Looks like collagen is all wrong in varicose veins:
1: Angiology. 2003 Jul-Aug;54 Suppl 1:S13-8. Links
Chronic venous insufficiency: dysregulation of collagen synthesis.Sansilvestri-Morel P, Rupin A, Badier-Commander C, Fabiani JN, Verbeuren TJ.
Division of Angiology, Servier Research Institute, Suresnes, France.
Varicose vein disease is a common condition. Its pathology is not well characterized. A disorganization of smooth muscle cells and extracellular matrix components in the venous wall have been described. The objective of this paper is to offer an explanation for the abnormal distensibility of varicose veins. The content of hydroxyproline was quantified in control and varicose human saphenous veins. The synthesis of collagen types I, III, and V was quantified in cultured venous smooth muscle cells and dermal fibroblasts of control subjects and patients with varicose veins. The proportion of collagen type III in the heterofibrils composed by collagen types I, III, and V was calculated. The level of hydroxyproline was increased in varicose veins, suggesting an increased content of collagen. This augmentation of collagen in diseased tissues appears to be correlated with an increase of collagen type I since the collagen I mRNA was overexpressed in varicose veins, whereas collagen type III mRNA was not altered. The quantification of collagen synthesis in cultured cells shows that proportion of collagen type III was significantly decreased in cultured smooth muscle cells and dermal fibroblasts derived from patients with varicose veins. The results indicate a deficiency in collagen type III in patients with varicose veins. Since collagen type III is involved in tissue elasticity, these results offer an explanation for the abnormal distensibility of varicose veins. Moreover, this defect seems to be generalized in different tissues and argues in favor of a genetic alteration of remodeling in these patients.
PMID: 12934753 [PubMed - indexed for MEDLINE]
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perhaps dysregulation of cytochrome p450 family is responsible:
1: Ann Pharm Fr. 2003 Jul;61(4):234-42. Links
[Cytochromes P450, vascular tone varicosis][Article in French]
Bertrand C, Batt AM.
Centre du Médicament, INSERM U525, 30 rue Lionnois, F54000 Nancy.
Chronic venous insufficiency is a complex pathology that is characterised by various symptoms such as venous hypertension, endothelium dysfunction, vascular wall remodelling due to smooth muscle cell hypertrophy and inflammation resulting from the release of pro-inflammatory cytokines from invading leucocytes. Age, hormonal excess, multiparity, sedentariness and prolonged heat exposure represent the main risk factors among many others including hypoxia and shear stress which also influence varicose pathology. Some members of the large cytochrome P450 (CYP) family that are involved in the biotransformation of steroids and arachidonic acid have been shown to be expressed in various cell types (endothelial cells, smooth muscle cells, macrophages) of cardiovascular tissues. The vascular metabolites produced by CYPs are important factors in the regulation of the vascular tone. Most CYPs are markedly expressed in all the cell types of varicose veins in relation to the overall vascular remodelling associated with smooth muscle hypertrophy and periendothelial leucocyte infiltration. Because CYPs produce various vasoactive arachidonic acid metabolites, their increased expression could play a role in the impairement of the vascular tone which is characteristic of varicose veins. Furthermore, polymorphisms, particularly the CYP3A5 polymorphism, may promote changes in the level of expression of CYPs and thus may influence varicose vein formation or functions. This suggests that CYP modulators could be potentially active drugs to treat chronic venous insufficiency symptoms and control its evolution.
PMID: 12843956 [PubMed - indexed for MEDLINE]
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1: Curr Drug Metab. 2004 Jun;5(3):225-34. Links
Cytochrome P450 in neurological disease.Liu M, Hurn PD, Alkayed NJ.
Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Advances in a multitude of disciplines support an emerging role for cytochrome P450 enzymes and their metabolic substrates and end-products in the pathogenesis and treatment of central nervous system disorders, including acute cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such as Alzheimer's and Parkinson's disease, as well as epilepsy, multiple sclerosis and psychiatric disorders, including anxiety and depression. The neural tissue contains its own unique set of P450 genes that are regulated in a manner that is distinct from their molecular regulation in peripheral tissue. Furthermore, brain P450s catalyze the formation of important brain signaling molecules, such as neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics and environmental neurotoxins. These unique characteristics allow this family of proteins and their metabolites to perform such vital functions in brain as neurotrophic support, neuroprotection, control of cerebral blood flow, temperature control, neuropeptide release, maintenance of brain cholesterol homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter levels and other functions important in brain physiology, development and disease.
PMID: 15180492 [PubMed - indexed for MEDLINE]
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1: Clin Exp Pharmacol Physiol. 2004 May-Jun;31(5-6):295-301. Links
Cytochromes P450 are differently expressed in normal and varicose human saphenous veins: linkage with varicosis.Bertrand-Thiebault C, Ferrari L, Boutherin-Falson O, Kockx M, Desquand-Billiald S, Fichelle JM, Nottin R, Renaud JF, Batt AM, Visvikis S.
INSERM U525, 30 rue Lionnois, F-54000 Nancy, France.
The expression of cytochrome P450 (CYP) enzymes and cyclo-oxygenases (COX) was investigated in human saphenous veins by reverse transcription-polymerase chain reaction analysis. Non-varicose veins were obtained from patients undergoing aortocoronary bypass grafting, whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins. In non-varicose veins, CYP1B1, CYP2C, CYP2E1 and CYP4A11 were detected, whereas CYP2J2, CYP3A5, COX-1 and COX-2 were detected almost exclusively in varicose veins. CYP4F2 was not detectable. Except for CYP4A11, the levels of individual CYP mRNA were higher in varicose veins than in control veins. Smooth muscle cell volume, determined by a colour image-analysis system, was increased approximately 1.5-fold in varicose veins. Because CYPs and COXs produce various vasoactive compounds, increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology. Then, CYP or COX modulators may be potentially active in the treatment of chronic venous insufficiency.
PMID: 15191401 [PubMed - indexed for MEDLINE]
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Maybe these cyps and coxes aren't so bad after all:
1: Circ Res. 2002 May 17;90(9):1020-7. Links
Comment in:
Circ Res. 2002 May 17;90(9):936-8.
Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids.Sun J, Sui X, Bradbury JA, Zeldin DC, Conte MS, Liao JK.
Vascular Medicine Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02139, USA.
Vascular smooth muscle cell (SMC) migration and proliferation contribute to neointimal hyperplasia and restenosis after vascular injury. The epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess vasodilatory, antiinflammatory, and fibrinolytic properties. To determine whether these compounds also possess antimigratory and antiproliferative properties, we stimulated rat aortic SMCs with either 20% serum or platelet-derived growth factor (PDGF-BB, 20 ng/mL). In a concentration-dependent manner, treatment with EETs, particularly 11,12-EET, inhibited SMC migration through a modified transwell filter by 53% to 60%. EETs, however, have no inhibitory effects on PDGF-stimulated SMC proliferation. Adenoviral-mediated overexpression of the CYP isoform, CYP2J2, in SMCs also inhibited serum- and PDGF-induced SMC migration by 32% and 26%, respectively; both effects of which were reversed by the CYP inhibitors SKF525A or clotrimazole, but not by the K(Ca) channel blocker, charybdotoxin, or the cyclooxygenase inhibitor, diclofenac. The effect of EETs correlated with increases in intracellular cAMP levels. Indeed, forskolin and 8-bromo-cAMP exert similar inhibitory effects on SMC migration as 11,12-EET and the effects of 11,12-EET were blocked by cAMP and protein kinase A (PKA) inhibitors. These findings indicate that EETs possess antimigratory effects on SMCs through the cAMP-PKA pathway and suggest that CYP epoxygenase-derived eicosanoids may play important roles in vascular disease and remodeling.
PMID: 12016269 [PubMed - indexed for MEDLINE]
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from wikipedia:
Forskolin is a labdane diterpene that is produced by the Indian Coleus plant (Coleus forskohlii). Forskolin is commonly used to raise levels of cyclic AMP (cAMP) in the study and research of cell physiology. Forskolin resensitizes cell receptors by activating the enzyme adenylyl cyclase and increasing the intracellular levels of cyclic Adenosine Monophosphate (cyclic AMP or cAMP). Cyclic AMP is an important signal carrier that is necessary for the proper biological response of cells to hormones and other extracellular signals. It is required for cell communication in the hypothalamus/pituitary gland axis and for the feedback control of hormones. It acts by activating protein kinase A.
Potential medical use
Applied with rolipram, forskolin provides a route to inhibition of colon cancer cell growth and survival. [1]
Forskolin is a vasodilator.
To date, there have been more than two clinical studies examining the effectiveness of forskolin as a weight loss aid. Only one has been subject to peer-review and published in a medical journal. This clinical study also observed forskolin's role in significantly increasing lean mass, bone mass, and testosterone in the subjects involved.[2] This research has led to companies marketing forskolin as a Bodybuilding supplement.
Forskolin may be helpful to control the underlying cause of glaucoma. The sometimes successful use of forskolin to reduce intraocular pressure may be due to its unique ability to stimulate adenylate cyclase activity and increase cyclic adenosine monophosphate (cAMP) which regulates and activates critical enzymes required for the cellular energy required to move fluid out of the eye.
Increase skin's natural resistance to burning under UV light (see links below)
Stimulate a tanning response when applied topically.
Reduce urinary tract infections and enhance the ability of antibiotics to kill bacteria that normally survive.
Forskolin can also be used to promote nerve repair by increasing cAMP concentrations. Forskolin can activate or upregulate the proliferation of Schwann cells in culture, together with Fibroblast growth factor or Transforming Growth Factor-Beta.
Various experimental studies are underway in using Forskolin as an adjuvant in treatment for diseases such as Parkinsons and/or nerve damage caused by trauma/accident.
1: Arch Biochem Biophys. 2005 Jan 15;433(2):413-20. Links
Vascular protective effects of cytochrome p450 epoxygenase-derived eicosanoids.Spiecker M, Liao JK.
Department of Medicine II, St. Josef-Hospital, Bochum Gudrunstrasse 56 44791 Bochum, Germany.
martin.spiecker@ruhr-uni-bochum.de <
martin.spiecker@ruhr-uni-bochum.de>
Cytochrome P450 epoxygenases metabolize arachidonic acid to biologically active eicosanoids. Primary epoxidation products are four regioisomers of cis-epoxyeicosatrienoic acid (EET), 5,6-, 8,9-, 11,12-, and 14,15-EET. One of the predominant epoxygenase isoforms involved in EET formation belongs to the CYP2 gene family. In humans, the P450 epoxygenase, CYP2J2, is expressed in the cardiovascular system, namely the endothelium, vascular smooth muscle, and cardiomyocyte. CYP2J2 possesses vascular protective effects, which include but are not limited to, protection against ischemia-reperfusion injury, suppression of reactive oxygen species following hypoxia-reoxygenation, inhibition of the pro-inflammatory transcription factor, nuclear factor-kappaB (NF-kappaB), attenuation of vascular smooth muscle migration, and enhancement of a fibrinolytic pathway. Although regioisomers of EET elicit these effects to varying degrees, 11,12-EET appears to be the most potent with respect to anti-inflammatory, anti-migratory, and pro-fibrinolytic effects. Thus, CYP2J2 and its derived arachidonic acid metabolites may play important roles in regulating vascular function under normal and pathophysiological conditions.
PMID: 15581597 [PubMed - indexed for MEDLINE]
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3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,