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Biomedical subjects

Ian Grant

Publications and source records attributed to Ian Grant.

8 recordsLinked to original sources
PubMed2004

Conjugated linoleic acids (CLAs) decrease prostate cancer cell proliferation: different molecular mechanisms for cis-9, trans-11 and trans-10, cis-12 isomers.

The aims of this study were to examine the anti-proliferative effects of different concentrations of a commercial preparation of conjugated linoleic acids (CLA) mixture of isomers [cis-9, trans-11 CLA (c9,t11 CLA): trans-10, cis-12 CLA (50:50)] and their constituent isomers on PC-3, a human prostatic carcinoma cell line, and to study their effects on gene expression (mRNA and protein levels) of different enzymes and oncoproteins involved in oncogenesis and progression of prostate cancer. This includes pathways for arachidonic acid metabolism [cyclooxygenase 1 (COX-1), 2 (COX-2) and 5-lipoxygenase (5-LOX)], apoptosis (bcl-2) and cell cycle control (p21(WAF/Cip1)). Our results indicate a significant decrease in PC-3 proliferation elicited by CLA, although with high variability between isomers. The trans-10, cis-12 CLA was the most effective isomer (55% inhibition). This isomer was also able to decrease bcl-2 gene expression and to increase p21(WAF1/Cip1) mRNA levels (60% increase at highest concentration). In contrast, cis-9, trans-11 had no effect on these proteins but had a clear effect on 5-LOX expression and to a lesser degree on COX-2 protein level isomers. In conclusion, the anti-proliferative effects on PC-3 of CLA mixture and their constituent isomers are not equivalent, due to the different pathways involved for individual isomers. Trans-10, cis-12 seems to work preferentially through modulation of apoptosis and cell cycle control, while c9,t11 CLA isomer affects arachidonic acid metabolism.

Arachidonate 5-Lipoxygenase↗
PubMed2004

Multifocal motor neuropathy: pathologic alterations at the site of conduction block.

The pathologic changes of nerves in multifocal motor neuropathy (MMN), a rare neuropathy with selective focal conduction block of motor fibers in mixed nerves, remain essentially unstudied. Fascicular nerve biopsy of 8 forearm or arm nerves in 7 patients with typical MMN was undertaken for diagnostic reasons at the site of the conduction block. Abnormalities were seen in 7 of 8 nerves, including a varying degree of multifocal fiber degeneration and loss, an altered fiber size distribution with fewer large fibers, an increased frequency of remyelinated fiber profiles, and frequent and prominent regenerating fiber clusters. Small epineurial perivascular inflammatory infiltrates were observed in 2 nerves. We did not observe overt segmental demyelination or onion bulb formation. We hypothesize that an antibody-mediated attack directed against components of axolemma at nodes of Ranvier could cause conduction block, transitory paranodal demyelination and remyelination, and axonal degeneration and regeneration. Alternatively, the antibody attack could be directed at components of paranodal myelin. We favor the first hypothesis because in nerves studied by us, axonal pathological alteration predominated over myelin pathology. Irrespective of which mechanism is involved, we conclude that the unequivocal multifocal fiber degeneration and loss and regenerative clusters at sites of conduction block explains the observed clinical muscle weakness and atrophy and alterations of motor unit potentials. The occurrence of conduction block and multifocal fiber degeneration and regeneration at the same sites suggests that the processes of conduction block and fiber degeneration and regeneration are linked. Finding discrete multifocal fiber degeneration may also provide an explanation for why the functional abnormalities remain unchanged over long periods of time at discrete proximal to distal levels of nerve and may emphasize a need for early intervention (assuming that efficacious treatment is available).

Adult↗
PubMed2004

Conjugated linoleic acid inhibits proliferation and modulates protein kinase C isoforms in human prostate cancer cells.

Prostate cancer is the second most common cancer in men. The disease etiology is poorly understood, but diet and lifestyle are contributory factors. Conjugated linoleic acids (CLAs), naturally occurring fatty acids in ruminant food products, have antitumor properties in animal models of cancer and antiproliferative effects on cancer cells in vitro. The cellular mechanisms by which CLAs elicit these effects are unclear, particularly for prostate cancer cells. We have previously identified protein kinase C (PKC) isoforms, alpha, delta, iota, mu, and zeta in LNCaP prostate cancer cells. The objective of this study was to determine the effects of CLAs (individual cis-9, trans-11 and trans-10, cis-12 isoforms and a 50:50 mixture) on PKC isoform abundance in LNCaP cells. Confluent cells were treated with 6, 25, and 50 microM CLA for 0.5, 6, and 24 h. Cytosol and membrane protein fractions were assayed for PKC isoforms (mainly alpha and delta but also iota, mu, and zeta) by Western blot analysis using specific antibodies. CLAs clearly modulated the abundance of these PKC isoforms, both positively and negatively, depending on the isoform, concentration of CLAs, and period of treatment. Increased PKC-delta and decreased PKC-iota membrane abundance was consistent with CLAs eliciting increased apoptosis and, in part, with their antitumor effects.

Cell Division↗
PubMed2003

Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants.

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is the only antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with alpha-tocopherol to inhibit lipid peroxidation. Peroxidation of lipids has been implicated in a number of pathophysiological processes, including inflammation and atherogenesis. We investigated the relative positive and negative effects of specific polyunsaturated fatty acids (PUFAs) and inflammatory cytokines on the activity and gene expression of the selenium-dependant redox enzyme GPx4. In human umbilical vein endothelial cells (HUVEC), GPx4 mRNA levels and activity were increased optimally by 114 nM selenium (as sodium selenite). Docosahexaenoic acid (DHA) and conjugated linoleic acid (CLA) further increased mRNA levels whereas arachidonic acid (ARA) had no effect; enzyme activity was decreased by DHA, was unaffected by CLA or was increased by ARA. GPx4 protein levels increased with selenium, ARA and DHA addition but not with CLA. Interleukin-1beta (IL-1beta) increased GPx4 mRNA, protein and activity whereas TNFalpha at 1 ng/ml increased activity while at 3 ng/ml it reduced activity and mRNA. Conversely, alpha-tocopherol reduced mRNA levels without affecting activity. These results indicate that lipids, cytokines and antioxidants modulate GPx4 in a complex manner that in the presence of adequate selenium, may favour protection against potentially proatherogenic processes.

Antioxidants↗
PubMed2002

Conjugated linoleic acids (CLAs) regulate the expression of key apoptotic genes in human breast cancer cells.

Conjugated linoleic acid (CLA) reduces mammary tumorigenesis in rodent models, induces apoptosis in rodent mammary tumor cell lines, and decreases expression of antiapoptotic bcl-2 in rat mammary tissue. This investigation focused on the cell mechanisms underlying the antitumor effects of CLA. Changes (mRNA, protein) in expression of major proapoptotic p53, p21WAF1/CIP1, bax, bcl-Xs genes, and the antiapoptotic bcl-2 gene were observed in malignant MCF-7 and MDA-MB-231 cells and in benign MCF-10a human mammary tumor cells in culture. CLA, but not linoleic acid (LA), inhibited proliferation in all cells; CLA mix was most effective. CLA increased DNA damage (apoptosis). CLA increased mRNA expression of p53 and p21WAF1/CIP1 (three- to fivefold and twofold, respectively) but either decreased bcl-2 by 20-30% or had no effect in MCF-7 and MCF-10a cells, respectively; protein expression reflected mRNA values. In MDA-MBA-231 (mutant p53) cells, mRNA for p53 was not changed, but p21WAF1/CIP1 and bcl-2 mRNA was increased. Protein expression largely reflected mRNA changes but, surprisingly, CLA completely suppressed mutant p53 protein in MDA-MB-231 cells. Apparent antiapoptotic effects of increased bcl-2 expression in MDA-MBA-231 cells were countered by increased proapoptotic p21WAF1/CIP1, Bax, and Bcl-Xs proteins. Findings indicate that CLA elicits mainly proapoptotic effects in human breast tumor cells through both p53-dependent and p53-independent pathways, according to cell type.

Apoptosis↗
PubMed2002

Spontaneous intracranial hypotension in the absence of magnetic resonance imaging abnormalities.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is a neurologic syndrome of unknown etiology, characterized by features of low cerebral spinal fluid (CSF) pressure, postural headache and magnetic resonance imaging (MRI) abnormalities. METHODS: Four symptomatic cases of SIH presented to our institution over a six-month period. Magnetic resonance imaging studies were performed in all four cases. Diagnostic lumbar puncture was done in all except one case. RESULTS: All of the patients on whom lumbar punctures were performed demonstrated low CSF pressure and CSF protein elevation with negative cultures and cytology. Three out of the four patients exhibited MRI findings of diffuse spinal and intracranial pachymeningeal gadolinium enhancement and extradural or subdural fluid collections. One patient had no MRI abnormalities despite prominent postural headache and reduced CSF pressure at lumbar puncture. All patients recovered with intravenous fluids and conservative treatment. CONCLUSIONS: Magnetic resonance imaging abnormalities are found in most, but not all patients, with SIH. Cerebral spinal fluid abnormalities can be detected even in patients with normal MRI studies. It is important to recognize the variability of imaging results in this usually benign disorder.

Adult↗
PubMed2002

Olive oil phenolics: effects on DNA oxidation and redox enzyme mRNA in prostate cells.

Hydroxytyrosol, tyrosol and caffeic acid effects on hydrogen peroxide-induced DNA damage, hydroperoxide generation and redox enzyme gene expression were studied in oxidative-stress-sensitive human prostate cells (PC3). Hydroxytyrosol led to lower levels of hydroperoxides, DNA damage, and mRNA levels of classic glutathione peroxidase (GPx) for all the studied concentrations. Only hydroxytyrosol was effective at low concentrations (10 microm). Tyrosol reduced DNA oxidation only at high (>50 microm) concentrations and increased hydroperoxides, GPx and phospholipid hydroperoxide GPx mRNA levels. Caffeic acid elicited effects between those of the other two phenolics. Results indicate that hydroxytyrosol is the only significant antioxidant phenolic in olive oil and may be the major component accounting for its beneficial properties. Tyrosol appeared to exhibit pro-oxidant effects (only at high concentrations) and caffeic acid was neutral. Both number and position of hydroxyl groups appear to play a role in the cellular effects of hydroxytyrosol.

Antioxidants↗