ORCID Profile
0000-0002-2154-2672
Current Organisation
Central Coast Local Health District
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Publisher: American Society of Hematology
Date: 21-10-2021
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.MEHY.2013.11.025
Abstract: The conflict between our 'primitive' genes and 'modern' lifestyle probably lies at the root of several disorders that afflict modern man. Atherosclerosis, which is relatively unknown among contemporary hunter-gatherer populations, has reached pandemic proportions in recent times. Being an evolutionary problem with several inter-related pathologies, current therapeutic strategy for treating atherosclerosis has inherent limitations. Reviewing evolution-linked risk factors suggests that there are four aspects to the etiology of atherosclerosis namely, decreased intestinal parasitism, oversensitivity of evolutionarily redundant mast cells, chronic underactivation of AMPK (cellular energy sensor) and a deficiency of vitamin D. A combination of these four causes appear to have precipitated the atherosclerosis pandemic in modern times. Man and worms co-existed symbiotically in the past. Massive de-worming c aigns could have disrupted this symbiosis, increasing nutritional availability to man (pro-obesity) at the cost of decreased immunotolerance (pro-atherogenicity). A reduction in helminth-induced chronic TH2 activation could also have enhanced TH1 polarization, eventually disrupting the reciprocal regulation of TH1/TH2 balance and resulting in atherosclerosis. The riddance of helminth infestations may have rendered mast cells immunologically redundant, making them oversensitive to inflammatory stimuli, thereby playing a pro-atherogenic role. AMPK activation exerts pleiotropic anti-atherogenic effects, such as suppression of fatty acid, cholesterol, protein synthesis, reduction of vascular smooth muscle proliferation, etc. As energy deficit is the chief stimulus for AMPK activation, the over-nourished modern man appears to be suffering from chronic underactivation of AMPK, legitimising the unrivalled supremacy of metformin, the oldest prescribed antidiabetic drug. The fact that humans evolved in the sunny tropics suggests that humans are selected for high vitamin D levels. Vitamin D deficiency is now linked to several conditions including increased risk of CV disorders, diabetes, etc. The manifold decrease in vitamin D levels in modern man justifies a need for supplementation. We therefore hypothesize that a judicious combination of mast cell stabilization, AMPK activation, vitamin D supplementation, and moderation in hygiene practices could be an evolution-based multimodal strategy for both preventing and mitigating the pandemic of atherosclerosis.
Publisher: Wiley
Date: 04-11-2015
Abstract: The replacement of the thiazolidinedione moiety with a thiazolidinone may yield antidiabetic compounds with similar pleiotropic effects. Hence, the aim of the present study was to explore the dose-related antihyperglycemic and hypolipidemic effects of two synthesized novel thiazolidin-4-one derivatives, one with a nicotinamide and the other with a p-chlorophenoxyacetamide substitution at the N3 position of the thiazolidinone ring (NAT1 and PAT1, respectively), in a rodent model of metabolic syndrome (MetS). Metabolic syndrome was induced in Wistar rats by neonatal administration of monosodium glutamate (i.p.) on 4 consecutive days followed by high-sucrose diet feeding for 6 months. The effects of NAT1 (33 and 66 mg/kg) and molar equivalent doses of PAT1 (40 and 80 mg/kg) on relevant biochemical parameters were evaluated. Because MetS is a state of chronic low-grade inflammation, we also evaluated the effects of these compounds on proinflammatory markers, namely interleukin (IL)-6, tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), and nitric oxide (NO). Both NAT1 and PAT1 attenuated hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, and glucose intolerance. PAT1 exhibited superior antihyperglycemic and antihypoalphalipoproteinemic effects than NAT1. However, NAT1 had a better triglyceride-lowering effect. At the lower dose tested, both compounds significantly reduced elevated malondialdehyde levels. In addition, PAT1 (80 mg/kg) restored hepatic superoxide dismutase enzyme levels. There was a tendency for NAT1 and PAT1 to inhibit elevated hepatic IL-6 and TNF-α levels, but the differences did not reach statistical significance. In addition, PAT1 exhibited in vitro anti-inflammatory activity by reducing proinflammatory ROS and NO levels in RAW264.7 macrophages. The novel thiazolidin-4-ones NAT1 and PAT1 could be potential pleiotropic drug candidates targeting MetS.
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/430734
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/802701
Abstract: Background . Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of gastrointestinal tract of immune, genetic, and environmental origin. In the present study, we examined the effects of sesamol (SES), which is the active constituent of sesame oil in the acetic acid (AA) induced model for IBD in rats. Methods . The groups were ided into normal control, AA control, SES, and sulfasalazine (SS). On day 7, the rats were killed, colon was removed, and the macroscopic, biochemical, and histopathological evaluations were performed. Results . The levels of MPO, TBARS, and tissue nitrite increased significantly ( P 0.05 ) in the AA group whereas they reduced significantly in the SES and SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. Conclusions . The mucosal protective effects of sesamol in IBD are due to its potential to reduce the myeloperoxidase and nitrite content.
Publisher: Springer Science and Business Media LLC
Date: 10-2014
DOI: 10.1016/J.PHAREP.2014.04.007
Abstract: Silymarin, a hepatoprotective agent, has poor oral bioavailability. However, the current dosage form of the drug does not target the liver and inflammatory cells selectively. The aim of the present study was to develop lecithin-based carrier system of silymarin by incorporating phytosomal-liposomal approach to increase its oral bioavailability and to make it target-specific to the liver for enhanced hepatoprotection. The formulation was prepared by film hydration method. Release of drug was assessed at pH 1.2 and 7.4. Formulation was assessed for in vitro hepatoprotection on Chang liver cells, lipopolysaccharide-induced reactive oxygen species (ROS) production by RAW 267.4 (murine macrophages), in vivo efficacy against paracetamol-induced hepatotoxicity and pharmacokinetic study by oral route in Wistar rat. The formulation showed maximum entrapment (55%) for a lecithin-cholesterol ratio of 6:1. Comparative release profile of formulation was better than silymarin at pH 1.2 and pH 7.4. In vitro studies showed a better hepatoprotection efficacy for formulation (one and half times) and better prevention of ROS production (ten times) compared to silymarin. In in vivo model, paracetamol showed significant hepatotoxicity in Wistar rats assessed through LFT, antioxidant markers and inflammatory markers. The formulation was found more efficacious than silymarin suspension in protecting the liver against paracetamol toxicity and the associated inflammatory conditions. The liposomal formulation yielded a three and half fold higher bioavailability of silymarin as compared with silymarin suspension. Incorporating the phytosomal form of silymarin in liposomal carrier system increased the oral bioavailability and showed better hepatoprotection and better anti-inflammatory effects compared with silymarin suspension.
Publisher: Frontiers Media SA
Date: 14-10-2016
Publisher: Springer Science and Business Media LLC
Date: 18-07-2015
DOI: 10.1007/S00011-015-0851-8
Abstract: Inflammation is a complex, metabolically expensive process involving multiple signaling pathways and regulatory mechanisms which have evolved over evolutionary timescale. Addressing multiple targets of inflammation holistically, in moderation, is probably a more evolutionarily viable strategy, as compared to current therapy which addresses drug targets in isolation. Polypharmacology, addressing multiple targets, is commonly used in complex ailments, suggesting the superior safety and efficacy profile of multi-target (MT) drugs. Phenotypic drug discovery, which generated successful MT and first-in-class drugs in the past, is now re-emerging. A multi-pronged approach, which modulates the evolutionarily conserved, robust and pervasive cellular mechanisms of tissue repair, with AMPK at the helm, regulating the complex metabolic/immune/redox pathways underlying inflammation, is perhaps a more viable strategy than addressing single targets in isolation. Molecules that modulate multiple molecular mechanisms of inflammation in moderation (modulating TH cells toward the anti-inflammatory phenotype, activating AMPK, stimulating Nrf2 and inhibiting NFκB) might serve as a model for a novel Darwinian "first-in-class" therapeutic category that holistically addresses immune, redox and metabolic processes associated with inflammatory repair. Such a multimodal biological activity is supported by the fact that several non-calorific pleiotropic natural products with anti-inflammatory action have been incorporated into diet (chiefly guided by the adaptive development of olfacto-gustatory preferences over evolutionary timescales) rendering such molecules, endowed with evolutionarily privileged molecular scaffolds, naturally oriented toward multiple targets.
Publisher: Medknow
Date: 2014
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.INTIMP.2012.10.028
Abstract: 6b,11b-Dihydroxy-6b,11b-dihydro-7H-indeno[1,2-b]naphtho[2,1-d]furan-7-one (DHFO), an easily synthesisable, orally bioavailable and relatively non-toxic small molecule synthesised in our lab, was previously reported to possess anti-oxidant, 5-lipoxygenase inhibitory, anti-inflammatory and peripheral analgesic activities. The present work deals with exploration of DHFO's efficacy in immunopathogenic chronic inflammatory conditions - arthritis and allergy. In carrageenan-induced inflammatory air pouch, which resembles the arthritic synovium, DHFO effectively reduced inflammatory redness and swelling and neutrophil infiltration. In complete Freund's adjuvant-induced arthritis, DHFO significantly decreased paw oedema and nitrite levels with efficacy comparable to diclofenac. DHFO inhibited neutrophil activation (observed as decreased myeloperoxidase levels), in both the in vivo models of inflammation. Interestingly, DHFO did not ulcerate the gastrointestinal tract, while diclofenac was observed to be extremely ulcerogenic. In antigen-induced active and passive anaphylaxis (allergy) models, DHFO dose-dependently prevented mesenteric mast cell (MC) degranulation with efficacy comparable to ketotifen. DHFO also inhibited compound 48/80 (C48/80)-induced paw oedema and peritoneal MC degranulation. DHFO stabilised p815 murine MCs stimulated by C48/80 and calcium ionophore-A23187, indicating an action downstream of calcium mobilisation. DHFO's anti-allergic mechanism could be two-pronged involving (1) inhibition of IgE production and/or (2) MC stabilisation. DHFO inhibited lipopolysaccharide (LPS)-induced pro-inflammatory mediator release (ROS, NO, IL-6 levels) and COX2 expression in RAW264.7 murine macrophages. Protein expression studies confirmed DHFO's ability to reduce nuclear levels of NF-κB in LPS-stimulated macrophages. Thus, DHFO is a promising non-ulcerogenic synthetic small molecule lead for immunopathogenic chronic inflammatory conditions.
Publisher: Informa UK Limited
Date: 03-10-2018
DOI: 10.1080/10715762.2018.1533636
Abstract: Inflammation is a protective immune response against invading pathogens, however, dysregulated inflammation is detrimental. As the complex inflammatory response involves multiple mediators, including the involvement of reactive oxygen species, concomitantly targeting proinflammatory and antioxidant check-points may be a more rational strategy. We report the synthesis and anti-inflammatory/antioxidant activity of a novel indanedione derivative DMFO. DMFO scavenged reactive oxygen species (ROS) in
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.CBI.2013.12.012
Abstract: Three thiazolidin-4-one derivatives were synthesized, purified and characterized by chromatographic and spectroscopic methods. In the in vitro assays, these compounds inhibited reactive oxygen species (ROS), nitrite and cytokine generation in RAW 264.7 murine macrophages and whole blood. These derivatives attenuated carrageenan-induced acute inflammation in rats. The most effective compound 4C possessed identical anti-inflammatory action at two doses (50 and 100 mg/kg). Further, the effect of compound 4C on locally induced inflammatory mediators was investigated in carrageenan-induced air pouch inflammation in rats. In this model, compound 4C inhibited the cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-6 (systemic and local). Additionally, compound 4C was able to reduce locally elevated prostaglandin-E₂ (PGE₂). Inhibition of leukocyte infiltration by compound 4C was correlated with reduced locally released myeloperoxidase (MPO). To conclude, compound 4C corrected the inflammatory condition by negative effect on cytokine (TNF-α, IL-6) network and prostaglandin-E₂ generation.
Publisher: Frontiers Media SA
Date: 20-02-2018
Publisher: Elsevier BV
Date: 09-2021
Publisher: Portland Press Ltd.
Date: 05-2017
DOI: 10.1042/CS20160846
Abstract: Oxidative stress is a consequence of up-regulation of pro-oxidant enzyme-induced reactive oxygen species (ROS) production and concomitant depletion of antioxidants. Elevated levels of ROS act as an intermediate and are the common denominator for various diseases including diabetes-associated macro-/micro-vascular complications and hypertension. A range of enzymes are capable of generating ROS, but the pro-oxidant enzyme family, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), are the only enzymes known to be solely dedicated to ROS generation in the vascular tissues, kidney, aortas and eyes. While there is convincing evidence for a role of NOX1 in vascular and eye disease and for NOX4 in renal injury, the role of NOX5 in disease is less clear. Although NOX5 is highly up-regulated in humans in disease, it is absent in rodents. Thus, so far it has not been possible to study NOX5 in traditional mouse or rat models of disease. In the present review, we summarize and critically analyse the emerging evidence for a pathophysiological role of NOX5 in disease including the expression, regulation and molecular and cellular mechanisms which have been demonstrated to be involved in NOX5 activation.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EJPS.2017.10.019
Abstract: From our lab, among the nineteen heterocyclic homoprostanoids (HHPs), three derivatives (compounds 3, 3b and 3c) exerted antioxidant and anti-inflammatory activity. Present study is an extension of the earlier work, and, is designed to establish their therapeutic potential in monoarthritis in rats. In addition, their possible mechanism of action would be investigated. A battery of in vitro tests such as lipopolysaccharide (LPS)-induced nitrite (NO)/reactive oxygen species (ROS) and NO/interleukin (IL)-6 generation in murine macrophages and whole blood (WhB), respectively were conducted. Later, in vitro cyclooxygenase (COX) enzyme inhibitory activity was also evaluated. All the tested compounds showed comparable efficacy against ROS and NO in LPS-stimulated murine macrophages. However, compound 3 did not exert inhibitory effect on LPS-induced NO/IL-6 generation in WhB assay. Compounds (3b and 3c) inhibited the NO generation in LPS-stimulated WhB. However, only compound 3b reversed the raised IL-6 levels in this assay. None of the test compounds inhibited COX iso-enzymes in the in vitro assay. All three HHPs showed comparable efficacy against carrageenan-induced paw inflammation. However, none of them exhibited any dose-dependent effect in this model. Based upon previous reports, compound 3c was explored against adjuvant-induced monoarthritis (AIA) in male Sprague-Dawley rats, where it exerted promising therapeutic effect. In addition to radiological and histological examinations of tibio-tarsal joint, various parameters such as chronic inflammation ain, clinical score, interleukin (IL)-6 levels and complete blood cell profile were evaluated in AIA rats. Chronic treatment with 3c halted the disease progression in rats, improved the overall health of animals, as demonstrated by haematological, clinical scoring and joint examinations (radiological and histopathological). Inhibitory effect on elevated IL-6 in AIA rats suggested the possible mechanism of 3c on cytokine signalling. Overall, the study supports the anti-arthritic potential of compound 3c.
Publisher: Springer Science and Business Media LLC
Date: 05-2013
DOI: 10.1016/S1734-1140(13)71043-0
Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of gastrointestinal tract of immune, genetic and environmental origin. In the present study, we examined the effect of sesamol (SES), the main anti-oxidative constituent of Sesamum indicum (sesame seed) Linn. in the dinitrochlorobenzene (DNCB)-induced model for IBD in rats. The groups were ided into normal control, DNCB control, SES and sulfasalazine (SS). On day 24, the rats were killed, colon removed and the macroscopic, biochemical and histopathological evaluations were performed. The levels of MPO, TBARS and nitrite increased significantly (p < 0.05) in the DNCB group, whereas reduced significantly in the SES, SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. IL-6 and TNF-α levels were significantly high in the DNCB group. We conclude the mucosal protective effect of SES on colon due to its potent antioxidant actions. Further investigation is required in a chronic model of different rodent strain for its role involved in the cytokine pathway.
Publisher: Elsevier
Date: 2014
No related grants have been discovered for Geetha Mathew.