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Biomedical subjects

M J Jackson

Publications and source records attributed to M J Jackson.

At least 55 records · Page 3Linked to original sources
PubMed2000

Hyperthermia to normal human skin in vivo upregulates heat shock proteins 27, 60, 72i and 90.

This study was performed to test the hypothesis that expression of heat shock proteins (HSPs) exhibits a spatially selective response within intact human skin following in vivo exposure to thermal stress. This response is believed to protect cells and tissues from further damage. Using Western blotting and immunohistochemistry, we studied the expression of a range of HSPs in normal human skin of 5 subjects prior to and following heating in vivo. The skin was heated to 41 +/- 0.5 degrees C for 1 h and biopsies were taken at 4, 8 and 24 h and from control, untreated skin. HSPs 27, 60, 72i, 90, 110 and heat shock constitutive (HSC)70 were expressed in normal skin, but the extent and distribution of these HSPs showed considerable variation. HSP27, 60 and 72i were found predominantly in the epidermis, whereas HSC70 showed weak epidermal staining but strong dermal expression. Heating the skin in vivo resulted in an increased skin content of HSP27, 60, 72i and 90, with maximal increase at 24 h following hyperthermia, while the skin content of HSC70 and HSP110 were unchanged. Significant increases in the content of HSP72i and HSP90 had occurred by 4 h following hyperthermia, with a mean +/-SEM of 206 +/- 50% and 197 +/- 38% of the control, untreated values, respectively (p<0.05). These findings indicate the complexity of HSP dynamics in human skin, and suggest that heating within the experimental range may protect the skin from further stresses for at least 24 h.

Adult↗
PubMed2000

Exercise, oxidative stress and ageing.

Skeletal muscle has the unique ability to increase the rate of oxygen usage during contraction. This has led several workers to suggest that by-products of this increased oxygen consumption, oxygen-derived free radicals, may be primarily responsible for exercise-induced damage to skeletal muscle. However, because of this rapidly changing redox state, skeletal muscle has developed a number of different endogenous mechanisms which adapt rapidly following a period of exercise. These include numerous structural and biochemical changes such as increased muscle activity of antioxidant enzymes and content of stress or heat shock proteins (HSPs). This adaptation is associated with protection against the potentially damaging effects of a second period of exercise. In addition, we have recently demonstrated a significant increase in free radical production during a period of nondamaging exercise, which is rapidly followed by a significant increase in the expression of antioxidant enzymes and HSPs, suggesting that a change in redox state of the muscle may act as signal for adaptation.

Adaptation, Physiological↗
PubMed1999

Interleukin-10 gene transfer activates interferon-gamma and the interferon-gamma-inducible genes Gbp-1/Mag-1 and Mig-1 in mammary tumors.

Expression of IL-10 as a transgene inhibits murine mammary tumor growth and metastasis. Using differential display methodology, we sought genes whose expression was modulated by IL-10. We compared mRNA isolated from parental murine mammary 66.1 tumors, as well as tumors derived from neo(r)-transfected cells and 6 different IL-10-expressing cell lines. We identified 2 cDNA products that were up-regulated in all 6 IL-10-expressing tumors in comparison to parental and 66-neo tumors. One cDNA corresponds to the murine guanylate-binding protein gene Gbp-1/Mag-1. The other cDNA corresponds to the chemokine Mig-1 (monokine induced by IFN-gamma). Both genes were originally identified in IFN-gamma-activated macrophages or macrophage cell lines. We now report that cultured mammary epithelial tumor cell lines also express both genes in response to treatment with IFN-gamma and LPS. Furthermore, IFN-gamma mRNA is elevated in IL-10-expressing tumors in comparison with parental or neo-transfected tumors. Thus, high-level expression of IL-10 as a transgene results in activation rather than suppression of IFN-gamma as well as 2 IFN-gamma-inducible genes. Up-regulation of host IFN-gamma is critical to anti-tumor activity since IL-10 no longer inhibits tumor growth in hosts with a deletion in the IFN-gamma gene. Additionally, Gbp-1/Mag-1 and Mig-1 gene induction no longer occur in IFN-gamma mutant mice.

Animals↗
PubMed1999

In vivo microdialysis-A technique for analysis of chemical activators of muscle pain.

The accurate measurement of the chemical activators of pain in skeletal muscle has proved to be a major challenge. This study examined the applicability of microdialysis to the measurement of pain-producing substances in skeletal muscle using a defined model of ischemia and reperfusion in the rat. Microdialysis probes were placed into muscle of anesthetized rats. Ischemia was induced for 4 h, followed by reperfusion for 1 h. Perfusates were analyzed for hypoxanthine, potassium, prostaglandin (PG) E(2) and histamine. A 20-fold increase in perfusate hypoxanthine concentration was seen prior to reperfusion (70.1 +/- 27.1 microM for ischemic versus 3.7 +/- 1.9 microM for control; P < 0.05). An initial increase in PGE(2) concentration was seen during ischemia (7.4 +/- 2.0 nM versus 3.4 +/- 1.4 nM; P < 0.05) and immediately post-reperfusion (17.9 +/- 5.2 nM versus 4.0 +/- 1.1 nM; P < 0.05). Potassium concentration was significantly increased following occlusion and reperfusion. This indicates the applicability of microdialysis to the measurement of pain-producing substances in muscle during ischemia and reperfusion. Further use will provide novel information on muscle pain both in defined model systems and in clinical situations in humans.

Animals↗
PubMed1999

Free radical activity following contraction-induced injury to the extensor digitorum longus muscles of rats.

The purpose of the study was to investigate the role of free radicals in the injury induced by a protocol of repeated pliometric (lengthening) contractions to the extensor digitorum longus (EDL) muscle in situ in rats. Previous data have indicated that prior treatment with the antioxidant polyethylene glycol-superoxide dismutase reduced the damage that was apparent at 3 days following this type of exercise. Three hours and 3 days following the protocol, the magnitude of the semiquinone-derived free radical signal observed by electron spin resonance spectroscopy (ESR) was not different for exercised and non-exercised skeletal muscles. A reduction in the protein thiol content of muscle was evident at 3 h, and was still apparent at 3 days. Three hours after the protocol, the total muscle glutathione content and the percentage in the oxidized form were unchanged, but by 3 days the percentage of muscle glutathione present in the oxidized form was elevated. The susceptibility of muscle to lipid peroxidation in vitro was reduced 3 days after the pliometric contractions. These data indicate that oxidation of protein thiols and glutathione may be involved in the secondary damage following pliometric contractions, but provide no evidence that the species involved were derived from mitochondrial semiquinone radicals.

Animals↗
PubMed1999

Free radicals in skin and muscle: damaging agents or signals for adaptation?

Much of the current literature regarding the biological effects of antioxidant nutrients has concentrated on their potential role in inhibiting or preventing tissue damage induced by free radical species produced during metabolism. Recent findings indicate that antioxidants may also have more subtle roles, regulating changes in gene expression induced by oxidizing free radical species. There is increasing evidence that free radicals act as signals for cell adaptation in a variety of cell types and the nature of the mechanisms by which free radical species influence gene expression is the subject of much current research. Processes such as these may be particularly important in tissues regularly exposed to varying amounts of oxidative stress as part of their normal physiological functions. Examples of such tissues include skin exposed to u.v. light and skeletal muscle subjected to repeated bouts of exercise.

Adaptation, Physiological↗
PubMed1999

An overview of methods for assessment of free radical activity in biology.

Assays which purport to assess free radical activity in biological systems are multiple. However, despite numerous published descriptions of new methods and modifications of methods to assess free radical activity in biological materials, there is still a lack of reliable techniques for quantification of activity in vivo. Analysis of a number of related indicators and use of a variety of approaches appears the only reliable way to evaluate these processes in vivo. In studies of free radical generation by contracting skeletal muscle we have attempted to use a variety of indicators, including measurement of endogenous antioxidant levels, measurement of indirect indicators of free radical activity (e.g. products of lipid peroxidation, DNA oxidation or protein oxidation) and, where possible, measurement of direct indicators of free radical activity by electron spin resonance techniques. In view of the relative lack of specificity of many available techniques, caution should be exerted in evaluating the numerous examples of isolated single measures of free radical activity which are present in the scientific literature.

Antioxidants↗
PubMed1999

Effect of antioxidant supplementation on the adaptive response of human skin fibroblasts to UV-induced oxidative stress.

The effect of supplementation with substances having antioxidant properties on the adaptive responses of human skin fibroblasts to UV-induced oxidative stress was studied in vitro. UVR was found to induce a substantial oxidative stress in fibroblasts, resulting in an increased release of superoxide anions and an increase in lipid peroxidation (shown by an elevated malonaldehyde content). Sub-lethal doses of UVR were also found to induce adaptive responses in the fibroblast antioxidant defences, with a transient rise in catalase and superoxide dismutase activities followed by a slower, large increase in cellular glutathione content. Supplementation of the fibroblasts with the antioxidants, Trolox (a water soluble analogue of alpha-tocopherol), ascorbic acid or beta-carotene, had differential effects on these responses. Trolox supplementation reduced the UVR-induced cellular oxidative stress and adaptive response in a predictable concentration-dependent manner. This was in contrast to ascorbic acid which increased superoxide release from fibroblasts. At low doses, ascorbate supplements also reduced the magnitude of the adaptive increases in catalase and superoxide dismutase activities and increase in glutathione content. Beta-carotene had a similar effect to ascorbic acid, reducing the extent of the adaptations to UVR at lower doses while simultaneously increasing superoxide release and malonaldehyde content. These in vitro data indicate that only the vitamin E analogue suppressed UVR-induced oxidative stress in a predictable manner and suggest that common dietary antioxidants may not be equally effective in reducing the potential deleterious effects of UVR-induced oxidative stress in skin.

Adaptation, Physiological↗
PubMed1999

Diagnosis and detection of deficiencies of micronutrients: minerals.

Determination of the presence or absence of a deficiency of one or more of the micronutrient minerals (usually described as trace elements) can be a complex problem, frequently requiring the integration of clinical, nutritional and biochemical data. Almost invariably, laboratory investigations are required and this short review describes the more common techniques applied for the various essential trace elements. Using a combination of techniques it is usually possible to determine, with confidence, whether an individual subject or small groups of subjects have a deficiency of a specific trace elements, but simple reliable tests which can be used in population studies are still lacking for several key elements. This problem appears most acute for studies of chromium, copper and zinc, deficiencies of which may have important roles in the pathogenesis of a variety of human disorders.

Deficiency Diseases↗
PubMed1999

Apoptosis in multinucleated skeletal muscle myotubes.

Several recent studies report endonuclease-mediated DNA degradation as evidence of apoptotic degeneration of skeletal muscle in the muscular dystrophies and other muscle disorders. Interpretation of the results of such studies is complicated by the ubiquitous presence of non-muscle cells within muscle in vivo and by a lack of knowledge concerning the nature of the process of apoptosis in postmitotic, multinucleated skeletal muscle and the potential mechanisms involved. Staurosporine treatment of C2C12 skeletal muscle myotubes induced several classic features of apoptosis, including cell and nuclear shrinkage with initial preservation of cellular membranes. Externalization of phosphatidylserine occurred within 2 hours of treatment, and myotubes contained procaspase 3, which seemed to be activated within 4 hours. DNA degradation was identified by transferase uridine triphosphate nick-end labeling within 4 hours, and DNA ladders were identified on agarose electrophoresis of genomic DNA within 8 hours. Thus, the process of apoptosis in postmitotic multinucleated skeletal muscle shares many of the characteristics of apoptosis in mononuclear mitotic cells. However, the pattern of degeneration does not seem to be compatible with that seen in the muscular dystrophies.

Animals↗
PubMed1998

Interleukin-10 gene transfer inhibits murine mammary tumors and elevates nitric oxide.

Transfection of cDNA for IL-10 into line 66.1 murine mammary tumor cells results in marked suppression of tumor growth and metastasis. Others have reported that nitric oxide has potent antitumor activity and IL-10 is known to regulate the inducible isoform of nitric oxide synthase (iNOS) expressed in macrophages. We identified nitric oxide production in mammary tumors as indicated by electron paramagnetic resonance detection of nitric oxide-hemoglobin (NO-Hb). IL-10 expression resulted in elevated levels of NO-Hb in mammary tumors. Immunohistochemical examination of mammary tumors for iNOS protein revealed few positively staining cells in parental or control neo-transfected tumors but strong iNOS staining in all IL-10 transfected tumors, consistent with the NO-Hb data. To determine if mammary epithelial tumor cells themselves, express nitric oxide synthase activity, cultured tumor cells were treated with pro-inflammatory cytokines and nitrite accumulation was assessed in the conditioned medium. All IL-10 producing cell lines accumulated uM concentrations of nitrite in response to short term (24 hr) cytokine stimulation. Cells not expressing IL-10 (parental and neo-transfectants) accumulated no nitrite under similar culture conditions. After longer stimulation (48 hr), parental and 66-neo cells accumulated lower amounts of nitrite. IL-10 gene transfer is associated with increased iNOS protein expression and enzymatic activity detected both in vitro and in vivo. Our findings suggest that the antimetastatic and antitumor activity of IL-10 is related to enhanced production of nitric oxide.

Adenocarcinoma↗
PubMed1998

A novel mitochondrial DNA point mutation in the tRNA(Ile) gene: studies in a patient presenting with chronic progressive external ophthalmoplegia and multiple sclerosis.

We report a new mutation, a G to A transition at nucleotide position 4298 within the mitochondrial tRNA(Ile) gene in a patient with chronic progressive external ophthalmoplegia and multiple sclerosis. The mutation, which alters an evolutionary conserved nucleotide within the anticodon stem, was heteroplasmic in skeletal muscle but was not present in the patient's blood. Single fibre PCR analysis revealed significantly higher levels of the G4298A mutation in cytochrome c oxidase (COX) negative fibres than in COX-positive fibres. This mutation represents the seventh pathogenic nucleotide substitution to be found in this gene and as such confirms the tRNA(Ile) gene as a susceptible "hot spot" for mitochondrial DNA point mutations. Of particular interest is that this patient has the clinical features of both multiple sclerosis and a mitochondrial DNA disorder.

Animals↗
PubMed1998

Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys.

Treatment of Parkinson's disease with L-dopa therapy leads to long-term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine A2A receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor disability in MPTP-treated common marmosets in a dose-dependent manner. However, KW-6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW-6002 induced little or no dyskinesia in MPTP-treated primates previously primed to exhibit dyskinesia by prior exposure to L-dopa. These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

C-myc is expressed in mouse skeletal muscle nuclei during post-natal maturation.

Previous data have indicated the presence of c-myc mRNA and protein in mature skeletal muscle, but whether the protein is present as a Myc/Max heterodimer capable of influencing transcription in that tissue or its potential role in pathological muscle tissue has not been examined. The expression of c-myc in normal and mdx dystrophic mouse skeletal muscle was therefore investigated. C-myc mRNA was detected by Northern hybridisation in normal and dystrophic mouse muscle from mice up to 40 days of age and immunohistochemical staining confirmed that c-myc protein was expressed in muscle fibre nuclei in the muscles of mice up to 40 days of age. The presence of Myc-containing complexes that are able to bind to the concensus Myc/Max binding site was demonstrated in these muscles using the electrophoretic mobility shift assay. These results show that c-myc protein is expressed in functional complexes in both normal and dystrophic mouse skeletal muscle during post-natal maturation. They also show that expression of c-myc in mouse skeletal muscle decreases to undetectable levels by about 40 days of age. Although no differences were detected between the expression of c-myc in mdx and control mouse muscle, these data show that muscle contains Myc protein which has previously been demonstrated to be capable of initiating programmed cell death in other tissues.

Animals↗