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Dive into the research topics where M. Helen Grant is active.

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Featured researches published by M. Helen Grant.


Chemico-Biological Interactions | 1998

The effect of the flavonoids, quercetin, myricetin and epicatechin on the growth and enzyme activities of MCF7 human breast cancer cells

E.Hazel Rodgers; M. Helen Grant

Humans ingest about 1 g of flavonoids daily in their diet, and they are increasingly being associated with cytoprotective antitumour properties. The mechanism(s) responsible for these effects have not yet been elucidated but may involve interaction with xenobiotic metabolising enzymes to alter the metabolic activation of potential carcinogens. We have investigated the effect of the flavonoids, quercetin (Q), myricetin (M) and epicatechin (E) on the growth, morphology and enzyme activities of MCF7 human breast cancer cells. Of the three flavonoids studied only Q caused a decrease in cell protein content and decreased the reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium). It also inhibited protein, DNA and RNA synthesis to the greatest extent. Q and M increased intracellular reduced glutathione (GSH) content, and Q altered the morphology of the cells after 24 h exposure to 25 microM. E and Q inhibited the O-deethylation of ethoxyresorufin (EROD) catalysed by cytochrome P450 CYPIA. In contrast, M increased the EROD reaction 2-fold. Q increased the activity of DT-diaphorase, NADPH cytochrome c reductase and glutathione reductase, while E increased only NADPH cytochrome c reductase activity. The effects on enzyme activities in vitro suggest that there is not only the potential for flavonoids to alter metabolic activation of carcinogens but also of therapeutically administered drugs in vivo. We are at present investigating the synergy between anti-cancer drugs and flavonoids in terms of anti-tumour efficacy.


Journal of Bone and Joint Surgery, American Volume | 2008

Inflammatory pseudotumor associated with femoral nerve palsy following metal-on-metal resurfacing of the hip. A case report.

Robert A.E. Clayton; Ian Beggs; Donald Salter; M. Helen Grant; James T. Patton; Daniel Porter

Metal-on-metal resurfacing arthroplasty of the hip has been used increasingly in Europe over the last ten years for the treatment of osteoarthritis of the hip in younger (<65 years of age), active patients. In 2005, 6,153 procedures were performed in England and Wales1. Marketing of the Birmingham hip replacement for resurfacing arthroplasty was approved by the United States Food and Drug Administration in May 2006. Metal-on-metal resurfacing of the hip is known to be associated with elevated concentrations of metal ions within the hip joint and systemically, but, to our knowledge as of this writing, no adverse effects of this process have been identified. However, the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) issued an alert in June 2007 about the Ultima metal-on-metal bearing total hip arthroplasty prosthesis (DePuy International, Leeds, United Kingdom) following reports of the need for early revision due to periprosthetic soft-tissue necrosis2. The bearing in question was a cobalt-chromium-molybdenum alloy similar to that used in the Birmingham hip replacement. We report the development of an ipsilateral mass associated with markedly elevated intralesional cobalt and chromium levels and a femoral nerve palsy in a patient who underwent a Birmingham metal-on-metal resurfacing arthroplasty of the hip one year previously. Our patient was informed that data concerning the case would be submitted for publication, and she consented. A sixty-three-year-old woman presented to another institution with painful idiopathic osteoarthrosis of the right hip. She had undergone a total abdominal hysterectomy, oophorectomy, and lysis of bowel adhesions five years previously but had no other contributory medical history. She underwent metal-on-metal resurfacing arthroplasty of the hip with the Birmingham hip replacement (Smith and Nephew Orthopaedics, Warwick, United Kingdom) in June 2005 (Fig. 1). The surgery and the early postoperative recovery were uncomplicated. Fig. 1 Pelvic radiograph made one …


Journal of Immunotoxicology | 2011

Effect of chromium and cobalt ions on primary human lymphocytes in vitro

Moeed Akbar; James M. Brewer; M. Helen Grant

Cobalt-chromium (Co-Cr) alloy metal-on-metal hip resurfacing is increasingly common among younger more active patients suffering from osteoarthritis. Recent reports have increased awareness of metal ions leaching from metallic articulations; this ion exposure may have adverse effects on the immune system. As previous studies reported alterations in lymphocyte number and function in patients with Co-Cr implants, we investigated effects of clinically relevant concentrations of Cr6+ and Co2+ on primary human lymphocytes in vitro. Here, both resting and activated (anti-CD3 ± anti-CD28 antibodies) primary human lymphocytes were exposed to Cr6+ or Co2+ (0.1–100 µM). Following 24 or 48 h of exposure, cell viability, proliferation, cytokine [interferon-γ (IFNγ and interleukin-2 (IL-2)] release, and apoptosis (with and without pre-treatment of cells with a caspase-3 inhibitor) were assessed. Exposure to 10 and 100 µM Cr6+ significantly decreased cell viability and increased apoptosis in both resting and activated lymphocytes. Cell proliferation and cytokine release were also significantly reduced in activated lymphocytes following exposure. The exposure of resting lymphocytes to 100 µM Co2+ resulted in significant decreases in cell viability accompanied by a significant increase in apoptosis. Activated lymphocytes also showed this response after exposure to 100 µM Co2+; in fact, activated cells were significantly more sensitive to Co2+ toxicity. Exposure to 10 µM Co2+ led to significant decreases in cell proliferation and cytokine release, but no significant increase in apoptosis, in activated cells. The results indicate that exposure to high concentrations of metal ions initiate apoptosis that results in decreased lymphocyte proliferation. IL-2 release is inhibited by both metal ions at concentrations that are not overtly toxic. However, metal ion concentrations not directly cytotoxic to lymphocytes may affect events at a molecular level, thereby impeding lymphocyte proliferation. Hence, this may contribute to altered immune system function in patients with Co-Cr implants.


Journal of Biomedical Optics | 2011

Effect of 405 nm high-intensity narrow-spectrum light on fibroblast populated collagen lattices: an in vitro model of wound healing

Richard Mcdonald; M. Helen Grant; S.J. MacGregor; J.G. Anderson; Michelle Maclean

High-intensity narrow-spectrum (HINS) 405-nm light is a novel technology developed to address the significant problem of health-care associated infection. Its potential for wound-decontamination applications is assessed on mammalian cells and bacteria. The fibroblast-populated collagen lattice (FPCL) is used as an in vitro model of wound healing, and the effect of HINS light on contraction is examined. Effects on cell proliferation, morphological changes, and α-smooth muscle actin (α-SMA) expression are investigated. Bactericidal effects are assessed using the bacterium Staphylococcus epidermidis. Low doses of HINS light were found to have no significant inhibitory effects on FPCL contraction, cell proliferation, or α-SMA expression. Doses of up to 18 Jcm(-2) had no significant inhibitory effects on FPCL cell numbers, and this dose was shown to cause almost complete inactivation of bacteria. These results show that HINS light has potential for disinfection applications without adversely influencing wound healing.


Journal of the Royal Society Interface | 2012

Acute inflammatory response to cobalt chromium orthopaedic wear debris in a rodent air-pouch model

Moeed Akbar; Alasdair R. Fraser; Gerard J. Graham; James M. Brewer; M. Helen Grant

This study used a rodent air-pouch model to assess the acute inflammatory response to cobalt–chromium (CoCr) alloy wear debris from a metal-on-metal hip resurfacing implant that may contribute to joint failure. Air-pouches were injected with either sterile phosphate-buffered saline, 1 μg lipopolysaccharide (LPS) or 2.5 mg CoCr wear debris. The in situ inflammatory response was monitored 4, 24, 48 and 72 h and 7 days later. A flow cytometric analysis of the inflammatory exudates showed that CoCr wear debris induced a different inflammatory pattern compared with LPS. LPS induced a strong early (4 h) neutrophil influx, with monocyte/macrophage influx peaking at 24 h, whereas CoCr wear debris initiated almost equal numbers of early monocyte/macrophage and neutrophil recruitment. Histological analyses also showed CoCr debris accumulated in the pouch wall and this was accompanied by vast cellular infiltration and fibrosis around the debris throughout the duration of the experiment. Assessment of inflammatory gene transcripts from air-pouch tissue showed that CoCr wear debris increased the expression of cytokines involved in promoting inflammation and fibrosis (IL-1β, TGF-β) and chemokines that promote the recruitment of neutrophils and monocytes/macrophages (CXCL2 and CCL2). The data suggest that inflammatory responses to CoCr debris induce a specific acute process in which the recruitment of monocytes/macrophages is key.


Toxicology in Vitro | 2015

Effects of CoCr metal wear debris generated from metal-on-metal hip implants and Co ions on human monocyte-like U937 cells

Olga M. Posada; Rothwelle Tate; M. Helen Grant

Hip resurfacing with cobalt-chromium (CoCr) alloy was developed as a surgical alternative to total hip replacement. However, the biological effects of nanoparticles generated by wear at the metal-on-metal articulating surfaces has limited the success of such implants. The aim of this study was to investigate the effects of the combined exposure to CoCr nanoparticles and cobalt ions released from a resurfacing implant on monocytes (U937 cells) and whether these resulted in morphology changes, proliferation alterations, toxicity and cytokine release. The interaction between prior exposure to Co ions and the cellular response to nanoparticulate debris was determined to simulate the situation in patients with metal-on-metal implants receiving a second implant. Effects on U937 cells were mainly seen after 120h of treatment. Prior exposure to Co ions increased the toxic effects induced by the debris, and by Co ions themselves, suggesting the potential for interaction in vivo. Increased TNF-α secretion by resting cells exposed to nanoparticles could contribute to osteolysis processes in vivo, while increased IFN-γ production by activated cells could represent cellular protection against tissue damage. Data suggest that interactions between Co ions and CoCr nanoparticles would occur in vivo, and could threaten the survival of a CoCr metal implant.


Toxicology in Vitro | 2009

Response to chronic exposure to hexavalent chromium in human monocytes.

Vijay Krishna Raghunathan; Elizabeth M. Ellis; M. Helen Grant

Elevated circulating levels of metal ions, particularly chromium, have been measured in the blood of patients with metal hip implants, and this has lead to concerns about the long term safety of the prostheses. For example, depletion of lymphocytes has been reported in vivo in patients with metallic prostheses, and correlated with elevated chromium and cobalt concentrations in blood. However, the implications for immune function are unclear. We have assessed the in vitro responses of U937 human monocytes to chronic exposure (4 weeks) to Cr (VI) ions at concentrations which have been measured in patients with metal artificial hip implants (0.05-0.5 microM). Chronic exposure to these low clinically relevant concentrations of Cr (VI) induced a potent adaptive response with elevated glutathione-S-transferase (pi) expression and increased activities and expression of reactive oxygen scavengers, superoxide dismutases, catalase and glutathione peroxidase. Such direct toxicity of Cr ions may contribute to the effects of metal implants on lymphocyte populations in vivo.


Toxicology in Vitro | 2008

Cr (VI) inhibits DNA, RNA and protein syntheses in hepatocytes: involvement of glutathione reductase, reduced glutathione and DT-diaphorase.

M. Gunaratnam; M. Helen Grant

In patients with orthopaedic implants, metallic particles have been shown to be disseminated widely throughout the body, particularly in the liver, spleen and lymph nodes. Levels of metal particles and ions in distant organs were highest in patients with loose, corroded prostheses, and when stainless steel and cobalt chrome alloy corrode, chromium is released predominantly as Cr (VI), a toxic ion. This manuscript investigates the interaction of Cr (VI) with liver cells in terms of inhibition of macromolecular synthesis, and the contribution of reduced glutathione (GSH), DT-diaphorase and glutathione reductase (GRd) to the toxicity of Cr (VI). Cr (VI) caused concentration dependent inhibition of protein, DNA and RNA synthesis in hepatocytes. GRd and to a lesser extent DT-diaphorase activities were involved in the generation of toxic intermediates. GRd activity was markedly inhibited during the reduction of Cr (VI), and GSH levels decreased. The concentrations of Cr (VI) found to inhibit macromolecular syntheses in this study are clinically relevant: it is therefore important to develop implants with minimum wear potential.


Basic & Clinical Pharmacology & Toxicology | 2017

Human hepatic HepaRG cells maintain an organotypic phenotype with high intrinsic CYP450 activity/metabolism and significantly outperform standard HepG2/C3A cells for pharmaceutical and therapeutic applications

Leonard J. Nelson; Katie Morgan; Philipp Treskes; Kay Samuel; Catherine Henderson; Claire LeBled; Natalie Homer; M. Helen Grant; Peter C. Hayes; John Plevris

Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, interdonor functional variability and early phenotypic alterations in PHHs restrict their use, whilst standard cell lines such as HepG2 lack a substantial and variable set of liver‐specific functions such as CYP450 activity. Alternatives include the HepG2‐derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype. Human HepaRG cells are an alternative organotypic co‐culture model of hepatocytes and cholangiocytes reported to maintain in vivo‐like liver‐specific functions, including intact Phase I–III drug metabolism. In this study, we compared C3A and human HepaRG cells using phenotypic profiling, CYP450 activity and drug metabolism parameters to assess their value as hepatic models for pre‐clinical drug testing or therapeutics. Compared with C3As, HepaRG co‐cultures exhibit a more organotypic phenotype, including evidence of hepatic polarity with the strong expression of CYP3A4, the major isoform involved in the metabolism of over 60% of marketed drugs. Significantly greater CYP450 activity and expression of CYP1A2, CYP2E1 and CYP3A4 genes in HepaRG cells (comparable with that of human liver tissue) was demonstrated. Moreover, HepaRG cells also preferentially expressed the hepatic integrin α5β1 – an important modulator of cell behaviour including growth and survival, differentiation and polarity. Drug metabolite profiling of phenacetin (CYP1A2) and testosterone (CYP3A4) using LC‐MS/MS and HPLC, respectively, revealed that HepaRGs had more intact (Phase I–II) metabolism profile. Thus, HepaRG cells significantly outperform C3A cells for the potential pharmaceutical and therapeutic applications.


Chemico-Biological Interactions | 2003

The toxicity of opiates and their metabolites in HepG2 cells

Mark Jairaj; David G. Watson; M. Helen Grant; G.G. Skellern

The toxicity of codeine (C), codeinone (CO), morphine (M), oxycodone (OC), pholcodine (P) and pholcodine-N-oxide (P-NOX) was assessed in HepG2 cells by determining cell viability via the measurement of lactate dehydrogenase (LDH) leakage through the membrane, depletion of reduced glutathione (GSH) and measurement of total protein content. Incubation of C, M, OC, P or P-NOX with HepG2 cells resulted in no significant loss of cell viability, depletion of GSH or decreased total protein content. In contrast, with CO there was a marked depletion of GSH with significant differences from control cells (P<0.05) being detected after as little as 5 min. This effect preceded the loss of cell viability and the decrease in total protein content. To identify the cause of GSH depletion during incubations with CO, the incubation solutions were analysed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Analysis showed that a codeinone-glutathione conjugate (CO-SG) had been formed. This adduct was synthesised and characterised by LC/MS/MS and by nuclear magnetic resonance spectroscopy (NMR). CO-SG was quantified in the incubation solutions using the synthesised standard substance. Results obtained in this study support the hypothesis that the toxicity of CO may be partly due to GSH depletion. The absence of LDH leakage and GSH depletion in the incubations containing C or OC suggests, that the presence of both a double bond at Delta 7 and an adjoining keto-group in the 6-position are necessary to elicit the toxicity of M analogues with regard to GSH depletion.

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J.G. Anderson

University of Strathclyde

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S.J. MacGregor

University of Strathclyde

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Philip Riches

University of Strathclyde

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G.A. Afolaranmi

University of Strathclyde

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J.C. Barbenel

University of Strathclyde

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J.D.S. Gaylor

University of Strathclyde

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