± 0.34 µM, respectively. It also inhibited NF-κB nuclear translocation by 52.93 ± 14.14% at a concentration of 31.85 µM.


Subject(s)
Lipopolysaccharides , NF-kappa B , Animals , Anti-Inflammatory Agents/pharmacology , Australia , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Mice , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 Cells , Tumor Necrosis Factor-alpha/metabolism
11.
Fitoterapia ; 162: 105266, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35961598

ABSTRACT

Phytochemical investigation of the leaves of the Australian rainforest tree Cryptocarya mackinnoniana led to the discovery of three new oxygenated phenyl alkyl acids, cryptocaryoic acids A - C and two known compounds, cryptocaryone and 2',6'-dihydroxy-4'-methoxychalcone. The structures of all the compounds were determined by detailed spectroscopic analysis. Mosher's analysis was used for absolute stereochemistry determination at C-11, while the remaining stereochemistry determination of the one remaining stereocenter C-13 was based on NOESY correlations. All compounds isolated were also evaluated for their anti-inflammatory properties by assessing their inhibitory effects on LPS and interferon-γ induced nitric oxide (NO) production and TNF- α release in RAW 264.7 macrophages. The new cryptocaryoic acids exhibited weak to moderate anti-inflammatory activity (NO inhibition) ranging from (18.4-56 µM).


Subject(s)
Cryptocarya , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Australia , Cryptocarya/chemistry , Interferon-gamma , Lipopolysaccharides/pharmacology , Molecular Structure , Nitric Oxide , Plant Leaves/chemistry , Rainforest , Tumor Necrosis Factor-alpha
12.
J Neural Transm (Vienna) ; 129(5-6): 755-771, 2022 06.
Article in English | MEDLINE | ID: mdl-35294663

ABSTRACT

Prof. Dr. Peter Riederer, the former Head of the Neurochemistry Department of the Psychiatry and Psychotherapy Clinic at the University of Würzburg (Germany), has been one of the pioneers of research into oxidative stress in Parkinson's and Alzheimer's disease (AD). This review will outline how his scientific contribution to the field has opened a new direction for AD treatment beyond "plaques and tangles". In the 1990s, Prof. Riederer was one of the first scientists who proposed oxidative stress and neuroinflammation as one of the major contributors to Alzheimer's disease, despite the overwhelming support for the "amyloid-only" hypothesis at the time, which postulated that the sole and only cause of AD is ß-amyloid. His group also highlighted the role of advanced glycation end products, sugar and dicarbonyl-derived protein modifications, which crosslink proteins into insoluble aggregates and potent pro-inflammatory activators of microglia. For the treatment of chronic neuroinflammation, he and his group suggested that the most appropriate drug class would be cytokine-suppressive anti-inflammatory drugs (CSAIDs) which have a broader anti-inflammatory action range than conventional non-steroidal anti-inflammatory drugs. One of the most potent CSAIDs is curcumin, but it suffers from a variety of pharmacokinetic disadvantages including low bioavailability, which might have tainted many human clinical trials. Although a variety of oral formulations with increased bioavailability have been developed, curcumin's absorption after oral delivery is too low to reach therapeutic concentrations in the micromolar range in the systemic circulation and the brain. This review will conclude with evidence that rectally applied suppositories might be the best alternatives to oral medications, as this route will be able to evade first-pass metabolism in the liver and achieve high concentrations of curcumin in plasma and tissues, including the brain.


Subject(s)
Alzheimer Disease , Anti-Inflammatory Agents , Curcumin , Neuroinflammatory Diseases , Alzheimer Disease/drug therapy , Amyloid beta-Peptides , Anti-Inflammatory Agents/therapeutic use , Curcumin/therapeutic use , Cytokines , Humans , Neuroinflammatory Diseases/drug therapy
13.
Nat Prod Res ; 36(17): 4364-4370, 2022 Sep.
Article in English | MEDLINE | ID: mdl-34612780

ABSTRACT

Two new phloroglucinols, acronyols A (1) and B (2) along with the four known (3-6) pholoroglucinols were identified following anti-inflammatory activity guided fractionation from the fruits of Acronychia crassipetala (family Rutaceae). The pholoroglucinols (1-6) were evaluated for their inhibitory effects on NO production and downregulation of TNF-α in RAW 264.7 macrophage cell lines.


Subject(s)
Fruit , Rutaceae , Animals , Anti-Inflammatory Agents/pharmacology , Mice , Phloroglucinol/pharmacology , RAW 264.7 Cells
14.
Fitoterapia ; 153: 104972, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34147546

ABSTRACT

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-ß-xylopyranosyl-1(1 â†’ 6)-O-ß-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.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Lignans/pharmacology , Magnoliopsida/chemistry , Animals , Anti-Inflammatory Agents/isolation & purification , Lignans/isolation & purification , Macrophages/drug effects , Mice , Molecular Structure , Nitric Oxide , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plant Leaves/chemistry , Queensland , RAW 264.7 Cells , Tumor Necrosis Factor-alpha
15.
Fitoterapia ; 150: 104843, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33539940

ABSTRACT

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 IC50 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.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Flavonoids/pharmacology , Myrtaceae/chemistry , Animals , Anti-Inflammatory Agents/isolation & purification , Australia , Flavonoids/isolation & purification , Macrophages/drug effects , Mice , Microglia/drug effects , Molecular Structure , Nitric Oxide/metabolism , Phosphorylation , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plant Leaves/chemistry , Plants, Medicinal/chemistry , RAW 264.7 Cells , Signal Transduction/drug effects
16.
Neurochem Int ; 142: 104897, 2021 01.
Article in English | MEDLINE | ID: mdl-33186611

ABSTRACT

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.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Inflammation Mediators/antagonists & inhibitors , Neurodegenerative Diseases/drug therapy , Plant Extracts/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Australia/epidemiology , Humans , Inflammation Mediators/metabolism , Neurodegenerative Diseases/epidemiology , Neurodegenerative Diseases/metabolism , Plant Extracts/chemistry , Plant Extracts/pharmacology
17.
Phytochemistry ; 176: 112426, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32505021

ABSTRACT

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 IC50 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.


Subject(s)
Triterpenes , Anti-Inflammatory Agents , Australia , Humans , Molecular Structure , Plant Extracts , Plant Leaves , Rainforest
18.
Fitoterapia ; 143: 104598, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32330577

ABSTRACT

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 (EC50), 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 EC50 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 EC50 value, and the most potent compound is the one with the lowest EC50. 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 (EDV50)" as the reciprocal of the EC50 (1/EC50). We show how the EDV50 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 EDV50 to point out the most potent compounds. We hope that the EDV50 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.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Biological Assay , Biological Products/pharmacology , Myrtaceae/chemistry , Phytochemicals/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Biological Products/chemistry , Chromatography, High Pressure Liquid , Mice , Molecular Structure , Nitric Oxide/metabolism , Phytochemicals/isolation & purification , Plant Extracts/chemistry , Plant Leaves/chemistry , RAW 264.7 Cells , Structure-Activity Relationship
19.
Fitoterapia ; 143: 104595, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32333959

ABSTRACT

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 (IC50) 42-55 µM. The structures of the new compounds were assigned based on a detailed spectroscopic interpretation.


Subject(s)
Myrtaceae/chemistry , Phloroglucinol/pharmacology , Xanthenes/pharmacology , Animals , Mice , Molecular Structure , Nitric Oxide/metabolism , Phloroglucinol/isolation & purification , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Queensland , RAW 264.7 Cells , Rainforest , Tumor Necrosis Factor-alpha/metabolism , Xanthenes/isolation & purification
20.
Neural Regen Res ; 14(8): 1430-1437, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30964069

ABSTRACT

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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