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COUNTLESS PATTERNS |
Chapter 4
In the course of any life, somatic cells can be the subject of these changes, and in some cases the cell may exhibit function(al) changes, or even steps which may lead to malignant diseases.
The host has a range of possible responses to pathogens, and these can be altered by nutrient aberrations (deficiencies, excesses or imbalances) as well as by toxic substances entering living systems or at times being produced by pathogens.
There are circumstances where organisms can exist in pathogenic and non-pathogenic forms, and others where more than one pathogen influences the disease entity.
How do we explain different responses to infective organisms.
Interest has often been focussed upon different immune mediated mechanisms to the same pathogen.
Why, for example, do some people exposed to a virus such as hepatitis B or C end up with a grumbling hepatitis gradually giving rise to cirrhosis, or liver cancer, while others do not?
Why is one response to mycobacterium leprae, lepromatous leprosy, and another neuromatous leprosy?
What does it mean when organisms such as cytomegalovirus, chlamydia pneumoniae, or periodontal pathogens can be found in ather omatous plaque (found through studies of samples of the artery wall obtained during coronary surgery?)
Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, tissue diseases like rheumatoid arthritis and so called reactive arthropathy, systemic lupus erythematosus and other collagen diseases, type 1 diabetes mellitus and multiple sclerosis, are all examples of diseases which appear to be examples of these specific host (with its particular genetic makeup), environment and antigen interactions.
There is an increasingly strong case that chronic fatigue syndromes are varieties of such responses.
In fact the Newcastle (New South Wales, Australia) University research group have evidence of 5 and possibly 6 subgroups of CFS.
The reader will have choices to try to explore the complex but stimulating glimpse of modern biology.
I have included enough material for the person with some biological knowledge to learn or update their knowledge of fundamental components and connections with important mechanisms in health and disease.
Cell signalling has been identified as crucial in coordination of living cellular and subcellular systems.
Early in the study of neurology, such signalling was identified and now has been greatly elaborated.
Neuro-transmitters and the receptors which they can occupy were determined, and the downstream cellular changes were mapped.
The molecule which can occupy a receptor site is called a ligand.
In the study of endocrinology there was an early emphasis on the hormones from the glands like the pituitary, thyroid, parathyroid, pancreatic islet cells, adrenals, and gonads (ovaries and testes)
When brain influences were added, neuro-endocrinology became a more encompassing term.
We could perhaps divide hormones/signallers into
(1) Amino acid derivatives,
(2) Small neuropeptides like GnrH and TRH
(3) Protein sized peptides like insulin, luteinizing hormone and parathyroid hormone,
(4) Steroid hormones like cortisol and oestrogens,
(5) Vitamin derivatives like retinoids (vitamin A) and vitamin DThe following material is included to give readers who are intrigued by biological mechanisms, opportunities to grasp the amazing interplay between cells and things which influence them.
It is exceedingly difficult to know how much detail should be provided here, in view of a mammoth amount of details in comprehensive literature.
Every thing that I now describe has a fuller elaborated depth.
These descriptions also can give us an idea of the gap in knowledge base between the majority of practising clinicians and the world leaders in this research.
Ion transport
There exist ligand-gated ion channels.
I will not develop concepts about ion channels here, except to say that all cells are involved with solute transport,These systems are typified by Na+, K+-ATPases and a Cl-, HCO3-exchanger.
Membrane transporters are integral membrane proteins and can be classified as carriers, channels and pumps.
Receptors and their ligands
Transmembrane receptors.
It has been exciting to discover that a huge number of transmembrane receptors consist of specific proteins capable of binding to guanosine linked with phosphate as guanosine triphosphate (GTP)
The heterotrimeric GTP binding proteins (G proteins) are used in a switch" on" and "off" response possible because of "on" being GTP-bound and "off "being GDP-bound states.
G protein coupled receptors (GCRs) have been cloned and identified in terms of structure and function.
Categories of ligands for GCRs are
Biogenic amines: acetylcholine, gamma-amino benzoic acid (GABA), adrenaline and noradrenaline, glutamate, histamine and serotonin.
Lipid derivatives: leucotrienes, platelet activating factors, prostacyclins and prostaglandins, and thromboxanes.
Peptides: Adreno-cortico tropic hormone (ACTH) angiotensin II, bombesin, bradykinin, C5A, calcitonin, cholecystokinin (CCK), chorionic gonadotrophin (CG), cortico-releasing hormone (CRH), endothelins, follicle stimulating hormone (FSH), glucagon, growth hormone releasing factor (GnRh) luteinizing hormone (LH), melanocyte-stimulating hormone (MSH), neuropeptide Y, neurokinin 1(substance P), NK2, NK3, opioids, oxytocin, secretin, somatostatin, thrombin, thyroid stimulating hormone (TSH), thyrotropin releasing hormone(TRH) and vasoactive intestinal peptide)
Sensory stimuli: Light, odorants, taste stimuli.
Other: Adenosine, AMP, ADP, ATP, cyclic AMP, cannabinoids, and Calcium ions.
This list is incomplete and new examples are being added as research unfolds.There are other major receptor types.
Tyrosine kinase linked receptors (RTKs) do not have an "on-off" action, but activated tyrosine kinase receptors assemble signalling complexes.
Examples of ligands acting on receptor tyrosine kinases (RTKs) are epidermal growth factor (EGF), insulin, platelet derived growth factor (PDF), fibroblast growth factor, and nerve growth factor (FGF).
Often RTKs are phosphorylated with specific functional effects.
Activated RTKs can generate binding sites, and recruit proteins for signal transductions.
There are genes that code for Ras proteins and regulation of mitogen signalling is initiated by most RTKs.
Ras proteins are a distinct group of GTP binding proteins distinct from heterotrimeric G proteins. Ras is a central regulator of cell growth and in some cells controls differentiation.
Ras mutations are important in malignant diseases.
Activation of p42 and p44 mitogen-activated protein kinases (MAPKs) leads to trans migration of the MAPK to the cell nucleus, where it can phosphorylate targets such as transcription factors (jun, myc, NF-IL6, and ATF-2
There are other tyrosine-kinase associated receptors which are used by a large number of plasma membrane receptor proteins.
This includes relatively simple single membrane-spanning receptors such as CD4, and receptors for IL2 and interferon alpha.
With more complex receptors there are functions such as T lymphocyte antigen receptors where non-variable domains of the MHC type II molecules from antigen presenting cells are ligands.
Another tyrosine kinase associated receptor type is responsive to interferons. These interferons are not mitogenic, but inhibit the growth of several types of cells by activating intracellular signalling molecules, which then evoke gene activations.
In this I am alluding to the details of how cytokines are ligands for their receptors and we will develop more about this when we come to the section on immunology.
In essence both of the above systems involve a ligand, an integral membrane receptor and components which amplify or specify the signal and response.
Substances found in nature may block a particular GPR.
Nuclear hormone receptors. (NHRs)
The active thyroid hormone tri-iodothyronine (T3) acts by binding to a particular kind of intranuclear receptor with high affinity and specificity.
This gives rise to transcriptional regulation of target genes.With parsimony in biology other functions may exist beyond receptor-mediated events.
(E.g T3 may have nongenomic effects such as activating kinases or calmodulin. It may even have effects on the multidrug resistance P glycoprotein)
There are nearly 100 known members of this family.
In this group of nuclear receptors we find
Androgen receptors (AR)
Glucocorticoid receptors (GR)
Oestrogen receptors (ER)
Progestogen receptors (PR)
Peroxisome proliferator- activated receptors (PPAR)
Retinoic acid receptors (RAR)
Retinoid X receptors (RXR)
Thyroid hormone receptors (TR)
Vitamin D receptors (VDR)If ligands are not known for some NHRs, those members may be called "orphan receptors"(e.g.steroidogenic factor-1 (SF-1), dosage sensitive sex reversal factor (DAX-1), hepatic nuclear factor 4 alpha (HNF4 )
GRs are largely in cytoplasm, whereas TRs are always intranuclear.
After binding, the GRs translocate to the nuclei.
The arrangements of all of these NHRs are similar.
All have * Amino-terminal A/B domains
*Central DNA binding domains with 2 zinc fingers (DBD)
*Hinge regions with nuclear localization signal carboxy terminal ligand binding domain (LBD) which mediate transcription control.Certain NHRs such as GRs and ERs can allow activation of cross-talk by activating or repressing signal transduction pathways.
Genetic poly morphisms have been defined for most of these receptors.
Most NHRs bind to DNA as dimers. Each monomer recognizes aDNA motif referred to as a "half-site"
Steroid receptors (GR,ER,PR,AR) bind to DNA as homodimers.
Consistent with this 2 fold symmetry their DNA sites are "palindromic."TRs, retinoid receptors, PPARs and VDRs bind to their DNA sites as heterodimers in combination with RXRs.
Their DNA half sites are arranged as direct repeats.Receptor specificity is determined by
(1) Sequence of half sites
(2) Orientation of the half sites and
(3) Spacing between half sites.I here elaborate on one of these NHRs
Peroxisome proliferator activated receptors (PPAR)
Nuclear peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation.
This subfamily consists of three isotypes, alpha (NR1C1), gamma (NR1C3), and beta/delta (NRC1C2) with a differential tissue distribution.
PPAR alpha is expressed primarily in tissues with a high level of fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal muscle.
PPAR beta is ubiquitously expressed.
PPAR gamma has a restricted pattern of expression, mainly in white and brown adipose tissues, whereas other tissues such as skeletal muscle and heart contain limited amounts.
Activation of the subtype PPAR-gamma improves insulin sensitivity.
Furthermore, PPAR alpha and gamma isotypes are expressed in vascular cells including endothelial and smooth muscle cells and macrophages/foam cells.
PPARs are activated by ligands, such as naturally occurring fatty acids, which are activators of all three PPAR isotypes.
In addition to fatty acids, humolones from hops (agonists for and ), several synthetic compounds, such as fibrates (alpha), angiotensin receptor blockers ( ), and thiazolidinediones (rosiglitazone and pioglitazone), bind and activate PPAR alpha and PPAR gamma.
Rosiglitazone, which acts on the alpha receptor, has some adverse effects on lipids, but pioglitazone, which acts on the gamma receptors, does not adversely affect lipids.
As well, apigenin, chrysin, and kaempferol significantly stimulated PPAR gamma transcriptional activity in a transient reporter assay. In addition, these three flavonoids strongly enhance the inhibition of inducible cyclooxygenase and inducible nitric oxide synthase promoter activities in lipopolysaccharide-activated macrophages, which contain the PPAR gamma expression plasmids.
There are also PPAR agonist actions with curcumin.
In order to be transcriptionally active, PPARs need to heterodimerize with the retinoid-X-receptor (RXR).
Upon activation, PPAR-RXR heterodimers bind to DNA specific sequences called peroxisome proliferator-response elements (PPRE) and stimulate transcription of target genes. PPARs play a critical role in lipid and glucose homeostasis, but lately they have been implicated as regulators of inflammatory responses.
A role for PPAR gamma in inflammation has also been reported in monocyte/macrophages, where ligands of this receptor inhibited the activation of macrophages and the production of inflammatory cytokines (TNF alpha, interleukin 6 and 1beta), although part of the anti-inflammatory effects of these ligands seems to be mediated by a mechanism not involving PPAR gamma.
All these findings suggest a role of PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases.
Actions of PPAR agonists will probably play important roles in many inflammatory diseases.
Protection from hepatic fibrosis is another recent hope, as Xu, Fu and Chen demonstrated, for the first time, that curcumin dramatically induced the gene expression of PPAR-gamma and activated PPAR-gamma in activated HSC. Blocking its trans-activating activity by a PPAR-gamma antagonist markedly abrogated the effects of curcumin on inhibition of cell proliferation.
Orphan nuclear receptors belong to this gene super-family but their target genes and physiological function are still being studied.
The "orphans" belonging to the PPAR, LXR and FXR family function as lipid and bile acid sensors while PXR and CAR function as xenobiotic sensors.
Small-molecule modulators of LXR and FXR control key genes involved in cholesterol and lipid metabolism. PXR is a highly promiscuous xenosensor that responds to xenobiotic ligands (antibiotics, statins, glucocorticoids) and induces the CYP 3A gene, thereby playing a role in hepatic protection and bile acid metabolism.
A related receptor from the gene subfamily, CAR, displays high ligand selectivity and modulation of its activity in humans may significantly alter metabolism of drugs and other xenobiotics.
The role of the ER relatives, the ERRs will become more apparent as ligands are identified and linked to target genes and physiological function. These targets offer multiple opportunities for therapeutic intervention with small-molecule drugs, in diseases related to neuronal function, inflammation, lipid homeostasis, metabolic function and cancer.
Homocysteine (Hcy) induces nuclear factor-B (NF-B). On the other hand, a negative correlation between high levels of Hcy and peroxisome proliferator-activated receptor (PPAR) expression has been demonstrated
Also, PPAR agonists inhibit the metalloproteinase activation in macrophage.
There is even evidence that intestinal flora influence PPAR expression in intestinal locations.
I will elaborate on cytokines and their receptors in a later chapter.
Do you marvel at these patterns?
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