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Biomedical subjects

Alan Wiseman

Publications and source records attributed to Alan Wiseman.

At least 19 recordsLinked to original sources
PubMed2006

p53 protein or BID protein select the route to either apoptosis (programmed cell death) or to cell cycle arrest opposing carcinogenesis after DNA damage by ROS.

p53 is a tumour-suppressor protein of human cells that prevents their entry into the route to carcinogenesis. Furthermore, p53 protein acts at the p53-response loci in genomic DNA to facilitate the switch-on of genes that can be expressed by the biosynthesis of routing-proteins for apoptosis or stalling of cellular proliferation (via cell cycle progression checkpoint arrests). Moreover, oxidative stress by reactive oxygen species (ROS) such as the hydroxyl radical (*OH) produced by ionizing radiation (carcinogenic) triggers p53 activation in response to the damage of DNA (followed by initiation of DNA-repair mechanisms). Phosphorylation of the BID protein may lead to the recovery from DNA-damage by ROS.

Apoptosis↗
PubMed2006

Crohn's disease leading to bowel cancer may be avoided by consumption of soya isoflavones: adjunct-chemotherapy with oxaliplatin.

Crohn's disease (inflammatory bowel syndrome) is caused by gut exposure to harmful reactive oxygen species (ROS) derived from oxygen, such as the superoxide anion ((.)O(2)'), the hydroxyl radical ((.)OH) or the peroxide anion (O(2)''): the superoxide anion is generated by breakdown of oxygen-peroxidised phospholipids membranes. Crohn's disease predisposes to bowel cancer in susceptible human sub-populations. It may be preventable in these as yet unpredictable sub-populations by dietary-based intervention strategies, such as the daily consumption of appropriate quantities of soya isoflavones. These isoflavonoids are ROS-directed antioxidants, and they include the phytoestrogens, daidzin and genistin present in soya foods (consumed also in dietary supplements). Oxaliplatin is a platinum-containing Pt(II) organometallic therapeutic agent that binds to tumour DNA. Oxaliplatin may provide, therefore, a form of chemotherapy for some bowel cancers especially when administered in adjunct-chemotherapies that employ inhibitors of proliferation of the tumour cell. Such inhibitors include 5-fluorouracil, which prevents the correct replication of tumour cell DNA that is an essential prerequisite for bowel tumour growth. Furthermore, the therapeutic index for adjunct-chemotherapy with toxic inhibitors of DNA replication and expression could potentially be raised significantly by an associated dietary regime. This should include supplementation daily, per or, with antioxidant isoflavones (or other bioflavonoids) in selected cases of unresponsive cancer of the bowel, to possibly seek to trigger the pathway of apoptosis (programmed cell death) in the tumour cells preferentially.

Administration, Oral↗
PubMed2005

Oxygen-induced reperfusion-injury is caused by ROS: Amelioration is possible by recombinant-DNA antioxidant enzymes and mimics in selected tissues.

Billions of years of photolytic cleavage of the water molecule has led to a build-up at sea-level of a "toxic" oxygen concentration in the atmosphere (to 20%). Unfortunately, this dioxygen is likely to be converted in the mitochondria (cell organelles) during cellular respiration to generate reactive oxygen species (ROS); including free-radicals such as superoxide anion (.O2') and hydroxyl radical (.OH) (peroxide O2") a ROS is not a free radical because its electrons are paired). Development of recombinant-DNA improved isoenzyme forms (or mimics) of antioxidant enzymes such as superoxide dismutases is predicted in this hypothesis to be utilised to ameliorate reperfusion-injury (and other oxygen-induced molecular pathology). Introduction into the human genome of the genes for expression of antioxidant enzymes, to order in particular tissues, is imminent. Furthermore, O2 itself will be recognised universally as a harmful gas that can subject the cell to oxidative stress; because it produces ROS, such as the superoxide anion when it acts as the terminal electron acceptor in cellular respiration in the production of water from hydrogen ions in mitochondria. In conclusion, therefore, oxygen-induced injury in humans can no longer be accepted during medical techniques such as reperfusion procedures, because this is associated with reperfusion-injury that can be the cause of several serious medical conditions arising from biomolecular pathology. Some of this is caused by isoforms of cytochromes P450 (CYP; EC 1.14.14.1) such as 3A4, 2D6 and 2C19. These can generate ROS in the liver at low substrate concentrations by futile recycling of oxygen.

Animals↗
PubMed2005

Therapeutic-antagonists of oestrogens can be produced for cancer and other therapies using cytochromes P450 (CYP).

Oestrogens such as 17beta-oestradiol initiates nuclear-gene transcription in gender-specified tissues such as the ovaries and mammaries; and unfortunately too in cancer cells derived from target tissues. Consequently, there has been the development of novel agents for particular cancer therapies that are antagonists of oestrogens for oestrogen-receptor (ER) binding and of drugs with ER-specific interference RNA (RNAi) abilities. Therapeutic-antagonists of oestrogens will be re-designed and biosynthesised and deployed to circumvent the gene DNA-transcription abilities of oestrogens and mimics: and their metabolites in oestrogen-target tissues (see above). Furthermore, opportunities will emerge for adjunct-chemotherapy of particular tissue cancers: and in the prevention of recurrence outcomes. Cytochromes P450 can play an important part in these developments especially for the production of novel metabolites of oestrogens as therapeutic-antagonists of oestrogen-stimulated cancers.

Animals↗
PubMed2005

Elimination of major side effects due to ROS of therapeuticals through biotransformation control of the 57 cytochromes P450 isoenzymes.

Drug biotransformations are controlled in the body by tissue-differentiated choice of a selection of the induced and constitutive 57 isoforms of the human cytochromes P450 (CYP). CYP are the mixed function oxidase enzyme family (EC 1.14.14.1: mono-oxygenases that contain iron-dependent protohaematin IX). Many of the major side effects of clinical therapeutical agents have been attributed to the generation of highly toxic "reactive oxygen species" (ROS). Such ROS generation can be circumvented however by the ability to exert control over which forms of CYP are present: and as to which are bioactive in tissues other than the drug-target ones. Up to 57 isoenzymes of human cytochromes P450 are likely to be present: generation of a variety of species of ROS can be anticipated therefore with outcomes that include cancer, premature ageing, heart (arterial) damage and osteoporosis (in association with oestrogen/testosterone imbalance). Moreover, therapeutic vaccines could be constructed to remove the most harmful forms of cytochromes P450. Designer CYP protein enzymes can now be readily constructed by genetic engineering techniques: these include site-directed mutagenesis to place the modified cyp gene in suitable enzyme expression location in particular tissues only. Furthermore, gene therapy could be arranged to augment (or replace activities lost) for example the production of insulin in the Islets of Langerhans of the pancreas by production of the appropriate form of human insulin in the liver.

Biotransformation↗
PubMed2005

p53 Protein is activated by Pin1: and also by Cu-SOD prion-like enzyme.

Peptidyl-proline isomerase (Pin1) is able to trigger some conformationally important change in the p53 protein: there is notable protection by p53 (tumour suppressor protein) of human cells that prevents their entry into the carcinogenesis-committed routeway. Pin1 controls the ready (low energy change) equilibrium between the cis and trans distinctive folding configurations differentially at a proline residue: this amino acid residue in proteins is unique in bending sharply its peptide chain (to 90 degrees change): in the cis rather than trans orientation with respect to the peptide bond to residue X "upstream" linked as XCONHR. Moreover p53 protein can arrest a cell cycle progression (or trigger apoptosis) by acting as a transcription factor to nuclear DNA acting at p53 nuclear responsive element controlling a larger number of genes that produce proteins that stop cell growth or stimulate apoptosis, in stressed cells. Oxidative stress by reactive oxygen species (ROS) is carcinogenic but also stops cell growth and triggers apoptosis, Cu-SOD removes ROS (see figure). Could superoxide dismutase (Cu-SOD), therefore, provide the DNA-damage direct second route (first route is binding of Pin1) in DNA-damaged cells to p53 activation? The p53 protein that prevents carcinogenesis is activated by Pin1. In addition, this p53 tumour suppressor protein is activated by Cu-SOD.

Amino Acid Motifs↗
PubMed2005

Oestrogen-receptors (ER) are likely to be promiscuous: wider role for oestrogens and mimics.

The anti-breast cancer drug tamoxifen that binds to ER is metabolised in human liver by CYP2D6 isoenzyme, whilst the metabolism of 17beta-oestradiol (by hydroxylation) is by phase I biotransformation in the liver to 2-hydroxyoestradiol and to 4-hydroxyoestradiol respectively by two isoenzymes of this mixed function oxidase CYP cytochromes P450 (EC 1.14.14.1); CYP1A2 and by CYP1B1. Nevertheless, it appears that the receptor (AhR) itself causes the expression of oestrogen-regulated target genes (studied by binding of dioxin). This is the result of an unknown signalling mechanism at the genome that is triggered directly by this receptor by binding promiscuously to ER (alpha or beta) sites. This has been observed even in the absence of oestrogens or mimics therefore in genome-binding investigations of target tissues such as uterus: oestrogen-receptor (ER) is likely to be promiscuous therefore. Furthermore, AhR (polycyclic aromatic hydrocarbon receptor), when activated by the binding of aromatic hydrocarbons (Ah) forms a complex with the aryl hydrocarbon nuclear-translocator chaperone protein (Arnt). It is this binding to xenobiotic response elements in DNA that initiates expression of the appropriate oestrogen-regulated target-genes in the uterus and other target tissues (including mammary, ovaries, and brain). The likely promiscuity of oestrogen receptors is proposed to be the cause of numerous side effects when oestrogen is involved in therapy, these can be manifest in hormone replacement therapy (HRT) and in the incorporation of synthetic oestrogens in the wide varieties of oral contraceptives now available.

Aryl Hydrocarbon Receptor Nuclear Translocator↗
PubMed2004

Gene therapy for the circumvention of inborn errors of metabolism (IEM) caused by single-nucleotide-polymorphisms (SNPs).

Single nucleotide polymorphisms (SNPs) are the result of point mutations in nuclear (and mitochondrial) DNA. Such localised damage to DNA (and its replicative mechanisms) may not be excised fully by the DNA repair mechanism in the genome: and therefore can become inheritable; subsequently to manifest later as an inborn error of metabolism (IEM). Causes of mutagenic damage to the DNA can include background radiation (such as emitted by radon gas), and by reactive oxygen species (ROS): and also by mutagenic chemicals that occur naturally (inter alia in the diet). Other causes of DNA damage are variable environmental hazards such as solar-derived short wave ultraviolet light A. Gene therapy involves the placement of missing genes into particular tissues by the harnessing of suitable vectors (originally these were animal viruses such as SV40). For example, gene therapy in the rat for diabetes has succeeded by liver-production of insulin (using genes obtained from pancreatic Islets of Langerhans cells). Many inborn errors of metabolism could be treated in this way: examples may include 100 haemoglobinopathies (such as sickle cell anaemia), phenylketonuria; and other diseases caused by lack of tissue-production of a particular enzyme (in its catalytically-active conformation).

Diabetes Mellitus↗
PubMed2004

Dietary alkyl thiol free radicals (RSS) can be as toxic as reactive oxygen species (ROS).

Harmful free-radicals, such as superoxide anion (a reactive oxygen species: ROS) are produced during aerobic respiration in all tissues because of only partial reduction of some oxygen molecules in mitochondria: this is due to one-electron reduction of each atom of oxygen, instead of four-electron reduction per molecule of oxygen to form water. Similarly, in liver, and many other tissues such as lung and brain, an electron transfer chain from NADPH to water occurs (with insertion of one oxygen atom into xenobiotic substrates) that uses cytochromes P450 (EC 1.14.14.1) as the electron acceptor. Here, futile recycling of electrons, in the absence of substrate produces the superoxide anion (*O2')--see above. Reactive oxygen species (ROS) and reactive sulfur species (RSS) may act in unison to damage biomolecules. For example, damage to biomolecules can occur by attack on phospholipid membranes, and also the targeting of DNA results in mutagenicity and associated carcinogenicity-related mutagenic damage. Free radical injury to low density lipoprotein (LDL) has been identified in the causation of atherosclerosis implicated in arterial disease, which can lead to heart attack and strokes.

Animals↗
PubMed2003

Limitations of in silico predictability of specificity of co-immobilised cytochromes P450 and mimics in food-bioprocessing.

Cytochromes P450 (EC 1.14.14.1) are mixed function oxidases (oxygenases) that can catalyse redox bioconversions of food components. Also, efficacious removal of undesirable components can be achieved using solid-support immobilised enzyme (IME) of a selection from 2700 isoforms of cytochromes P450 (CYP). Cytochromes P450 co-immobilised with other enzymes, or protein receptors, may be used to confer a secondary order of regio- or stereo-specificity of chiral bioconversion: these can be predictable in silico by utilisation of QSARs (quantitative structure/activity relationships).

Biotechnology↗